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CONTRIBUTORS  TO  VOLUME  I 

ADAMI,  J.  GEORGE,  M.D.,  F.R.S. 

ANDERS,  JAMES   M.,  M.D. 

BRUCE,  DAVID,  C.B.,  F.R.S.,  D.Sc,  M.B.,  CM.  (Edin.) 

CALKINS,  GARY  N.,  Ph.D. 

CHITTENDEN,  RUSSELL   H.,  Ph.D.,  LL.D. 

CRAIG,  CHARLES   P.,  M.D. 

EDSALL,  DAVID   L.,  M.D. 

FUTCHER,  THOMAS  B.,  M.B. 

GORDON,  ALFRED,  M.D. 

HOV/ARD,  L.  O.,  Ph.D. 

HUTCHISON,  ROBERT,  M.D.,  F.R.C.P.  (Lond.) 

LAMBERT,  ALEXANDER,  M.D. 

MENDEL,  LAFAYETTE  B.,  Ph.D. 

NOGUCHI.   HIDEYO,  Sc.M.,   M.D. 

NOVY,  FREDERICK  G.,  M.D. 

OSLER,  V/ILLIAM,  M.D. 

STEPHENS,  J.  V/.V/..  M.D.  (Cantab.) 

STILES,  CHARLES  V/ARDELL,  Ph.D.,  D.Sc. 

STILL,  GEORGE  P.,  M.A.,  M.D.  (Cantab.)'.  F.R.C.P.  (Lond.) 

STRONG,  RICHARD   P.,  M.D. 

TAYLOR,  ALONZO   ENGLEBERT,  M.D. 

WRIGHT.  JAMES  HOMER.  M.D.,  Hon.   S.D.  (Harv.) 


MODERN  MEDICINE 


ITS  THEOEY  AND  P11A(]TICE 

IN  OEIGINAL  CONTRIBUTIONS  BY  AMEIUCAN  AND 
FOREIGN  AUTHORS 


EDITED  J5Y 


WILLIAM  OSLER.  M.D. 


7 

REGIUS  PROFESSOR  OF  MEDICINE    IN    OXFOKD    UMVERSITY,   ENGLAND;    HONORARY   PROFESSOR    OF    MEDICINE    IN 

THE    JOHNS    HOPKINS    UNIVEIISITV,   BALTIMORE;    FORMERLY    PROFJOSSOlt    OF    CLINICAL    MEDICINE    IN 

THE  UNIVERSITY    OF    PENNSYLVANIA,   PHILADELPHIA,   AND    OF    THE   INSTITUTES   OF  MJCDICINE 

IN  MCGILL  UNIVERSITY,  MONTREAL,   CANADA 


ASSISTED  BY 


THOMAS  MCCEAE,  M.D. 


ASSOCIATE   PROFESSOR  OF  MEDICINE  AND   CLINICAL  THERAPEUTICS  IN  THE  JOHNS  HOPKINS  UNIVERSITY, 
BALTIMORE;   FELLOW   OF  THE   ROYAL  COLLEGE   OF   PHYSICIANS,   LONDON 


VOLUME    I 

EVOLUTION     OF     INTERNAL     MEDICINE— PREDISPOSITION    AND 
IMMUNITY-DISEASES  CAUSED  BY  PHYSICAL,  CHEMICAL  AND 
ORGANIC   AGENTS-BY   VEGETABLE   PARASITES-BY 
PROTOZOA-BY  ANIMAL  PARASITES-NUTRITION- 
CONSTITUTIONAL  DISEASES 

ILLUSTRATE  D 


PHILADELPHIA  AND    NEW  YORK 
LEA   BROTHERS   &   CO. 


/^c 


,9s^ 

llol 


Entered  according  to  the  Act  of  C!ongress,  in  the  year  1907,  by 

LEA    &    FEBIGER 
in  the  Office  of  the  Librarian  of  Congress.     All  rights  reserved. 


I 


PUBLISHERS'   NOTE. 


A  NEW  era  has  come  in  medicine,  the  age  of  cosmopohtanism. 
As  in  finance  and  trade,  the  world  has  become  a  single  country. 
The  cause  of  this  solidarity  is  to  be  found  in  modern  improvements 
in  communication  which  obliterate  time,  distance  and  the  artificial 
boundaries  of  geography,  making  mankind  a  single  family,  and 
immediately  distributing  for  the  benefit  of  its  members  the  knowledge 
of  every  advance,  wherever  attained.  Only  one  obstacle  remains, 
namely,  difference  of  language,  and  this,  though  it  will  always  exist, 
is  practically  overcome  by  the  familiarity  which  the  leaders  in  the 
profession  must  now  possess  with  the  writings  of  their  compeers  in 
other  tongues. 

It  is  more  necessary  in  medicine  than  in  any  other  sphere  of  human 
effort  that  the  world-knowledge  should  be  placed  at  the  command  of 
all.  Physicians  of  the  dominant  language,  English,  have  just  cause 
for  satisfaction  in  realizing  that  this  is  now  to  be  accomplished  in  their 
own  tongue,  and  under  the  leadership  of  one  best  fitted,  by  common 
consent,  to  develop  this  idea  in  its  most  complete  and  fruitful  manner. 
Physician,  philosopher,  litterateur,  he  unites  in  the  highest  degree  all 
the  necessary  qualifications  for  marshalling  the  leaders  in  the  most 
beneficent  of  professions  in  a  great  effort  for  the  common  good. 
Nothing  has  been  spared  for  the  full  accomplishment  of  this  purpose, 
and  now,  from  the  record  of  twenty-three  centuries,  every  sincere 
follower  of  the  masters  of  medicine  has  at  command  a  fund  of 
accumulated  knowledge  greater  than  any  of  them  could  have 
possessed.  The  full  resources  of  the  modern  world  have  been 
brought  to  bear  upon  this  work,  and  it  is  now  submitted  to  the 
profession  for  judgment  as  to  its  conception  and  execution. 

(V) 


CONTRIBUTORS  TO  VOLUME  I. 


J.  GEORGE  ADAMI,  M.D.,  F.R.S., 

Professor  of  Pathology  in  the  McGill  University,  Montreal,  Canada. 

JAMES  M.  ANDERS,  M.D., 

Professor  of  the  Theory  and  Practice  of  Medicine  and  Clinical  Medicine  in  the 
Medico-Chirurgical  College;  Consulting  Physician  to  the  Jewish  Hospital 
Association  of  Philadelphia;  Consulting  Physician  to  the  Widener  Home  for 
Crippled  Children,  Philadelphia. 

DAVID  BRUCE,  C.B.,  F.R.S.,  D.Sc,  M.B.,  CM.  (Edin.), 
Colonel,  British  Army, 

GARY  N.  CALKINS,  Ph.D., 

Professor  of  Protozoology  in  the  Columbia  University,  New  York  City. 

RUSSELL  H.  CHITTENDEN,  Ph.D.,  LL.D., 

Professor  of  Physiological  Chemistry  in  the  Sheffield  Scientific  School  of  Yale 
University,  New  Haven,  Conn. 

CHARLES  F.  CRAIG,  M.D., 

First  Lieutenant  and  Assistant  Surgeon  in  the  U.  S.  Army. 

DAVID  L.  EDSALL,  M.D., 

Assistant  Professor  of  Medicine  in  the  University  of  Pennsylvania,  Medical 
Department,  Philadelphia. 

THOMAS  B.  FUTCHER,  M.B., 

Associate  Professor  of  Medicine  in  the  Johns  Hopkins  University;  Associate 
in  Medicine  in  the  Johns  Hopkins  Hospital,  Baltimore,  Md. 

ALFRED  GORDON,  M.D., 

Associate  in  Mental  and  Nervous  Diseases  in  the  Jefferson  Medical  College, 
Philadelphia;  Examiner  of  the  Insane  at  the  Philadelphia  General  Hospital; 
Neurologist  to  the  Mt.  Sinai  and  Douglas  Memorial  Hospitals,  Philadelphia. 

L.  O.  HOWARD,  Ph.D., 

Chief  of  the  Bureau  of  Entomology  of  the  U.  S.  Department  of  Agriculture, 
Washington,  D.  C. 

ROBERT  HUTCHISON,  M.D.,  F.R.C.P.  (Lond.), 

Assistant  Physician  to  the  London  Hospital  and  to  the  Hospital  for  Sick  Chil- 
dren, Great  Ormond  Street,  London,  England. 

ALEXANDER  LAMBERT,  M.D., 

Professor  of  Clinical  Medicine  in  the  Cornell  University  Medical  College; 
Attending  Physician  in  the  Bellevue  Hospital,  New  York  City. 

LAFAYETTE  B.  MENDEL,  Ph.D., 

Professor  of  Physiological  Chemistry  in  the  Sheffield  Scientific  School,  Yale 
University,  New  Haven,  Conn. 

(vii) 


vIH  CONTRIBUTORS  TO   VOLUME  I 

HIDEYO  NOGUCHI,  Sc.M.,  M.D., 

Assistant  of  the  Rockeleller  Institute  for  Medical  Research,  New  York  City. 

FREDERICK  G.  NOVY,  M.D., 

Professor  of  Bacteriology  in  the  University  of  Michigan,  Ann  Arbor,  Mich. 

WILLIAM  08LER,  M.D., 

Rogius  Professor  of  Medicine  in  Oxford  University,  England. 

J.  W.  W.  STEPHENS,  M.D.  (Cantab.), 

Walter  Myers  Lecturer  on  Tropical  Medicine  in  the  University  of  Liverpool, 
Liverpool,  England. 

CHARJ<ES  WARDELL  STILES,  Ph.D.,  D.Sc, 

Chief  of  the  Division  of  Zoology  in  the  Hygienic  Laboratorj^  U.  S.  Public  Health 
and  Marine  Hospital  Service,  Washington,  D.  C. 

GEORGE  FREDERIC  STILL,  M.A.,  M.D.  (Cantab),  F.R.C.P.  (Lond.), 

Profe._;sor  of  Diseases  of  Children  in  King's  College,  London;  Physician  for 
Diseases  of  Children  in  King's  College  Hospital;  Assistant  Physician  to 
the  Hospital  for  Sick  Children,  Great  Ormond  Street,  London,  England. 

RICHARD  P.  STRONG,  M.D., 

Director  of  the  Biological  Laboratory;  Professor  of  Tropical  Medicine  in  the 
Manila  Government  Medical  School,  Manila,  P.  I. 

ALONZO  ENGLEBERT  TAYLOR,  M.D., 

Professor  of  Pathology  in  the  University  of  California,  Medical  Department, 
San  Francisco,  Cal. 

JAMES  HOMER  WRIGHT,  M.D.,  Hon.  S.D.  (Harv.), 

Assistant  Professor  of  Pathology  in  the  Medical  School  of  Harvard  University; 
Director  of  the  Pathological  Laboratory  of  the  Massachusetts  General 
Hospital,  Boston,  Mass. 


CONTENTS  OF  VOLUME  I. 


INTKODUCTION. 

PAGE 

THE  EVOLUTION  OF  INTERNAL  MEDICINE ^^ 

By  William  Osler,  M.D. 


PART  I. 

HEREDITY  AND  PREDISPOSITION. 

CHAPTER  I. 

INHERITANCE  AND  DISEASE ^^ 

By  J.  George  Adami,  M.A.,  M.D.,  F.R.S. 


PAET  II. 
DISEASES  CAUSED  BY  PHYSICAL  AGENTS. 

CHAPTER  II. 

LIGHT,  X-RAYS,  ELECTRICITY 51 

By  Alfred  Gordon,  M.D. 

CHAPTER  III. 

AIR "^ 

By  Alfred  Gordon,  M.D. 

CHAPTER  IV. 

HEAT  AND  COLD 76 

By  Alfred  Gordon,  M.D. 

(ix) 


X  CONTENTS  OF  VOLUME  1 

PART  III. 

DISEASES  CAUSED  BY  CHEMICAL  AGENTS. 
CHAPTER  V. 

PAGB 

CHRONIC  LEAD  POISONING 84 

By  David  L.  Edsall,  M.D. 

CHAPTER  ^'I. 

CHRONIC  ARSENIC  POISONING 114 

By  David  L.  Edsall,  M.D. 

CHAPTER  VII. 

OTHER  METALLIC  POISONS,  MERCURY,  PHOSPHORUS,  Etc.       .112 
By  David  L.  Edsall,  M.D. 

CHAPTER  VIII. 

CARBON  MONOXIDE  POISONING,    ILLUMINATING  GAS  POISON- 
ING, COMBUSTION  PRODUCT  POISONING,  CHRONIC  CARBON 

BISULPHIDE  POISONING 141 

By  David  L.  Edsall,  M.D. 


PART  lY. 

DISEASES  CAUSED  BY  ORGANIC  AGENTS. 

CHAPTER  IX. 

ALCOHOL 157 

By  Alexander  Lambert,  M.D. 

CHAPTER  X. 

OPIUM,  MORPHINISM,  COCAINE 203 

By  Alexander  Lajibert,  M.D. 

CHAPTER  XL 

FOOD  POISONS 223 

By  Frederick  G.  Novy,  M.D. 

CHAPTER  XII. 
SNAKE  VENOMS 247 

By  Hideyo  Noguchi,  Sc.M.,  M.D. 


CONTENTS  OF  VOLUME  I  Xl 

CHAPTER  XIII. 

PAGE 

AUTO-INTOXICATIONS 266 

ByAlonzo  Englebert  Taylor,  M.D. 

CHAPTER  XIV. 

AUTO-INTOXICATIONS    ASSOCIATED    WITH    PROTEIN,    PURIN, 

CARBOHYDRATE  AND  FAT  METABOLISM 297 

By  Alonzo  Englebert  Taylor,  M.D. 


PART  V. 

DISEASES  DUE  TO  VEGETABLE  PARASITES  OTHER  THAN 

BACTERIA. 

CHAPTER  XV. 

ACTINOMYCOSIS 327 

By  James  Homer  Wright,  A.M.,  M.D.,  Hon.  S.D.  (Harv.) 

CHAPTER  XVI. 

NOCARDIOSIS,     MYCETOMA,     OIDIOMYCOSIS,     BLASTOMYCOSIS, 

PULMONARY  ASPERGILLOSIS,  MYCOSIS  MUCORNIA     .      .      .340 
By  James  Homer  Wright,  A.M.,  M.D.,  Hon.  S.D.  (Harv.) 


PART  VI. 

DISEASES  CAUSED  BY  PROTOZOA. 

CHAPTER  XVII. 
THE  PROTOZOA 353 

By  Gary  N.  Calkins,  Ph.D. 

CHAPTER  XVIII. 

MOSQUITOES 370 

By  L.  O.  Howard,  Ph.D. 

CHAPTER  XIX. 

THE  MALARIAL  FEVERS 392 

By  Charles  F.  Craig,  M.D. 


xli  CONTENTS  OF   VOLUME  I 

CHAPTER  XX. 

PAOB 

BLACK-WATER  FEVER 449 

By  J.  AV.  W.  Stki'hens,  M.D.  (Cantab.) 

CHAPTER  XXI. 

TR^TANOSOMIASIS 460 

By  Col.  IUvid  Bhuce,  C.B.,  F.l^S.,  D.Sc,  M.B.,  CM.  (Rdin.). 

CHAPTER  XXII. 

AMCEBIC  DYSENTERY 488 

]^Y  BicH.vHi)  P.  Sthono,  M.D. 


PAP.T  VII. 
DISEASES  CAUSED  BY  ANIMAL  PARASITES. 

CHAPTER  XXIII. 

GENERAB  DISCUSSION 525 

By  Charles  Wakdell  Stiles,  Ph.D.,  D.Sc. 

CHAPTER  XXIV. 

DISTOMATOSIS— TREMATODE  OR  FLUKE  INFECTIONS       .      .      .535 
By  Charles  Wardell  Stiles,  Ph.D.,  D.Sc. 

CHAPTER  XXV. 

T.FXIASIS— CESTODE  INFECTION 557 

By  Charles  Wardell  Stiles,  Ph.D.,  D.Sc. 

CHAPTER  XXVI. 

ROUND-WORM  INFECTION— NEMATHELMINTHES     .....  582 
By  Charles  Wardell  Stiles,  Ph.D.,  D.Sc. 

CHAPTER  XXVII. 

LEECHES,    ACARIASIS,    TONGUE-WORM    INFECTIONS,     MYRIA- 

PODA,  PARASITIC  INSECTS 626 

By  Charles  Wardell  Stiles,  Ph.D.,  D.Sc. 


CONTENTS  OF   VOLUME  I  xlii 

PART  VIII. 
NUTRITION. 

CHAPTER  XXVIII. 

PAGE 

GENERAL    CONSIDERATION    OF    METABOLISM,    NORMAL    AND 

IN  DISEASE 639 

By  Russell  H.  Chittenden,  Ph.D.,  LL.D., 

AND 

Lafayette  B.  Mendel,  Ph.D. 


PART  IX. 

CONSTITUTIONAL  DISEASES. 

CHAPTER  XXIX. 

DIABETES  MELLITUS 747 

By  Thomas  B.  Futcher,  M.B. 

CHAPTER  XXX. 

DIABETES  INSIPIDUS 799 

By  Thomas  B.  Futcher,  M.B. 

CHAPTER  XXXI. 

GOUT 808 

By  Thomas  B.  Futcher,  M.B. 

CHAPTER  XXXII. 

OBESITY 845 

By  James  M.  Anders,  M.D. 

CHAPTER  XXXIII. 

RICKETS 864 

By  George  Frederic  Still,  M  A.,  M.D.  (Cantab),  F.R.C.P.  (Lond.). 

CHAPTER  XXXIV. 

SCURVY  (SCORBUTUS) 893 

By  Robert  Hutchison,  M.D.,  F.R.C.P.  (Lond.) 


INTRODUCTION. 

THE   EVOLUTION   OF   INTERNAL  MEDICINE. 
By  WILLIAM  OSLER,  M.D. 


Scarcely  twenty  years  have  passed  since  the  completion  of  Pepper's 
System  of  Medicine.  The  distinguished  abiUty  of  its  Editor  and  the 
important  group  of  contributors  with  whom  he  was  associated  combined 
to  produce  a  treatise  which  profoundly  influenced  medicine  in  America. 
Twenty  years  are  a  very  brief  space  of  time,  but  science  has  been  progress- 
ing with  extraordinary  rapidity,  sufficient  to  make  even  that  important 
work  out-of-date,  though  not  in  all  particulars.  As  in  Reynolds' 
System,  in  Virchow's  liandhuch,  and  in  von  Ziemssen's  Encyclopedia, 
so  in  that  System  there  are  articles  Avhich  still  retain  their  freshness, 
and  must  for  many  years  be  valuable  for  reference.  Meanwhile  in 
England  AUbutt's  System,  now  in  a  second  edition,  has  proved  a  worthy 
successor  to  Reynolds.  In  Germany,  where  such  publications  are 
planned  on  a  vast  scale  in  comparison  with  the  American  and  English 
works,  the  great  Handbuch  of  Nothnagel,  in  twenty-four  volumes,  has 
just  been  completed;  and  a  selection  from  the  volumes  is  appearing  in 
English  dress.  The  days  of  the  Encyclopedias  in  France  appear  to  have 
passed,  at  any  rate  years  have  gone  since  the  issue  of  the  last  volume  of 
Dechambre ;  but  the  Traite  of  Charcot  and  Bouchard  has  passed  through 
two  editions,  and  there  have  been  issued  several  works  of  a  similar 
character,  though  on  a  less  extensive  scale.  American  publishers  have 
shown  no  little  enterprise  in  the  same  direction.  The  System  of  Medicine, 
by  Loomis  and  Thompson  (1897-1898) ;  The  Twentieth  Century  Practice 
of  Medicine  (1895-1900);  Buck's  Reference  Handbook,  second  edition 
(1900-1904),  and  the  American  edition  of  selected  volumes  from  Noth- 
nagel's  System,  already  referred  to,  have  been  of  the  greatest  service  to 
the  profession. 

The  need  for  new  works  of  this  type  is  strongly  emphasized  by  a  com- 
parison of  the  present  volume  with  the  first  volume  of  Pepper's  System. 
It  seems  scarcely  credible  that  in  so  many  directions  in  so  short  a  time  the 
entire  outlook  on  the  science  of  medicine  can  have  been  so  revolutionized. 
To  give  three  instances  in  illustration :  our  views  on  heredity  have  been 
profoundly  modified  by  the  studies  of  Weismann,  Mendel,  and  others, 
and  we  are  fortunate  in  Modern  Medicine  to  have  the  subject  presented 
by  Professor  Adami  in  so  clear  and  attractive  a  manner  that  it  will  be 
most  helpful  to  all  students.  In  no  direction  has  there  been  such  progress 
as  in  our  knowledge  of  the  chemical  processes  of  the  body.     At  the  same 

(  XV  ) 


xvl  INTRODUCTION 

time  the  ncfossarily  iiiipcrtVct  state  of  organic  clioniistrv  has  given  an 
undue  prominence  to  certain  lialf-truths,  and  no  dej)artnient  of  medicine 
has  lent  itself  more  easily  to  pseudo-sciiMice.  The  elaborate  sections  by 
Professor  Taylor  and  by  Professor  Chittenden  illustrate  how  surely  we 
are  reaching  a  position  of  accurate  and  sound  knowledge.  INIore  j)articu- 
larly  is  this  the  case  with  the  complicated  processes  of  normal  metaljolism, 
and  we  are  in  consequence  better  able  to  understand  antl  study  intelli- 
gently the  perversions  met  with  in  disease.  No  articles  in  this  volume 
are  deserving  of  more  careful  study  by  all  who  wish  to  appreciate  the 
new  standpoint  in  physiological  and  ])athological  chemistry.  In  1885 
we  had  not  realized  clearly  our  position  with  regard  to  the  infectious 
diseases.  The  extension  of  our  knowledge  of  the  causative  agents  of 
the  acute  infections  has  been  followed  by  a  study  of  the  laws  of  immunity, 
which  has  not  only  revolutionized  general  })athol()gy,  but  has  also 
opened  out  new  lines  of  treatment.  Vaccines,  antitoxins,  curative  sera 
of  various  kinds  have  been  discovered,  and  with  this  rajjid  progress  it 
is  not  astonishing  that  at  times  we  have  gone  too  fast  and  too  far,  and 
that  there  have  been  the  disappointments  and  failures  invariably  associated 
with  human  endeavor,  but  these  only  serve  to  bring  into  sharper  contrast 
the  solid  results  which  the  labor  of  two  decades  has  secured.  No  single 
advance  is  more  striking  than  that  relating  to  our  knowledge  of  the 
protozoa  as  causes  of  disease.  The  brilliant  researches  of  Theobald 
Smith  on  Texas  fever  were  the  first  to  make  the  profession  appreciate 
the  part  which  this  class  of  organisms  played  in  the  acute  infections, 
and  gave,  moreover,  the  demonstration  of  a  scientific  method  and 
insight  of  a  most  remarkable  character. 


II. 

Like  other  departments  of  jjhilosophy,  medicine  began  Avith  an  age  of 
wonder.  The  accidents  of  disease  and  the  features  of  death  aroused 
surprise  and  stimulated  interest,  and  a  beginning  was  made  when  man 
first  asked  in  astonishment.  Why  should  these  things  be?  Surrounded 
everywhere  by  mysteries,  he  projected  his  own  personality  into  the  world 
about  him,  and  peopled  heaven  and  earth  with  Powers,  responsible  alike 
for  the  good  and  for  the  evil,  who  were  to  be  propitiated  by  sacrifices  or 
placated  by  prayers.  Satisfying  the  inborn  longing  of  the  human  mind 
for  an  explanation,  these  celestial  creatures  of  his  handiwork  presided 
over  every  action  of  his  life.  For  countless  ages  man  regarded  disease 
as  a  manifestation  of  these  powers;  the  evil  eye  and  demoniacal  possession, 
the  murrain  on  the  cattle,  and  the  sickness  that  destroyeth  in  the  noon- 
day had  alike  a  supernatural  origin.  Crude  and  bizarre  among  the  primi- 
tive nations,  these  ideas  of  disease  received  among  the  Greeks  and  Romans 
a  practical  development  worthy  of  these  great  peoples.  There  have  been 
systems  of  so-called  divine  healing  in  all  the  great  civilizations,  but,  for 
beauty  of  conception  and  for  grandeur  of  detail  in  the  execution,  all 
are  as  nothing  in  comparison  with  the  cult  of  the  Son  of  Apollo,  of 
yEsculapius,  the  God  of  healing.  To  him  were  raised  superb  struc  ures 
which  were  filled  with  the  most  sublime  products  of  Greek  art,  and 
which  were  at  once  temples  and  sanatoria.     Among  the  most  important 


THE  EVOLUTION  OF  INTERNAL   MEDICINE  xvii 

were  those  of  Cos,  Cnidos,  Epidaurus,  Croton,  Cyrerie  and  Rhodes. 
The  elaborate  ritual  of  the  cure  is  well  described  in  the  Plutus  of 
Aristophanes.  Real  cures  were  often  efl'ccted  and  the  inscriptions  tell 
of  the  touching  and  simple  faith  which,  then  as  now,  forms  so  impor- 
tant a  factor  in  the  healing  of  many  diseases.  In  other  cases  change 
of  air  and  scene,  the  baths,  and  massage  effected  a  cure.  Hypnotism  (?), 
diet,  gymnastic  exercises,  and  games  formed  part  of  the  treatment. 
In  dreams  which  came  in  the  "temple  sleep"  the  god  indicated  the  special 
treatment  to  be  carried  out.  These  temples  were  really  sacred  sanatoria 
situate  in  beautiful  localities  and  greatly  resorted  to  by  people  of  all 
classes.  At  first  they  appear  to  have  had  close  associations  with  the 
secular  medicine  of  the  day  and  to  have  represented  depositories  of 
empirical  knowledge,  but  later  they  become  hot-beds  of  jugglery  and 
deception. 

Scientific  medicine,  the  product  of  a  union  of  religion  with  philosophy, 
had  its  origin  in  a  remarkable  conjunction  of  sifts  and  conditions  among 
the  Greeks  in  the  fifth  and  sixth  centuries.  '  "There  was  the  teeming 
wealth  of  constructive  imagination  united  with  the  sleepless,  critical 
spirit  which  shrank  from  no  test  of  authority;  there  was  the  most  powerful 
impulse  to  generalization  coupled  with  the  sharpest  faculty  for  descrying 
and  distinguishing  the  finest  shades  of  phenomenal  peculiarity;  there 
was  the  religion  of  Hellas,  which  afforded  complete  satisfaction  to  the 
requirements  of  sentiment,  and  yet  left  the  intelligence  free  to  perform  its 
destructive  work;  there  were  the  political  conditions  of  a  number  of 
rival  centres  of  intellect,  of  a  friction  of  forces  excluding  the  possibility  of 
stagnation,  and,  finally,  of  an  order  of  state  and  society  strict  enough  to 
curb  the  excesses  of  'children  crying  for  the  moon,'  and  elastic  enough 
not  to  hamper  the  soaring  flight  of  superior  minds.^  We  have  already 
made  acquaintance  with  two  of  the  sources  from  which  the  spirit  of 
criticism  derived  its  nourishment,  the  metaphysical  and  dialectical 
discussions  practised  by  the  Eleatic  philosophers  and  the  semi-historical 
method  which  was  applied  to  the  myths  by  Hecatpeus  and  Herodotus. 
A  third  source  is  to  be  traced  to  the  schools  of  the  physicians.  These 
aimed  at  eliminating  the  arbitrary  element  from  the  view  and  knowledge 
of  nature,  the  beginnings  of  which  were  bound  up  with  it  in  a  greater  or 
less  degree,  though  practically  without  exception  and  by  the  force  of  an 
inner  necessity.  A  knowledge  of  medicine  was  destined  to  correct  that 
defect,  and  we  shall  mark  the  growth  of  its  most  precious  fruits  in  the 
increased  power  of  observation  and  the  counterpoise  it  offered  to  hasty 
generalizations,  as  well  as  in  the  confidence  which  learned  to  reject  unten- 
able fictions,  whether  produced  by  luxuriant  imagination  or  by  a  'prion 
speculations,  on  the  similar  ground  of  self-reliant  sense  perception."^ 

Greek  medicine  did  not  originate  with  Hippocrates,  who  in  reality 
represents  to  us  the  embodiment  of  a  period  in  which  he  only  forms  the 
most  striking  figure.  As  he  remarks  in  the  book  On  Ancient  Medicine, 
"but  all  these  requisites  belong  of  old  to  medicine,  and  an  origin  and 
way  have  been  found  out  by  which  many  and  elegant  discoveries  have 
been  made  during  a  length  of  time,  and  others  will  yet  be  found  out,  if 
a  person  possessed  of  the  proper  ability,  and  knowing  these  discoveries 

^  Gomperz,  Greek  Thinkers,  vol.  i. 


xv{[{  INTRODUCTION 

whifli  have  been  made,  should  jjrocced  from  them  to  prosecute  his 
investigations."'  At  the  two  most  famous  of  the  /Eseula])ian  temples, 
Cnidos  and  Cos,  rational  metlieine  began  to  develoj)  about  the  sixth 
century  B.C.  "It  was  not  the  priests  who  were  the  ])ionecrs  of  progress, 
but  the  temple  doctors,  the  so-called  Asclepiads,  who  in  historic  times 
had  a  very  slight  connection  with  the  cult,  possibly  none  whatever,  and 
were  free  to  i>ractise  their  calling,  at  their  own  (liscretion,  outside  the 
sacred  precincts  or  even  in  foreign  coimtries.  In  any  case  in  the  century 
immediately  preceding  the  time  of  Hip])ocrates,  the  AsclejMads  of  Cnidos 
or  Cos  were  only  a  shar])ly  defined  grou])  of  (!reek  doctors,  distinguished 
from  the  rest  bv  a  rigid  organization  which  found  expression  in  definite 
rules  and  formalities.  These  had  for  their  object  to  incorporate  in  the 
guild  of  Askle]Mos  those  only  who,  closely  united  by  their  common  venera- 
tion of  the  god  of  healing,  and  by  similar  scientific  opinions,  made  it  their 
goal  to  excel  in  the  practice  of  medicine.  They  bound  themselves  by 
oath  to  maintain  the  dignity  of  the  art,  to  preserve  a  high  morality  in  the 
practice  of  their  calling,  to  show  gratitude  toward  their  teachers,  fraternal 
feeling  toward  the  offspring  of  those  teachers,  and  to  guard  against 
profanation  of  the  secrets  of  their  profession."^ 

The  view  of  disease  in  the  Hippocratic  writings  shows  how  strong  was 
the  influence  of  the  philosophers,  particularly  of  Empedocles  and  Pytha- 
goras. As  in  the  Macrocosm  there  were  four  elements,  fire,  air,  earth, 
and  water,  so  in  man,  the  Microcosm,  there  were  four  elements,  blood, 
mucus,  yellow  bile,  and  black  bile,  of  which  the  blood  represented  the 
heat,  the  mucus  the  cold,  the  yellow  bile  the  dryness,  the  black  bile  the 
moisture.  Health  consisted  in  a  harmony  or  due  admixture  of  these 
humors,  disease  in  a  dyscrasia  or  imperfect  admixture.  This  humoral 
pathology  of  the  Hippocratic  school  dominated  the  profession  for  more 
than  two  thousand  years.  From  Pythagoras  may  be  traced  directly  the 
doctrine  of  critical  days,  which  still  lingers  in  the  profession  and  of  which 
one  hears  among  the"  laity.  Hippocrates  introduced  into  medicine  the 
art  of  observation,  the  critical  judgment  of  observed  facts,  and  a  rational 
induction  from  them,  freed  from  speculation  and  theory.  This  has  been 
the  objective,  practical  method  followed  since  his  day  by  all  the  great 
masters  of  medicine,  and  it  has  been  the  instrument  by  which  we  have 
obtained  our  descriptive  knowledge  of  disease.  Briefly  stated,  from  the 
Greeks  we  obtained  in  the  first  place  the  conception  of  medicine  as  an 
art  based  on  careful  observation,  and  as  a  science  an  integral  part  of  the 
science  of  man  and  of  nature;  and,  secondly,  those  high  moral  ideals 
which  have  ahvays  inspired  the  profession,  so  well  expressed  in  the 
Hippocratic  oathi  which  has  been  called  one  of  the  most  memorable  of 
human  documents. 

After  the  death  of  Hippocrates  Greek  medicine  continued  to  flourish 
under  the  INIacedonian  regime,  and  at  Alexandria,  with  the  fostering  care 
of  the  Ptolemies,  reached  a  very  high  plane.  Anatomy  and  physiology, 
in  particular,  were  studied  with  the  greatest  care  and  many  important 
discoveries   were   made,   particularly    by  Herophilus   and   Erasistratus. 

'  This  is  brought  out  very  clearly  in  Mollet's  La  Medecine  chez  Us  Grecs  avant 
Hippocrate,  1906. 

^  Neuberger,  Geschichte  der  Medizin,  vol.  i. 


THE  EVOLUTION  OF  INTERNAL  MEDICINE  xix 

Had  we  full  knowledge  of  the  writings  of  these  two  great  physi(.'ians 
we  should  probably  find  that  they  had  made  many  valuable  observations 
in  clinical  medicine  and  pathology.  For  example,  Erasistratus  described 
ascites  with  great  care,  and  knew  of  its  associations  with  hardening  of 
the  liver  and  disease  of  the  spleen. 

In  the  intellectual  capture  of  Rome  by  the  Greeks,  medicine  played  a 
not  inconsiderable  part,  and  Greek  physicians  rose  to  positions  of  dignity 
and  importance  which  have  rarely  since  been  equalled  in  any  country  or 
at  any  period  by  the  leaders  of  our  profession.  One  of  these,  Asclepiades, 
the  founder  of  the  school  of  Methodists,  opposed  the  prevailing  humoral 
pathology  and  placed  the  changes  met  with  in  diseases  largely  in  the 
solids  of  the  body.  The  Methodists  made  no  special  contribution  to 
diagnosis,  but  Asclepiades  seems  to  have  been  a  shrewd  and  careful 
physician,  placing  greater  stress  upon  exercise,  baths,  massage,  and  diet 
than  upon  the  treatment  of  disease  by  medicines.  The  centuries  imme- 
diately preceding  and  following  the  birth  of  Christ  saw  medicine  flourish 
remarkably  throughout  the  Roman  world.  In  addition  to  the  Methodists 
there  were  the  Dogmatists,  the  Eclectics,  the  Pneumatists,  from  none 
of  whom  did  medicine  receive  any  very  fertile  contributions.  Clinically 
one  of  the  most  interesting  figures  of  this  period  is  Aretaeus,  whose  works 
have  a  strong  Hippocratic  flavor  and  whose  clinical  pictures  of  disease 
have  rarely  been  equalled.  The  student  who  wishes  to  get  a  picture  of 
Greco-Roman  medicine  of  this  period  should  read,  on  the  one  hand, 
Celsus,  who  gives  a  remarkable  summary  of  the  medical  and  surgical 
knowledge  of  the  day,  and,  on  the  other,  Pliny,  whose  descriptions  abound 
with  the  fads  and  fancies  of  popular  medicine. 

The  great  Greek  practitioner  of  the  period,  and  in  some  ways  the 
greatest  figure  in  the  history  of  medicine,  is  Galen,  who  was  born  in 
Pergamos  about  the  year  a.d.  130.  He  lived  only  for  part  of  his  life 
in  Rome,  where  he  was  the  physician  to  successive  emperors  and  occupied 
a  position  of  commanding  dignity.  In  every  department  of  medicine 
this  remarkable  man  was  a  reformer  and  an  innovator.  In  opposition 
to  the  prevailing  views  of  the  Empirics  and  the  Methodists,  he  placed  the 
whole  foundation  of  the  art  in  anatomy  and  physiology.  He  restored 
the  Hippocratic  methods  and  the  humoral  pathology  of  the  master. 
Galen's  researches  in  anatomy  were  of  the  most  extensive  character,  and 
in  this  subject,  as  well  as  upon  the  nature  and  treatment  of  disease,  his 
views  were  accepted  as  gospel  until  the  Renaissance.  The  four  humors 
were  somewhat  modified  by  him  under  the  influence  of  the  Pneumatics, 
who  introduced  the  doctrine  of  the  spirits — animal,  natural,  and  vital — 
which  so  long  held  sway.  The  special  interest  to  us  here  is  that  to  him 
may  be  traced  the  second  great  instrument  which  has  influenced  the 
advance  of  clinical  medicine,  namely,  experiment.  He  was  the  first 
great  experimental  clinician.  We  owe  to  him  elaborate  studies  upon 
the  action  of  the  heart,  and  he  narrowly  missed  discovering  the  general 
circulation  of  the  blood.  He  made  careful  observations  on  the  physiology 
of  respiration,  and  recognized  the  difference  between  diaphragmatic  and 
intercostal  breathing.  By  experiments  on  the  nervous  system  he  demon- 
strated the  differences  between  the  motor  and  the  sensory  nerves,  and 
even  distinguished  the  motor  and  sensory  roots  leaving  the  spinal  cord. 
In  these  and  other  studies  he  far  eclipsed  his  predecessors,  and  as  an 


XX  INTRODUCTION 

experimcMitor  lu"  had  no  successor  of  llio  same  calibre  until  Harvey.  In 
treatment  he  was  a  follower  of  Hippocrates,  trusting  to  nature,  and  both 
diet  and  gymnastics  ])layed  an  important  role  in  his  system.  Greek 
medicine  had  now  reached  its  climax,  and  with  Galen  the  first  great 
chapter  in  the  history  of  scientific  medicine  closes.  It  is  one  of  the  most 
remarkable  and  in  a  way  an  incxj)licable  feature  in  history  that,  having 
made  a  beginning  of  such  brilliancy,  the  scientific  study  of  disease  should 
have  made  little  or  no  progress  for  the  next  fourteen  or  fifteen  centuries. 
Into  the  causes  of  this  sterility  this  is  not  the  place  to  inquire.  During 
the  long  period  three  great  names  ruled  all  minds,  Ptolemy,  Aristotle, 
and  Galen,  and  men  were  content  to  accept  the  geographic  system  of 
the  one,  the  natural  history  and  philosophy  of  the  other,  while  the  infalli- 
bility of  the  great  Pergamitc  became  the  first  article  of  belief  among  all 
practitioners  of  medicine. 

Through  the  middle  ages  the  continuity  of  Greek  mcnlicine  was  main- 
tained, first,  by  the  writers  of  the  Byzantine  school,  whose  works  are  of 
value  chiefly  as  compilations,  of  which  those  of  Oribasius  and  Paul  of 
il'jgina  are  the  most  im])()rtant;  and  secondly,  by  th(^  Arabians,  who  came  in 
contact  with  (ireck  medicine  in  the  East  and  in  Egypt.  For  them  Aristotle 
and  Galen  were  the  great  masters,  but  departing  from  the  plain  methods 
of  observation  and  induction,  Arabian  writers  rejoiced  in  dogmatism  and 
subtle  dialectics.  They  introduced  a  new  pharmacy  with  many  new 
drugs  from  the  East,  and  with  them  came  many  new  chemical  processes. 
Sadly  mixed  as  it  was  with  alchemy,  in  their  crude  science  we  find  the 
germs  of  modern  chemistry.  Some  of  the  Arabians  became  great  clin- 
icians and  made  notable  and  accurate  contributions  to  clinical  medicine. 
To  Rhazes  we  owe  the  first  good  account  of  smallpox.  They  also  recog- 
nized measles!  Avicenna  became  the  greatest  name  in  Arabian  medicine, 
and  throughout  the  latter  part  of  the  middle  ages  his  authority  rivalled 
that  of  Galen.  There  was  a  third  narrow  stream  through  which  Greek 
medicine  Avas  preserved,  namely,  the  old  Universities,  and  particularly 
the  school  of  Salernum  in  Southern  Italy.  In  the  early  middle  ages,  from 
the  tenth  to  the  twelfth  centuries,  it  maintained  the  Greek  tradition  and 
was  recognized  as  the  leading  school  of  medicine  in  Europe.  Though  its 
derivation  is  unknown,  the  school  possessed  a  continuity  in  thought  with 
the  old  Greek  writers.  Later  the  school  of  Salernum  became  tinctured 
with  Arabian  medicine,  but  through  it  the  writings  of  Galen  and 
Hippocrates,  mixed  with  the  accretions  from  Arabian  sources,  filtered 
into  modern  Europe. 

Practically  throughout  the  middle  ages  there  was  no  such  thing  as  an 
accurate  study  of  clinical  medicine.  In  what  is  known  as  the  scholastic 
period,  the  three  centuries  before  the  Renaissance,  authority  and  dogma 
ruled  supreme,  and  philosophy  and  medicine  alike  were  a  confused 
jumble  of  Greek  and  Arabian  authorities.  The  Renaissance  influenced 
clinical  medicine  in  three  ways:  First,  it  restored  once  and  for  all  the 
methods  of  Hippocrates  and  of  Galen.  The  careful  study  of  descriptive 
anatomy  by  Vesalius  and  his  successors  restored  to  men  the  lost  art  of 
clear,  indepen/Ient  vision.  Secondly,  in  the  revolt  against  dogmatism 
and  authority  a  new  chemistry  arose,  at  first,  in  the  hands  of  Paracelsus 
and  others,  crude  and  unscientific,  yet  it  laid  the  foundation  for  all  our 
subsequent   studies,  and   through   van    Helmont   and   the   seventeenth 


THE  EVOLUTION  OF  INTERNAL  MEDICINE  xxi 

century  chemists  has  led  to  the  present  most  fruitful  results.  Thirdly, 
we  may  trace  as  a  direct  effect  of  the  Renaissance  the  revival  of  experi- 
ment in  medicine  which  had  been  introduced  by  Galen.  The  work  on 
metabolism  by  Sanctorms,  and  the  demonstration  by  Harvey  of  the 
circulation  of  the  blood  gave  an  immense  imjx'tus  to  the  scientific  investi- 
gation of  the  functions  of  the  body  and  of  the  causes  of  disease.  It 
cannot  be  said  that  Harvey's'  work  had  any  very  special  influence  on 
clinical  medicine  except  in  conjunction  with  the  mechanical  philosophy 
of  Descartes  and  the  foundation  of  the  so-called  iatro-mechanical  school. 
How  little  actual  progress  had  been  made  in  clinical  medicine  is  illus- 
trated by  what  a  leading  practitioner,  Willis,  in  the  middle  of  the 
seventeenth  century  thought  of  such  a  disease  as  inflammation  of  the  lungs. 
The  essential  cause  was  believed  to  be  that  the  blood  boiled  feverishly, 
and  "sticking  within  the  yiore  narrow  passages  of  the  lungs  engendered 
there  an  obstruction  causing  inflammation."  Neither  in  the  description 
of  the  symptoms  nor  in  the  discussion  of  the  prognosis  is  there  any  radical 
advance  upon  the  position  of  Hippocrates  and  of  Galen.  A  case,  the 
particulars  of  which  he  gives,  shows  the  heroic  character  of  the  treatment: 
"I  drew  blood  twice  or  thrice  day  after  day."  "Frequent  clysters  were 
administered;  moreover,  apozems,  juleps,  also  spirits  of  ammoniac  and 
poAvder  of  fish  shells  were  administered  by  turns,"  When  phlebotomy 
was  no  longer  safe  very  large  blisters  were  applied  to  the  arms  and  thighs. 
One  is  surprised  to  learn  that  the  patient  recovered,  but  he  suffered 
greatly  from  the  blisters  which  did  "run  hugely  and  afterwards  for  almost 
a  month  daily  discharged  great  plenty  of  a  most  sharp  ichor." 


III. 

Not  truly  scientific  and  uninfluenced  by  his  friends,  Boyle  and  Locke, 
(who  appreciated  fully  the  importance  of  the  scientific  movement  of  the 
day),  Sydenham  restored  in  a  measure  the  practical  methods  of  the 
Hippocratic  school,  careful  observation,  guided  by  common  sense.  If  to 
that  remarkable  conception  of  diseases  as  objects  of  study  and  classifica- 
tion, as  in  the  subjects  of  botany  and  natural  history,  Sydenham  had 
added  the  methods  of  Harvey,  experiment  and  postmortem  observation, 
the  real  revolution  in  clinical  medicine  might  not  have  had  to  wait  until 
the  beginning  of  the  nineteenth  century.  A  prince  among  practical 
physicians,  the  limitations  imposed  upon  himself  restricted  his  view,  and 
Sydenham  never  got  to  the  "seats  and  causes  of  disease"  as  did  his  great 
successor,  Morgagni;  but  as  a  portrayer  of  their  objective  features  he  has 
had  few  equals,  and  in  this  he  even  bettered  the  instruction  of  his  master, 
Hippocrates.  In  his  study  of  fevers  Sydenham  displayed  a  remarkable 
independence,  not  more  in  the  graphic  pictures  which  he  has  left  us 
than  in  his  insistence  upon  the  importance  of  a  knowledge  of  their  natural 
history  as  a  basis  of  rational  treatment.  That  he  was  led  away  by  too 
great  belief  in  an  epidemic  constitution  was  only  to  be  expected  in  so  close 
a  follower  of  Hippocrates.  No  one  before  him  had  so  clearly  grasped 
the  conception  that  the  manifestations  of  a  fever  represented  the  efforts 
of  nature  to  get  rid  of  the  injurious  agents  causing  the  disease.  ISIany 
of  his  descriptions  of  chronic  diseases  have  never  been  surpassed,  and  hi§ 


xxii  INTRODUCTION 

account  of  chorea,  of  hysteria,  and  of  <2:out  have  become  classical  in  the 
literature.  But  it  was  in  treatment  that  he  showed  a  still  more  revolu- 
tionary spirit.  He  had  a  supreme  faith  in  nature  as  the  true  healer,  to 
whom  the  physician  played  a  secondary  j)art,  assisting  her  when  she  was 
feeble,  restraining  her  when  excessive  and  violent.  That  many  diseases 
got  well  if  left  to  themselves  was  a  novel  doctrine  in  the  seventeenth 
century.  But  it  was  in  his  new  method  of  treating  fever,  and  ])articularly 
smallpox,  by  cooling  measures,  plenty  of  drink  and  fresh  air,  that  he 
departetl  most  strongly  from  the  ])ractice  of  his  day  and  achieved  signal 
success.  One  of  the  most  interesting  figures  in  the  history  of  clinical 
medicine,  Sydenham  has  impressed  his  method  on  his  countrymen,  who 
have  always  cared  less  for  the  theoretical  conceptit)ns  than  for  the  prac- 
tical, common-sense  aspects  in  the  consideration  of  disease.  Several  of 
Sydenham's  contemj)oraries  in  England  werij  keen  clinical  physicians 
who  have  left  on  record  valuable  contributions  to  medicine.  Glisson 
in  particular  may  be  mentioned  as  a  man  in  whom  were  combined  the 
anatomical  and  clinical  features  so  characteristic  of  the  teachers  of  this 
period.  His  treatise,  de  Rachididc,  1G50,  is  the  first  extensive  monograph 
on  a  single  disease  published  in  England  (Cains'  Sweating  Sickness, 
published  a  century  earlier,  had  not  the  same  ambitious  scope).  Not 
only  are  the  clinical  aspects  of  the  disease  given  in  great  detail,  but  the 
morbid  anatomy  and  the  etiology  also  are  fully  discussed.  Morton,  too, 
was  an  admirable  systematic  writer  and  his  works  Pyretologia  (1692)  and 
Phthisiologia  (16S9)  show  accurate  study,  and  the  subjects  are  presented 
in  a  more  orderly  and  logical  way  than  in  the  writings  of  Sydenham. 

Brilliant  and  even  revolutionary  as  was  the  work  of  this  small  group 
of  English  physicians,  it  did  not  immediately  influence  the  progress  of  clin- 
ical medicine  until  the  advent  of  the  Dutch  Hippocrates,  Boerhaave,  upon 
whom  fell  the  mantle  of  Sydenham.  But  meanwhile  there  had  arisen  on  the 
Continent  the  iatro-physical  school,  based  upon  the  mechanical  concep- 
tions of  the  Cartesian  philosophy  and  supported  by  the  experiments  of 
Sanctorius,  of  Harvey,  of  Borrelli  and  others.  Silvius,  of  Leyden,  and 
Pit  cairn,  ]\Iead  and  Friend  were  the  chief  exponents  of  this  system,  in 
which  everything  was  explained  in  terms  of  mathematical  reasoning; 
and  while  it  did  good  service  in  combating  the  dominant  doctrine  of  the 
humors,  the  extravagance  of  its  professors  hastened  the  downfall  of  a 
school  which,  after  all,  rested  on  a  strong  basis  of  truth. 

As  with  nearly  everything  of  value  in  the  practical  aspects  of  modern 
life,  agriculture,  horticulture,  banking,  colonization,  etc.,  so  in  clinical 
medicine  the  Dutch  were  our  masters.  The  great  Italian  teachers  of  the 
sixteenth  and  seventeenth  centuries  were  also  practitioners,  and  there 
must  have  been  some  instruction  in  the  art  as  well  as  in  the  science  of 
medicine,  but  it  was  everywhere  desultory  and  unsystematic  until  the 
Dutch  physicians  organized  regular  clinical  instruction  as  part  of  the 
University  teaching.  Professor  Pell  tells  me  that  the  hospital  clinic  at 
Utrecht  preceded  that  at  Leyden,  but  it  was  at  this  latter  place,  under 
the  influence  of  Boerhaave,  that  it  became  most  eft'ective.  The  history 
of  this  University  illustrates  the  importance  of  men  in  forming  an  educa- 
tional centre;  students  flocked  to  it  from  all  parts  of  Europe  to  sit  at  the 
feet  of  such  teachers  as  Silvius,  Grotius,  the  younger  Scaliger,  Bidloo,  and 
Pitcairn.     After  teaching  botany  and  chemistry,  Boerhaave  succeeded 


THE  EVOLUTION  OF  INTERNAL   MEDICINE  xxili 

to  the  chair  of  physic  in  1714.  With  an  unusually  wide  ^u-neva]  training, 
a  profound  knowledge  of  the  chemistry  of  the  day,  and  an  accurate 
acquaintance  with  all  aspects  of  the  liistory  of  the  jirofession,  he  had  a 
strongly  objective  attitude  of  mind  toward  disease,  following  closely  the 
methods  of  Hippocrates  and  Sydenham.  He  adopted  no  special  system, 
but  studied  disease  as  one  of  the  phenomena  of  nature.  His  clinical 
lectures,  held  bi-weekly,  became  exceedingly  popular  and  were  made 
attractive  not  less  by  the  accuracy  and  care  with  which  the  cases  were 
studied  than  by  the  freedom  from  fanciful  doctrines  and  the  frank  honesty 
of  the  man.  He  was  much  greater  than  his  published  work  would 
indicate,  and,  as  is  the  case  with  many  teachers  of  the  first  rank,  his 
greatest  contributions  were  his  pupils.  No  teacher  of  modern  times  has 
had  such  a  following.  Among  his  favorite  pupils  may  be  mentioned 
Haller,  the  physiologist,  and  van  Swieten,  the  founder  of  the  Vienna 
school. 

Edinburgh  had  had  very  close  affiliations  with  Leyden,  and  one  of 
Boerhaave's  predecessors  was  Archibald  Pitcairn,  who  subsequently 
returned  to  his  native  city  and  had  an  important  influence  in  building 
up  the  university,  the  medical  school  of  which  was  not  organized  until 
1726.  The  Leyden  methods  of  instruction  were  introduced  by  pupils 
of  Boerhaave,  of  whom  John  Rutherford  was  the  most  distinguished. 
He  began  to  teach  at  the  Royal  Infirmary  in  1747.  I  have  a  manuscript 
of  his  clinical  lectures  delivered  in  the  wdnter  session  of  1748-49,  from 
which  we  may  get  a  good  idea  of  his  plan  of  teaching.  He  says:  "The 
method  I  propose  to  pursue  is,  to  examine  every  patient  before  you,  lest 
any  circumstances  should  be  overlooked.  I  shall  undertake  this  by  a 
plan  which  wall  be  the  most  useful  I  can  think  of.  I  shall  give  you  the 
history  of  his  disease  in  general;  secondly,  inquire  into  the  cause  of  it, 
and,  thirdly,  give  you  my  opinion  how  the  disease  is  likely  to  terminate 
and  lay  down  the  indication  of  cure,  or  when  any  extraordinary  symp- 
toms arise  you  shall  have  notice  of  it  that  you  may  see  the  reason  of 
altering  my  prescriptions." 

Those  were  happy  days  for  the  medical  student,  as  a  few  paragraphs 
later  he  says:  "I  do  not  mean  by  this  that  you  should  all  take  degrees, 
for  I  am  far  from  thinking  that  a  diploma  furnishes  a  man  with  medical 
knowledge.  His  improvement  in  this  art  depends  on  his  own  study 
and  industry."  Three,  four,  and  even  five  patients  w^ere  shown  on  the 
same  day,  and  great  care  was  taken  to  keep  the  students  informed  of 
the  progress  of  patients  who  had  been  seen  by  them.  Weeks  afterw^ard 
a  memorandum  is  given,  perhaps,  of  the  postmortem.  The  history, 
the  symptoms,  and  the  prognosis  are  very  well  considered,  but  one  misses 
the  physical  examination  and  an  accurate  consideration  of  the  pathology 
and  morbid  anatomy.  Groups  of  cases  were  considered  together,  as 
illustrated  by  Lecture  23,  in  wdiich  a  series  of  cases  of  scurvy,  that  had 
been  "in  the  house,"  were  considered  together. 

Directly  inspired  from  Leyden,  the  Edinburgh  school  soon  outstripped 
all  its  compeers.  In  the  main  thoroughly  practical  and  objective,  as 
witnessed,  for  example,  in  the  w^ork  of  Whytt,  it  illustrated  also  the  specu- 
lative nature  of  the  Scottish  character  in  two  systems  of  medicine  which 
had  great  vogue.  Cullen,  who  was  Whytt's  successor  in  the  chair  of 
institutes,  became  the  most  prominent  teacher  of  medicine  in  his  day  in 


xxiv  ixrmmvcTioN 

the  Eno'lisli-spcakinf];  world.  lie  was  a  most  inspiring  lecturer  and  a 
thoroughly  good  clinical  teacher.  While,  ])erhai)s,  it  is  scarcely  correct 
to  say  that  he  introduced  a  system,  yet  he  was  the  first  to  attach  special 
importance  to  the  nervous  system  as  influencing  disease.  A  more  defi- 
nite system,  comparable  with  the  older  ones  which  prevailed  on  the 
Continent  in  the  seventeenth  and  eighteenth  centuries,  was  the  Brunonian, 
introduced  by  John  Brown,  a  {)upil  of  Cullen.  "^riie  essence  of  this 
consisted  in  an  insistence  upon  debility  as  the  fundamental  factor  in 
disease,  and  the  necessity  of  always  maintaining  a  suj^porting  line  of 
treatment.  Few  systems  of  medicine  have  ever  stirred  such  bitter  con- 
troversy, and  in  Charles  Creighton's  account  of  Brown^  we  read  that  as 
late  as  1802  the  University  of  Gottingen  was  so  convulsed  by  contro- 
versies on  the  merits  of  the  Brunonian  system  that  contending  factions 
of  students  in  enormous  numbers,  not  unaided  by  the  professors,  met  in 
combat  in  the  streets  on  two  consecutive  days  and  had  to  be  dispersed 
by  a  troop  of  Hanoverian  hoi-se. 

In  England  antl  the  colonies  the  influence  of  the  Edinburgh  school 
became  supreme.  I.ondon  had  no  properly  organized  medical  teaching. 
In  the  hospitals  the  surgeons  gave  good  instruction  and  there  was  an 
admirable  system  of  pupils  and  dressers.  But  to  medicine  proper  little 
or  no  attention  had  been  paid.  One  of  the  physicians  of  the  hospital 
lectured  on  medicine,  materia  medica,  and  chemistry,  chiefly  to  men 
who  were  to  become  apothecaries  or  general  practitioners.  To  take 
the  INI.D.  degree,  men  had  to  go  to  Edinburgh  or  abroad,  or  they  took 
the  Oxford  or  Cambridge  INI.D.,  after  keeping  a  certain  number  of  terms. 
Throughout  the  eighteenth  century  the  methods  and  practice  of  Boer- 
haave  had  great  influence  in  London.  Many  of  the  Fellows  of  the  College 
of  Physicians  had  been  his  pupils.  His  works  were  translated  and  fre- 
quently reprinted,  but,  without  university  organization  and  without 
systematic  instruction,  the  clinical  teaching  was  carried  on  in  a  very 
desultory  manner.  Toward  the  end  of  the  century  several  men  trained 
in  Edinburgh  methods  became  distinguished  teachers  and  workers  in 
the  London  hospitals,  of  whom  William  Saunders  may  be  taken  as  an 
example.  A  pupil  of  Cullen,  he  became  in  1770  physician  to  Guy's 
Hospital  and  at  once  began  to  lecture  upon  medicine  and  to  give  clinical 
instruction.  He  was  a  hard  worker  and  a  keen  clinical  observer,  as  his 
papers  on  lead  colic,  on  the  diseases  of  the  liver,  and  on  delirium  tremens 
amply  testify.  Gilbert  Blane  and  Matthew  Baillie  were  both  Glasgow 
men.  The  latter,  a  graduate  of  Oxford,  was  the  best  clinical  physician 
of  his  day  in  London,  but  no  doubt  he  got  most  of  his  pathological  and 
clinical  training  from  his  uncles,  William  and  John  Hunter.  Fothergill 
and  Lettsom,  Halford,  Holland,  Bright,  Paris,  Humphry  Davy,  Caleb 
Parry,  and  Marshall  Hall  were  Edinburgh  men. 

To  Edinburgh  all  the  abler  young  men  from  the  English  colonies  went 
for  their  medical  education.  Bard,  M«jrgan,  Shippen,  Rush,  W^istar, 
Hossack  and  others  brought  back  to  Amt^rica  the  traditions  and  methods 
of  its  schools;  and  it  was  not  until  the  third  decade  of  the  nineteenth 
century  that  the  tide  of  students  turned  toward  France.  Early  in  that 
decade  it  was  a  group  of  young  Edinburgh  men.  Holmes,  Robertson, 

'  Dictionari/  of  National  Biography. 


THE  EVOLUTION  OE  INTERNAL  MEDICINE  xxv 

Stevenson,  and  Caldwell,  who  Ijcgan  medical    instrneiion   In  Montreal, 
from  which  originated  the  Medical  Faculty  of  McCjriil  College. 

Boerhaave  and  his  pupils  extended  the  range  of  observation  and  in  a 
measure  restored  to  medicine  that  robust  common  sense  which  hacl  been 
the  distinguishing  feature  of  both  Plippocrates  and  Sydenham.  At  the 
end  of  the  eighteenth  century  men  were  floundering  in  a  sea  of  speculation 
and  there  was  no  definiteness  in  diagnosis  nor  any  safe  basis  for  treatment. 
The  next  great  step  came  from  an  extension  of  the  Hippocratic  method 
to  the  dead-house,  the  study  of  morbid  anatomy  in  association  with 
clinical  observation. 


IV. 

Many  of  the  sixteenth  and  seventeenth  century  physicians  had  keen 
appreciation  of  the  value  of  postmortem  examinations.  Harvey  has 
a  most  interesting  paragraph  on  the  subject,'  and  his  works  testify  to  the 
zeal  with  which  he  sought  for  the  more  hidden  causes  of  disease;  but 
with  no  one  in  the  seventeenth  century  did  morbid  anatomy  become  a 
life  study,  and  no  one  had  realized  its  true  position  in  the  science  of 
medicine  until  Morgagni  (1683-1771)  published  the  De  Sedibus  et 
Causis  Morborum  per  Anatomen  Indagatis  (1761).  Others  before  this 
date  had  made  interesting  collections  of  cases:  Ridley  in  England,  and 
Bonetus  of  Geneva,  who  published  the  Sepulcretum  Anatomicum  in  1679. 
Valuable  as  is  this  great  work,  it  had  not  the  profound  influence  of 
the  De  Sedibus,  as  it  was  a  collection  of  cases  from  the  literature,  and 
lacked  that  freshness  and  interest  which  Morgagni  was  able  to  give  to  his 
reports.  In  them  for  the  first  time  we  find  a  careful  clinical  study  of  the 
symptoms  of  disease  and  an  equally  careful  examination  of  the  organs 
after  death.  It  was  the  novelty  of  the  mode  of  presentation  quite  as  much 
as  the  vivid  picture  of  disease  that  made  Morgagni's  work  mark  an 
epoch  in  the  history  of  clinical  medicine.  Even  today  it  is  a  storehouse  of 
valuable  facts,  and  several  of  the  sections,  more  particularly  that  on  the 
heart  and  bloodvessels,  are  so  rich  in  original  descriptions  that  no  man's 
education  in  morbid  anatomy  can  be  said  to  be  complete  without  an 
acquaintance  with  its  pages.  The  example  of  the  great  Italian  was  soon 
followed  in  other  countries,  particularly  in  England  and  in  France.  John 
Hunter,  with  his  insatiable  hunger  for  knowledge  of  all  sorts,  was  equally 
great  as  a  morbid-  and  as  a  comparative  anatomist.  The  Hunterian 
specimens  in  the  great  Museum  at  Lincoln's  Inn  Fields  bear  witness 
to  the  accuracy  of  his  descriptions,  to  the  insistence,  when  possible, 
upon  clinical  details,  and  to  the  keen  appreciation  which  he  had  of  the 
importance  of  the  study  of  morbid  anatomy  in  the  education  of  medical 
men.  His  brother  William,  also  an  enthusiastic  student  of  morbid 
anatomy,  formed  an  important  collection,  and  the  specimens  and  notes  in 
his  museum,  now  at  Glasgow^  show  that  he  too  was  alive  to  the  value 

1  "The  examination  of  a  single  body  of  one  who  has  died  of  tabes  or  some 
other  disease  of  long  standing,  or  poisonous  nature,  is  of  more  service  to  med- 
icine than  the  dissection  of  the  bodies  of  ten  men  who  have  been  hanged." 
Letter  to  Riolan. 


xxvl  INTRODUCTION 

of  the  new  method  of  combining  clinical  with  anatomical  work.  ISIatthew 
Baillie,  their  nephew,  gave  to  the  world  the  fruits  of  their  researches, 
combined  with  his  own,  in  the  Morbid  Anatomy  published  in  1793  and 
followed  in  1799  by  his  well-known  Atlas.  Texts  and  plates,  alike 
admirable,  formed  the  most  important  contribution  to  practical  medicine 
made  in  England  during  the  eighteenth  ccnturv,  if  we  exclude  -Tenner's 
vaccinations.  The  Scries  of  Kngravincjs  was  the  first  of  its  kind  to  be 
published,  and  the  accuracy  of  the  drawings  and  the  careful  descriptions 
made  it  for  years  a  standard  work,  and  indeed  the  plates  may  still  be  used 
in  illustrating  lectures.  But  the  new  science  reached  its  fullest  develop- 
ment in  France,  and  helped  to  promote  the  revolution  in  clinical  medicine 
which  was  effected  in  that  country  during  the  first  three  decades  of 
the  nineteenth  century.  To  the  school  of  Bichat,  who  was  essentially  a 
morbid  anatomist,  we  owe  the  fruitful  studies  which  gave  us  our  modern 
outlook  on  the  processes  of  disease.  Corvisart  and  Bayle,  Broussais, 
Laennec,  Louis,  Chomel,  and  iVndral  revived  Das  Anatomischen 
Denken  (Virchow)  of  INIorgagni. 

With  the  old  Hippocratic  method,  however,  which  had  been  used  for  cen- 
turies, and  which  Morgagni  had  simply  transferred  from  the  bedside  to  the 
dead-house,  it  would  have  been  impossible  to  get  beyond  the  great  Itahan. 
Hitherto  the  sense  of  sight  had  dominated  in  the  examination  of  the 
patient,  supplemented  to  some  extent  by  the  sense  of  touch.  Now  the 
hand  and  ear  were  to  take  an  equal  share,  and  the  eye  was  to  have  its 
powers  enormously  extended  by  the  use  of  the  microscope.  From  the 
Inventum  Novum  of  Auenbrugger  (1761)  we  may  date  the  introduction 
of  modern  clinical  methods  into  medicine.  His  discovery  illustrates  the 
fate  of  a  truth  announced  prematurely.  The  time  was  not  ripe,  and  the 
art  of  percussion  had  to  await  the  keen  mind  of  Corvisart  before  its 
importance  was  recognized.  The  greatest  stimulus  ever  given  to  internal 
medicine  was  the  discovery  of  auscultation  by  Laennec,  whose  work 
V Aiisndtation  Mediate  (1819)  not  merely  introduced  a  new  method, 
but  was  also  a  treatise  on  diseases  of  the  heart  and  lungs,  combining 
the  results  of  clinical  study  and  anatomical  investigation.  With  this 
book  began  an  entirely  new  era  in  medicine.  Rich  in  the  descriptions  of 
diseases  hitherto  unrecognized  and  unrecognizable,  this  immortal  work  not 
only  placed  a  new  and  powerful  method  in  the  hands  of  physicians,  but 
also  gave  an  enormous  stimulus  to  the  study  of  internal  diseases.  The 
researches  of  Louis  correlated  the  symptoms  and  physical  signs  with  the 
anatomical  appearances  in  pulmonary  tuberculosis  and  in  typhoid  fever. 
Chomel,  Andral,  Bretonneau,  Rayer,  Piorry,  Cruveilhier  and  others 
jCaught  the  new  spirit  and  made  Paris  the  centre  of  medical  instruction 
for  the  whole  world.  This  revolution  in  internal  medicine  was  effected 
simply  by  an  extension  of  the  Hippocratic  method  from  the  bedside  to  the 
dead-house  and  by  the  correlation  of  the  signs  and  symptoms  of  a  disease 
with  its  anatomical  appearances.  It  was  by  this  method  that  Richard 
Bright  opened  up  an  entirely  new  chapter  in  his  studies  on  the  relation  of 
disease  of  the  kidneys  to  dropsy  and  to  albuminous  urine.  It  had  already 
been  shown  by  Blackwell  and  by  Wells,  the  celebrated  Charleston  (S.  C.) 
physician,  that  the  urine  contained  albumin  in  many  cases  of  dropsy, 
but  it  was  not  until  Bright  began  a  careful  investigation  of  the  bodies  of 
patients  who  had  presented  these  symptoms,  that  he  discovered  the 


THE  EVOLUTION  OF  INTERNAL  MEDICINE  xxviJ 

association  of  various  forms  of  disease  of  the  kidney  with  anasarea  and 
albuminous  urine.  In  no  direction  was  the  liarvcst  of  this  combined 
study  more  abundant  than  in  the  complicated  and  confused  subject  of 
fever.  The  work  of  Louis  and  of  his  pupils,  W.  W.  Gerhard  and  others, 
revealed  the  distinction  between  typhus  and  typhoid  fever,  and  so  cleared 
up  one  of  the  most  obscure  problems  in  pathology. 

Throughout  the  nineteenth  century  this  clinico-pathological  investiga- 
tion of  disease  has  widened  enormously  our  diagnostic  powers,  and  the 
physician  today  who  wishes  to  obtain  a  sound  knowledge  of  the  natural 
history  of  disease  must  adopt  Morgagni's  method  of  "anatomical  thinking." 
Skoda  in  Vienna,  Schoenlein  in  Berlin,  Graves  and  Stokes  in  Dublin, 
Marshall  Hall,  C.  J.  B.  Williams,  and  many  others  introduced  the  new 
and  exact  methods  of  the  French  and  created  a  new  clinical  medicine. 
A  very  strong  impetus  was  given  by  the  researches  of  Virchow  on  cellular 
pathology,  which  removed  the  seat  of  disease  from  the  tissues,  as  taught  by 
Bichat,  to  the  individual  elements,  the  cells.  The  introduction  of  the  use 
of  the  microscope  in  clinical  work  widened  greatly  our  powers  of  diagnosis, 
and  we  obtained  thereby  a  very  much  clearer  conception  of  the  actual 
processes  of  disease.  In  another  way,  too,  medicine  was  greatly  helped 
by  the  rise  of  experimental  pathology,  which  had  been  introduced  by 
John  Hunter,  was  carried  along  by  Magendie  and  others,  and  reached  its 
culmination  in  the  epoch-making  researches  of  Claude  Bernard.  Not  only 
were  valuable  studies  made  on  the  action  of  drugs,  but  also  our  knowledge 
of  cardiac  pathology  was  revolutionized  by  the  work  of  Traube,  Cohnheim, 
and  others.  In  no  direction  did  the  experimental  method  effect  such  a 
revolution  as  in  our  knowledge  of  the  functions  of  the  brain.  Clinical 
neurology,  which  had  received  a  great  impetus  by  the  studies  of  Todd, 
Romberg,  Lockhart,  Clarke,  Duchenne  and  Weir  Mitchell,  was  completely 
revolutionized  by  the  experimental  work  of  Hitzig,  Fritsch  and  Ferrier. 
Under  Charcot  the  school  of  French  neurologists  gave  great  accuracy  to 
the  diagnosis  of  obscure  affections  of  the  brain  and  spinal  cord,  and  the 
combined  results  of  the  new  anatomical,  physiological,  and  experimental 
work  have  rendered  clear  and  definite  what  was  formerly  the  most  obscure 
and  complicated  section  of  internal  medicine. 

The  latter  part  of  the  nineteenth  century  saw  a  complete  revolution  in 
our  conception  of  the  etiology  of  infectious  diseases.  The  idea  of  a 
contagium  vivum,  of  a  living  agent  which  multiplied  in  the  body  and 
caused  the  symptoms  of  disease,  had  long  been  entertained,  and  the 
analogies  between  the  fermentation  of  fluids  and  disease  had  been  fre- 
quently suggested.  The  brilliant  researches  of  Pasteur  placed  the 
bacterial  origin  of  certain  diseases  on  a  firm  scientific  basis.  Grasping 
the  idea  that  the  putrefactive  and  suppurative  processes  in  wounds  were 
due  to  bacteria,  Lister  revolutionized  surgery,  and  has  made  possible 
operations  which  have  widened  enormously  the  work  of  surgeons,  with  a 
result  that  today  our  art  is  more  medico-chirurgical  than  it  has  ever  been 
before.  But  the  full  importance  of  the  new  studies  was  not  realized  until 
Robert  Koch  discovered  in  rapid  succession  the  causes  of  several  of  the 
most  destructive  of  epidemic  diseases.  Then  with  Laveran's  description 
of  the  malarial  parasite  came  the  recognition  of  the  importance  of  protozoa 
as  causes  of  disease.  All  this  work  has  modified  clinical  medicine  in 
several  important  directions.     The  detection  of  specific  parasites  has  been 


xxvlii  INTRODUCTION 

a  great  help  to  diagnosis,  as,  for  example,  in  tuberculosis.  The  knowledge 
of  the  precise  etiology  has  enal)led  us  to  take  intelligent  precautions  for 
the  prevention  of  the  disease,  and  the  measures  for  sanitary  control  of 
the  acute  infections  have  been  strenglhened  a  hundredfold  by  the  studies 
of  the  past  (piarter  of  a  century.  In  another  direction  the  new  science 
has  had  a  most  frtiitful  aj){)lication.  With  the  introduction  of  vaccination 
against  smalljwx,  Jenner  laid  the  foiuidation  for  the  modern  work,  still 
only  in  its  beginnings,  which  deals  Mith  vaccines,  antitoxins,  and  curative 
sera.  When  one  considers  the  comparatively  short  space  of  time  which 
has  elapsed  since  Koch's  discovery  of  the  tubercle  bacillus,  we  may  be 
grateful  that  so  much  has  been  accomplished,  and  in  spite  of  many 
disappointments  the  situation  is  one  full  of  hope  for  the  future. 

However  produced,  the  ultimate  processes  of  disease  represent  chemical 
changes  in  the  fluids  and  tissues  of  the  body,  and  in  this  direction,  too, 
the  advances  of  the  past  half-century  have  liad  a  profound  influence  on 
clinical  medicine.  Oin-  knowledge  of  normal  metabolism  has  progressed 
with  startling  rapidity  and  warrants  the  belief  that  before  long  we  shall 
have  a  safe  platform  from  which  to  investigate  "to  a  finish"  such  serious 
perversions  as  are  present  in  gout,  diabetes,  etc.  Already  the  studies 
upon  internal  secretions  have  not  only  given  us  a  clear  conception  of  the 
functions  of  certain  organs,  but  have  also  enabled  us  to  treat  success- 
fully such  otherwise  incurable  maladies  as  myxoedema.  From  the  new 
science  of  physical  chemistry  much  may  be  expected,  and  one  of  the 
most  encouraging  signs  is  the  increasing  attention  paid  by  the  younger 
physicians  to  problems  which  demand  the  most  accurate  chemical 
technic[ue.  In  the  immediate  future  it  is  along  chemical  lines  that  we 
may  look  for  the  greatest  advance,  and  of  this  there  is  no  more  satis- 
factory indication  than  the  simultaneous  appearance  quite  recently  in 
England  and  the  United  States  of  journals  devoted  to  biochemistry. 


V. 

A  work  of  the  scope  of  the  present  one  has  a  very  different  value 
to  dift'erent  persons.  It  is  designed  primarily  for  the  practitioner  who 
wishes  to  keep  himself  informed  of  the  existing  state  of  our  knowledge 
in  clinical  medicine.  Elaborate  discussions  upon  doubtful  problems 
have  been  avoided,  and,  as  far  as  possible,  a  clear  statement  is  given 
without  unnecessary  references  to  the  literature.  Authors  have  been 
selected  who  are  acknowledged  authorities,  and  while  it  is  not  always 
easy  for  a  writer  who  is  saturated,  so  to  speak,  with  his  subject  to  keep 
within  limits,  and  to  remember  the  practical  character  of  the  men  for 
whom  he  is  writing,  I  hope  we  have  been  able  to  keep  an  even  balance 
between  the  condensation  of  the  text-book  and  the  elaborate  treatment 
of  the  monograph.  The  first  consideration  in  a  work  of  this  kind  is 
that  it  shall  be  lielpful.  To  fulfil  this  reqtiirement  we  have  had  some- 
times to  introduce  matter  whic-h  may  seem  foreign  to  a  system  of  medicine. 
A  section  on  Protozoa,  for  example,  such  as  that  given  by  Professor 
Calkins,  is  indispensable  for  the  appreciation  of  the  importance  of  this 
class  of  parasites,  and  in  a  brief  article  written  for  the  purpose  the 
practitioner  will  get  information  of  a  character  better  suited  to  his  needs 


THE  EVOLUTION  OF  INTERNAL  MEDICINE  xxix 

than  from  a  manual  of  zoology.  So,  too,  for  the  stiifly  and  prevention 
of  malaria  and  of  yellow  fever  a  knowledge  (jf  the  structure,  vari(;tie,s, 
and  life  history  of  the  mosquito  is  necessary,  but  the  most  recent  infor- 
mation of  this  sort  is  not  easily  to  be  had  from  ordinarily  procurable 
books. 

There  are  several  ways  in  which  a  work  of  this  kind  may  be  most 
helpful  to, a  man  in  general  practice.  It  may  put  him  on  the  right  course 
and  give  him  his  bearings  when  he  has  been  blown  about  without  compass 
by  every  wind  of  doctrine.  For  instance,  studied  carefully,  the  mas- 
terly presentation  of  the  subject  of  Auto-intoxication  by  Dr.  Taylor,  in  the 
present  volume,  will  give  him  the  "light  and  leading"  necessary  for  an 
intelligent  appreciation  of  one  of  the  most  complex  and  confused  depart- 
ments of  medicine.  While  much  remains  to  be  done,  we  have  enough 
positive  knowledge  to  enable  us  to  approach  the  clinical  side  of  the  ques- 
tion in  an  intelligent  manner,  unburdened  from  much  of  the  nonsense  of 
the  auto-intoxication  propaganda  of  the  past  twenty  years.  Accurate  clin- 
ical investigation  must  accompany  chemical  research,  and,  while  the  two 
cannot  often  be  combined  by  a  man  in  active  practice,  there  is  no  reason 
why  he  should  not  appreciate  the  problem  with  sufficient  clearness  to 
enable  him  to  furnish  unbiased  observations  of  the  greatest  value  and  to 
give  to  his  patients  the  benefit  of  the  most  advanced  scientific  knowledge. 
Since  upon  diet  more  than  upon  any  other  single  factor  depends  the  health 
of  the  community,  it  behooves  every  physician  to  give  to  this  subject  his 
closest  attention.  In  fully  one-half  of  the  patients  he  is  called  upon  to 
treat,  indigestion  plays  a  most  important  role,  and  this  may  be  traced  to 
improper  food,  improper  methods  of  preparation,  or  to  faulty  habits  of 
eating.  The  real  difficulty  is  less  with  the  profession  than  in  getting  the 
public  to  carry  out  certain  plain  and  well-recognized  rules.  The  Yale 
studies  bring  into  prominence  the  importance  of  new  views  which  will 
appeal  strongly  to  physicians  who  have  long  held  that  we  all  take  too 
much  food  and  particularly  too  much  meat.  From  the  important  section 
on  Metabolism  by  Professors  Chittenden  and  Mendel  the  practitioner  will 
get  the  scientific  data  upon  which  he  may  base  rational  plans  of  dietetic 
treatment  in  many  diseases,  and  much  information  of  the  greatest  use  in 
his  incessant  propaganda  against  the  gastronomic  follies  of  the  public. 
In  these  and  in  other  sections  the  authors  will  be  found  to  have  simplified 
the  abstruse  and  complicated  knowledge  of  the  chemical  laboratories, 
and  to  have  presented  it  in  a  form  readily  assimilable  by  the  men  who 
have  to  use  it.  Such,  I  believe,  is  the  chief  function  of  a  system  of 
medicine. 

VI. 

It  cannot  be  too  often  or  too  forcibly  brought  home  to  us  that  the  hope 
of  the  profession  is  with  the  men  who  do  its  daily  work  in  general  practice. 
Our  labors  are  in  vain — all  the  manifold  contributions  of  science,  the 
incessant  researches  into  the  complex  problems  of  life,  normal  and  per- 
verted, the  profound  and  far-reaching  conclusions  of  the  thinkers  and 
originators — all  these  are  Nehushtan,  sounding  brass  and  tinkling  cymbals, 
unless  they  result  in  making  men  better  able  to  fight  the  battle  against 
disease,  better  equipped  for  their  ministry  of  healing.     Gradually,  often 


XXX  INTRODUCTION 

insensibly,  tiie  practical  advances  of  the  laboratory  and  of  the  hospital 
reach  the  men  Avith  whom,  after  all,  rests  the  final  testing  of  all  onr  efforts. 
The  work  in  practical  sanitation,  the  last  word  in  the  prevention  of  disease, 
the  carrying  ont-  new  methods  of  treatment,  the  exchange  of  the  old 
accoutrements  for  the  new  weapons  and  the  new  methotis  of  warfare, 
these  rest  with  the  rank  and  file  of  the  jirofession  who  make  efi'ective  and 
translate  into  practice  the  new  knowledge. 

The  medical  journals,  the  medical  societies,  the  post-graduate  schools 
all  help  in  this  good  work,  and  both  the  profession  and  the  public  now 
appreciate  how  im])ortant  it  is  that  ])hysicians  should  keep  well  abreast  of 
the  times.  The  difficulty  lies  often  with  the  individual  men  who  fall  into 
routine  and  slovenly  habits  of  practice,  and  who  never  get  more  than  a 
superficial  smattering  of  the  science  and  of  the  art  of  medicine.  Even 
the  most  industrious  and  ambitious,  absorbed  in  a  limited  field,  find  it 
hard  to  get  new  life  into  the  old  material,  and,  confronted  on  all  sides  by 
difficult  jjroblems  which  press  for  solution,  they  turn  for  aid  to  the  men 
who  have  made  these  problems  their  special  study,  and  it  is  in  such 
works  as  the  present  that  these  teachers  and  workers  embody  or  codify, 
so  to  speak,  the  current  knowledge  of  the  day. 

After  all,  the  important  question  for  each  young  man  to  ask  himself  as 
he  begins  practice  is :  How  can  I  carry  on  my  education  so  as  to  get  the 
best  possible  returns  out  of  life  and  do  the  best  that  is  in  my  power  for 
my  fellow-creatures  ?  There  are  several  cardinal  defects  which  stand  in 
the  way  of  the  evolution  of  the  sound  clinical  practitioner:  Lack  of 
preliminanj  practical  training.  The  medical  curriculum  is  not  yet  so 
arranged  as  to  give  our  young  men  enough  clinical  work  in  their  senior 
years.  So  full  and  complicated  has  the  course  become  that  it  is  very 
hard  for  the  teachers  to  adjust  it  to  the  new  conditions.  We  ask  too  much, 
and  expect  too  much,  of  the  student;  bvit  if  we  could  have  him  properly 
prepared  at  the  schools  and  colleges,  if  everywhere  the  preliminary 
sciences  were  taught  outside  the  medical  school,  there  would  be  no  diffi- 
culty in  giving  a  man  in  four  years  a  good  start  in  his  profession,  and  this 
is  all  that  the  best  of  teachers  in  the  best  of  medical  schools  can  do 
for  him.  In  our  well-organized  physiological,  anatomical,  histological, 
embryological,  chemical  (physiological),  pharmacological,  and  patho- 
logical laboratories  the  teaching  has  become  more  and  more  thorough 
and  practical,  but  when  we  come  to  the  "bread  and  butter"  subjects  we 
are  not  always  prepared  to  give  teaching  of  the  same  character.  The 
hospitals  and  dispensaries  are  numerous  enough,  and  there  is  no  lack 
of  patients ;  but  there  is  not  that  constant,  close,  personal  contact  of  student 
with  patient  in  which  alone  the  art  of  medicine  can  be  learned.  There 
is  not  that  control  of  hospitals  by  the  universities  necessary  to  ensure 
proper  facilities  for  students,  nor  are  the  arrangements  of  the  hospitals 
always  such  as  to  meet  the  demands  of  modern  clinical  Avork.  There  is 
still  too  much  theoretical  Teaching  for  senior  students,  and  in  a  majority 
of  the  schools  the  number  of  teachers  in  medicine,  surgery,  obstetrics  and 
the  specialties  is  wholly  inadequate.  In  only  a  few  hospitals  is  the  out- 
patient department  arranged  for  clinical  teaching,  and  the  clinical 
laboratory  is  not  everywhere  recognized  as  a  .tine  qua  von.  If  we  could 
turn  our  third  and  fourth  year  students  into  the  hospitals  and  make  them 
part  and  parcel  of  its  machinery  (just  as  much  as  the  nurses  who  have 


THE  EVOLUTION  OF  INTERNAL  MEDICINE  xxxi 

usurped,  I  fear,  some  of  their  duties,  and  have  advantages  that  they  do 
not  possess)  we  eould  give  them  at  least  a  good  introduction  to  their  Hfe- 
work;  and  a  man  could  enter  upon  practice  with  a  rational  outlook  on 
disease,  and  be  prepared  to  continue  his  education  with  the  help,  not  at 
the  expense,  of  the  public.  But  all  this  is  changing  rapidly,  and  year  by 
year  the  men  who  leave  our  schools  are  better  educated  and  in  every  way 
better  fitted  to  practise  medicine  intelligently.  Lack  of  critical  jndgment 
is  another  serious  obstacle  in  the  way  of  the  young  man.  It  is  hard  to 
get  life's  spectacles  adjusted,  so  hard  to  get  clear  vision,  where  so  much 
is  obscure.  The  faculty  of  "right  judgment  in  all  things"  is  granted  to 
few  men,  but  the  physician  to  be  of  any  value  must  at  least  aspire  to  that 
round-about  common  sense  which  was  so  distinguishing  a  feature  in 
Sydenham.  It  may  be  cultivated,  but  with  caution,  as  it  is  one  of  the 
virtues  more  readily  acquired  when  not  too  consciously  sought.  Slow 
of  growth,  and  the  fruit  of  a  seasoned  experience,  good  clinical  judgment 
only  comes  with  careful  study,  and  is  best  seen  in  men  who  appreciate 
the  value  of  thoroughness  in  their  work.  The  mental  attitude  controls 
the  course  of  a  man's  evolution  as  a  clinical  physician.  While  nothing 
can  be  more  fatal  than  a  cold  Pyrrhonism  in  which  everything  is  doubted, 
in  the  midst  of  so  much  credulity,  lay  and  professional,  it  is  well  for  the 
young  man  to  take  as  a  motto  the  saying  of  that  wise  old  pre-Hippocratic 
poet-physician,  Epicharmus,  of  Syracuse:  "Be  sober  and  distrustful; 
these  are  the  sinews  of  the  understanding."  Credulity  is  of  the  very 
essence  of  human  nature  and  we  physicians  are  not  exempt  from  the 
common  lot.  Our  work  is  an  incessant  collection  of  evidence,  weighing 
of  e'/idence,  and  judging  upon  the  evidence,  and  we  have  to  learn  early 
to  make  large  allowances  for  our  own  frailty,  and  still  larger  for  the 
weaknesses,  often  involuntary,  of  our  patients.  The  history  of  medicine 
is  full  of  instances  of  self-deception  on  the  part  of  the  best  of  men,  and  it 
is  well  that  the  young  man  should  at  the  outset  be  humble,  as  he  is  not 
likely  to  escape  altogether.  Science  has  done  much  in  revolutionizing 
mankind,  but  man  remains  the  same  credulous  creature  as  he  has  been 
in  all  ages.  Tar-Avater,  Perkin's  tractors,  laying  on  of  hands,  Christian 
Science,  Lourdes,  and  the  other  miracle-working  shrines  illustrate  the 
deep,  intense  credulity  from  which  science  has  not  yet  freed  mankind  and 
is  not  likely  to  do  so.  It  is  an  aspect  of  human  nature  which  we  must 
accept  and  sometimes  utilize,  remembering  the  remark  of  Galen:  "He 
cures  the  greatest  number  in  whom  most  men  have  most  faith." 

It  is  for  the  practitioner  to  make  the  new  facts  of  science  efficient  and 
useful,  to  translate  science  into  practice  Often  a  very  prolonged  affair 
from  inherent  difficulties  connected  with  the  complicated  mechanism 
of  man's  body,  this  is  sometimes  a  source  of  discouragement,  and  we 
hear  complaints  of  the  slowness  of  progress  in  medicine,  and  of  the 
inability  of  physicians  at  once  to  turn  to  practical  account  some  striking 
discovery.  The  history  of  science  teaches  us  that  it  takes  many  years 
from  the  announcement  of  the  fact  to  its  full  application.  From  Faraday's 
work  on  electromagnetic  induction  to  the  making  of  dynamos  for  com- 
mercial purposes  was  a  longer  period  than  from  Claude  Bernard's 
discovery  of  internal  secretion  to  the  successful  treatment  of  a  case  of 
myxoedema  with  thyroid  extract.  In  making  a  new  application  of  science 
the  stages  are  well  defined.     First  there  is  the  discovery  of  the  phenom- 


xxxii  IXTRODUCTION 

enun  cajjuhle  of  utili/.atiuii.  Then  comes  an  inventor  who  recognizes 
the  jK).s.sibihty  of  its  practical  a])plication.  He  may  require  the  help  of 
a  skilled  engineer  who  correlates  the  commercial  and  manufacturing 
conditions  to  be  dealt  with;  and  finally  there  is  the  capitalist  who  furnishes 
the  means  to  make  the  invention  of  practical  utility.  In  the  science  of 
medicine,  to  make  efficient  in  everv-day  practice  the  ne^v  discoveries 
regarding  the  functions  of  the  body  and  the  phenomena  of  disease  is  a 
very  difficult  matter.  There  is  much  knowledge  which  cannot  always 
be  made  helpful.  It  may  add  to  the  clearness  of  the  clinical  picture  and 
enable  us  perluips  to  recognize  the  nature  and  state  of  a  disease  without 
benefiting  in  the  slightest  the  poor  victim  of  it.  A  knowledge  of  the 
structure  and  of  the  fimctions  of  the  motor  paths  may  be  of  no  use  whatever 
in  a  case  of  com))lete  destruction  by  a  clot  in  the  internal  capsule;  but  in 
the  very  next  case,  one  of  syphilis  of  the  brain,  or  in  one  of  tumor  of  the 
cord,  in  the  full  utilization  of  this  same  knowledge  may  rest  the  issues 
of  life  and  death.  Just  as  in  the  mechanical  sciences,  it  takes  a  combina- 
tion of  human  activities  in  several  stages  of  effort  to  reap  the  benefit  of 
any  discovery,  so  it  is  in  medicine.  The  anatomist,  the  physiologist,  the 
]iathologist,  the  clinician,  and  the  surgeon — in  as  many  stages  as  from 
Faraday's  discovery  of  electromagnetic  induction  to  the  manufacture  of 
a  dynamo — all  had  to  combine  before  a  brain  tumor  could  be  removed 
successfully.  Between  Claude  Bernard's  discovery  of  internal  secretion 
and  the  cure  of  a  case  of  myxoedema  every  department  of  medicine  was 
taxed.  To  be  exploited  prematurely  in  practice  is  the  common  fate  of 
all  new  scientific  facts.  Not  content  to  wait  for  full  knowledge,  men 
hastily  draw  conclusions  from  imperfect  data.  Consider  the  dross  with 
A\hich  the  ]:)in-e  gold  of  Claude  Bernard's  discovery  has  been  mixed  in  an 
organotherapy  often  as  irrational  as  that  practised  in  tlie  middle  ages. 


VII. 

Intertwined  as  the  subject  is  wath  the  complicated  sciences  of  physiology, 
organic  chemistry,  and  physics,  to  make  sol  d  contributions  to  clinical 
medicine  we  must  systematize  the  work  much  more  than  has  hitherto 
been  possible.  The  trustees  and  managers  of  hospitals  should  apj^reciate 
more  fully  than  they  do  at  present  the  scientific  needs  of  these  institutions. 
To  do  justice  to  the  patients,  to  carry  out  modern  lines  of  treatment, 
indeed,  to  diagnosticate  skilfully,  require  now  the  assistance  of  trained 
laboratory  workers  who  should  form  part  of  the  staff.  It  is  impossible 
for  any  man,  no  matter  how  industrious,  to  keep  abreast  at  all  points 
Avith  tlie  chemical  and  bacteriological  technique.  Two  important  changes 
are  necessary  before  hospitals  are  in  a  position  to  do  the  best  possible 
work  in  clinical  medicine: 

First,  in  many  institutions  the  number  of  attending  physicians  should 
be  reduced.  In  small  hospitals  of  a  total  capacity  of  one  hundred 
and  fifty  beds  the  medical  w'ards  should  be  placed  in  charge  of  one  man. 
In  the  larger  city  hospitals  separate  medical  services  should  be  arranged 
w'ith  from  sixty  to  one  hundred  beds  in  each.  The  profession  should  learn 
to  recognize  the  worker  in  internal  medicine  as  a  man  wdio  has  to  devote 
so  much  time  to  his  studies  that  it  is  impossible  for  him  to  take  general 


THE  EVOLUTION  OF  INTERNAL  MEDICINE      _     xxxiii 

practice,  and  in  a  way  he  is  a  specialist,  in  the;  broad  sense  of  (he  term, 
like  the  surgeon.  The  development  of  clinical  medicine  is  retard(;fl  hy 
the  present  system  of  appointing  genc^ral  practitioners,  often  the  busiest 
and  most  successful  men,  in  charge  of  the  wards.  Ntjwadays  only 
under  exceptional  circumstances  does  a  man  of  energy  and  perseverance 
evolve  from  these  surroundings  into  a  thoroughly  trained  clinical  investi- 
gator. In  saying  this  I  do  not  forget  that  from  these  conditions  arose 
the  very  men  who  have  contributed  most  to  medicine  in  America,  men 
of  the  stamp  of  W.  W.  Gerhard,  Austin  Flint,  Da  Costa  and  Pepper. 
But  the  times  are  changing,  and  I  know  that  I  express  the  feelings  of 
hospital  physicians  themselves  when  I  state  that  a  reorganization  is 
urgently  demanded  along  the  lines  here  indicated.  Not  only  in  the 
larger  cities,  but  in  towns  of  from  fifty  to  one  hundred  thousand  inhaljitants 
the  well-equipped  medical  clinic  is  the  most  urgent  need  of  the  profession. 
Secondly,  the  internal  organization  of  the  hospitals  must  be  changed 
to  meet  the  new  demands.  A  larger  number  of  house  physicians  is 
required,  who  should  be  graded  so  that  raw,  inexperienced  graduates 
should  not  be  put  at  once  in  full  charge  of  patients.  A  clinical  laboratory 
with  chemical  and  bacteriological  assistants  should  be  provided  for  each 
service,  or,  in  the  smaller  hospitals,  one  would  suffice  for  all  departments. 
This  need,  now  generally  recognized  for  hospitals  connected  with  medical 
schools,  is  of  equal  importance  in  the  smaller  hospitals.  An  example  of 
what  organization  can  do  in  this  direction  is  afforded  by  the  remarkable 
clinic  which  has  been  built  up  in  Rochester,  Minnesota,  by  the  Mayo 
brothers,  who  have  made  that  little  town  a  world-known  resort  for  both 
physicians  and  surgeons,  and  whose  success  has  been  due  as  much  to  their 
careful  attention  to  the  laboratory  side  of  their  work  as  to  the  technique  for 
which  they  have  become  so  famous. 

Lastly,  my  earnest  hope  is  that  this  series  of  volumes  may  be  of 
service  in  that  education  which  each  one  of  us  has  to  work  out  for  himself  in 
practice.  Set  on  the  right  path  in  the  schools  it  should  not  be  difficult  for  a 
man  to  keep  in  touch  with  the  advances  of  science,  and  to  give  his  patients 
the  benefit  of  all  those  accessories  which  are  so  important  in  the  recog- 
nition and  successful  treatment  of  disease.  Just  as  the  clinical  laboratory 
is  a  necessity  to  the  hospital  physician  engaged  in  the  solution  of  the  most 
advanced  problems  in  medicine,  so  the  private  laboratory  is  indispensable 
in  the  every-day  work  of  the  busy  practitioner.  Urine  analysis,  blood 
counts,  sputum  examinations,  chemical  analysis  of  stomach  contents,  all 
these  should  be  done  at  home:  at  first,  by  the  physician  himself,  while  not 
too  busy;  later  by  an  assistant.  This  may  seem  to  be  asking  a  great  deal 
in  the  heavy  routine  of  the  day,  but  it  is  not  asking  too  much,  and  it  will  be 
done  more  and  more  when  we  send  out  our  students  familiar  by  long  prac- 
tice with  the  use  of  the  microscope  and  other  instruments  of  precision.  It 
makes  the  practice  of  medicine  of  absorbing  interest  when  one  feels  he 
is  approaching  the  study  of  a  case  equipped  with  modern  methods,  and 
it  is  the  neglect  of  these  accessories  that  makes  so  many  men  fall  into  slip- 
shod habits  of  diagnosis,  and  still  more  careless  methods  of  treatment. 
Asked  the  single  most  powerful  weapon  today  in  the  hands  of  the  pro- 
fession against  quackery  of  all  sorts,  I  would  answer:  the  little  laboratory 
room  attached  to  the  office  of  the  general  practitioner.     Nor  is  it  asking 


xxxiv     .  IXTRODUCTION 

the  impossible.  I  know  many  busy  men  who  utihze  to  the  full  all  these 
resources  of  our  art.  1  would  like  to  call  the  attention  of  my  colleagues  to 
the  papers  on  this  question  by  my  friend,  M.  H.  Fussell,'  of  Philadel- 
phia. Nor  is,  it  impossible  in  general  practice  to  become  an  active  and 
valued  contributor  to  the  literature  of  the  j)rofcssion.  It  should  not  be 
forgotten  that  Robert  Koch  was  a  district  physician  when  he  made  his 
memorable  researches  upon  anthrax.  One  of  the  most  distinguished 
scholars  of  his  day  was  Robert  Adams,  a  village  surgeon. 

The  young  physician  should  not  be  disturbed  by  the  thought  that  it 
requires  special  abilities  to  rise  superior  to  one's  environment.  It  is 
the  average  man  with  a  set  and  steady  determination  to  equip  himself 
at  all  points  who  is  more  likely  to  succeed  than  any  other.  The  way 
is  open  to  all.  For  those  whose  training  in  the  medical  school  has  been 
defective  the  post-graduate  school  is  available,  and  a  month  or  two 
every  few  years  s])ent  at  a  good  hospital  and  in  laboratory  work  add  to 
a  man's  mental  capital  and  make  him  of  greater  value  to  the  public  and 
to  his  colleagues. 

It  is  astonishing  how  much  there  is  in  the  daily  round  if  men  would 
but  keep  the  open  mind  and  look  upon  life  as  a  progressive  education. 
The  times  have  changed,  and  we  have  travelled  far  from  the  days  when 
the  father  of  medicine  jotted  down  his  notes  upon  fever  cases  in  Abdera 
and  elsewhere.  We  know  more  and  enjoy  larger  opportunities,  and  with 
them  have  greater  responsibilities,  but  could  Hippocrates  return  he  would 
find  no  change  in  those  essential  duties  in  which  he  is  still  our  great 
exemplar.  They  are  four:  so  to  study  our  cases  as  to  acquire  facility 
in  the  art  of  diagnosis,  which  must  everywhere  precede  the  rational 
treatment  of  disease;  so  to  grow  in  critical  judgment  that  we  may  learn 
to  appreciate  the  relative  value  of  the  symptoms  and  physical  signs,  and 
give  to  the  patient  and  to  his  friends  a  forecast  or  prognosis;  so  to  conduct 
the  treatment  that  the  patient  may  be  restored  to  health  at  the  earliest 
possible  period,  or,  failing  that,  be  given  the  greatest  possible  measure  of 
relief,  whether  by  drugs,  the  action  of  which  he  should  carefully  study,  so 
as  to  have  a  strong  and  abiding  faith  in  those  which  have  been  tried  and 
not  found  wanting,  by  diet,  by  exercise,  or  by  all  the  physical  means  avail- 
able, and  often  by  the  exercise  of  his  own  strong  personality;  and,  lastly, 
so  to  arrange  sanitary  and  hygienic  measures  that,  wherever  possible,  dis- 
ease may  be  prevented.  Could  Hippocrates  meet  again  a  class  of  students 
at  some  modern  Cos,  and  discuss  the  changes  which  twenty-five  centuries 
had  wrought,  he  would  dwell  upon  this  latter  development  of  the  science 
and  of  the  art  as  the  crowning  benefit  which  the  profession  has  bestowed 
upon  the  race,  and  he  would  repeat  again  those  noble  Avords  which  have 
found  in  this  triumph  their  practical  realization:  To  serve  the  art  of 
medicine  as  it  should  be  served,  one  must  love  his  fellow-men. 

1  The  University  Medical  Magazine,  1891,  1896,  1898,  1900.  The  Journal  of 
the  American  Medical  Association,  1901,  1902.  The  Philadelphia  Medical 
Journal,  1901,  1902. 


PART  I. 
HEREDITY  AND  PREDISPOSITION. 


CHAPTER  I. 

INHERITANCE  AND  DISEASE. 
By  J.  G.  ADAMI,  M.  A.,  M.D.,  F.R.S. 

It  is  difficult  to  realize  that  the  essential  nature  of  procreation  has  been 
known  to  us  for  scarce  a  generation.  That  the  conjugation  of  the  two 
parents  is  essential,  was  obvious  ab  ovo;  that  there  resulted  from  that  union 
an  individual  possessing  characteristics  referable  to  both  parents,  was 
equally  clear;  nay,  more:  it  was  well  known  that  characters  not  pro- 
nounced in  the  parents  but  traceable  to  an  earlier  generation  on  either  side 
could,  not  infrequently,  be  made  out.  But  why  this  should  be,  remained  a 
profound  mystery.  True  it  is  that  Leeuwenhoeck,  in  1677,  demonstrated 
the  existence  of  spermatic  filaments  in  the  seminal  fluid  of  various  ani- 
mals, yet  for  close  on  two  centuries  the  part  played  by  these  spermatozoa 
was  a  matter  of  debate.  Only  in  1852  was  it  clearly  established  that  the 
spermatozoon  penetrates  the  envelope  of  the  ovum;  only  in  the  "seven- 
ties" was  it  determined  through  the  researches  of  Van  Beneden  (1875) 
and  later  by  those  of  Strassburger,  O.  Hertwig,  Fol,  and  Boveri,  that 
the  changes  following  the  entrance  of  the  spermatozoon  into  the  ovum, 
centre  round  the  fusion  of  the  nuclear  material  of  the  one  with  that 
of  the  other,  and  that  from  the  moment  of  this  fusion  dates  the  beginning 
of  the  life  history  of  a  new  individual. 

Stated  in  the  simplest  terms,  the  new  individual  is  the  result  of  the  union 
of  a  single  cell  from  the  male  parent  with  a  single  cell  from  the  female. 
These  two  cells  are  in  their  turn  the  derivatives  of  cells  which,  from  a  very 
early  period  of  embryonic  life,  can  be  seen  to  have  been  segregated  for  re- 
productive purposes,  and  apparently  for  nothing  else.^    The  individual 

^  Recent  studies  by  Bouin  and  Ancel  demonstrate  that  the  internal  secretion  of 
the  testicles,  and  the  influence  which  the  presence  of  this  again  exerts  upon  the 
general  metabolism,  is  connected  not  with  the  germinal  epithelium  (the  cells  of  the 
tubules),  but  with  certain  characteristic  interstitial  cells  lying  between  the  tu- 
bules. For  a  very  clear  resume  of  the  extent  to  which  the  germ-cells  are  thus  segre- 
gated from  an  early  period  in  the  different  genera  of  animals,  see  Bigelow's  article 
on  "  Heredity ," Buck' s  Reference  Hand-hook  of  the  Medical  Sciences,  4,  '02,  650. 
2  17 


18  HEREDITY  AND  PREDISPOSITION 

ova  already  exist  at  birth,  and  lie  latent,  or  at  most  very  slowly  increase 
in  size  until  close  upon  the  time  when  they  are  to  be  discharj^ed.  The 
spermatozoa  similarly  are  derived  from  cells  of,  apparently,  a  simple  un- 
ditt'ercntiated  tvj^e,  and  are  developed  from  these  shortly  before  they  are 
discharged.  In  other  words,  neither  ovum  nor  spermatozoon  is  the 
result  of  a  piecing;  toijcthcr  of  contributions  from  the  various  tissues  and 
organs  of  the  body;  neither  is  a  microcosm — a  microscopic  representa- 
tion of  the  adult  organism.  They  arc  not  pangenctic;  both  are  derived 
from  the  germinal  tissue,  which  is  evidently  set  apart  from  the  first,  so  as 
not  to  be  subjected  to  the  performance  of  functions  other  than  those  of 
reproduction.  The  only  functions  we  can  recognize  as  performed  by 
them,  prior  to  their  liberation,  arc  assimilation  and  growth,  and,  in  the 
case  more  particularly  of  the  male  germ-cells,  concomitant  multiplication. 
When  we  come  to  study  the  details  of  the  process  of  fusion  we  find 
that  while  the  cell-substance  of  the  fertilized  ovum  is  contributed  by  the 
female  cell  and  the  centrosome'  by  the  male,  the  one  constituent  contrib- 
uted with  a  remarkable  quantitative  equality  Ijy  both  cells,  is  the  nuclear 
material,  or  chromatin.^  So  striking,  in  fact,  are  the  preparatory  changes 
in  connection  with  the  nucleus  of  each  cell,  so  elaborate  the  coidredanse 
which  precedes  the  fusion  of  the  nuclear  materials  of  the  two  cells,  that 
no  other  conclusion  is  possible  than  that  here  in  this  fusion  of  nuclear 
material  is  the  central  act  of  sexual  reproduction;  and  once  we  accept — 
as  we  are  forced  to  accept — that  there  may  be  equally  and  interchange- 
ably inheritance  of  features  peculiar  to  either  parental  stock,^  we  are 

'  E.  B.  Wilson  and  Naohide  Yatsu  ha^•e  brought  fonvard  positive  proof  that  the 
centrosome  is  not  of  nuclear  origin,  hut  can  be  reformed  in  the  cytoplasm  of  cells 
deprived  of  their  nuclei  (Proc.  8oc.  Exp.  Biology  and  Medicine;  American  Medi- 
cine, 1905,  p.  493). 

^  To  this  statement  a  reservation  must  be  noted  as  the  result  of  the  recent 
studies  of  Ilenking,  Montgomery,  McClung  of  Kansas,  and  E.  B.  Wilson.  Among 
hemipterous  insects  the  sperm  mother  cells  give  rise  to  spermatocj'tes  of  two 
orders,  so  that  in  certain  species  one-half  of  the  future  spermatozoa  recei\'e  an 
"accessory"  chromosome;  in  other  species  what  is  a  peculiarly  large  chromosome 
in  the  one  set  of  cells  is  represented  by  a  minute  chromosome  in  the  other.  The 
ova  of  these  insects  in  their  development  exhiliit  no  such  difference.  As  McClung 
first  noted  {Biological  Bulletin  3,  1902,  43)  the  only  distinction  which  separates 
the  resultant  fertilized  cells  into  two  approximately  equal  groups  is  sex,  and  we 
are  logically  forced  to  the  conclusion  that  the  peculiar  chromosome  has  some 
liearing  upon  this  differentiation.  The  distinction  has  thus  far  been  established 
for  the  hemiptera  alone.  In  other  insects  (Aphides)  two  types  of  ova  have  been 
noted  gi\'ing  rise  to  male  and  female  respectively.  Thus  it  is  not  yet  possible  to 
make  any  general  statement  regarding  differentiation  of  chromosomes  and  the 
determination  of  se.x.  Even  in  these  cases  it  is  but  one  or  an  uneven  pair  out  of 
the  .series  of  chromosomes  that  is  implicated;  sets  of  chromosomes  of  varying 
size  and  shape  are  to  be  recognized  in  the  nuclei  that  undergo  fusion,  and  these 
pair  with  remarkable  accuracy  {Vide  Arnold  and  Moore,  Proceedings  of  the  Royal 
Society,  Series  B.,  77,  1906,  .563). 

^  The  most  striking  example  of  this  equality  of  the  male  and  female  elements  is 
contained  in  the  observations  of  von  Giirtner  (confii-med  by  Mendel  and  others) 
upon  the  hybridization  of  peas,  in  which  by  the  cross-fertilization  of  two  differ- 
ent species  ("A"  and  "B")  it  was  found  that  identical  hybrids  were  produced 
whether  the  pollen  of  A  was  employed  to  fertilize  the  egg-cells  of  B,  or  the  pollen 
of  B  to  fertilize  the  egg-cells  of  A.  It  is  true  we  do  not  get  this  happening  among 
mammals.  Your  mule,  the  offspring  of  a  jackass  and  a  mare,  is  a  different  animal 
from  the  hinny  or  jennet,  the  offspring  of  a  stallion  and  a  jennj^-ass;  but  here  it 
must  be  recalled  that  the  inter-uterine  development,  within  the  donkey  and  the 
mare  respectively,  must  materially  modify  the  progeny  in  these  two  cases. 


INHERITANCE  AND  DISEASE  19 

forced  to  conclude  that  what  is  inherited  is  contained  in,  and  carried  by, 
the  nuclear  chromatin.  From  this  it  follows  surely  that  the  only  con- 
ditions which  are  capable  of  being  inherited,  are  conditions  which  have 
told  upon  and  modified  the  nuclear  material  of  the  germ-cells  of  either 
parent  prior  to  or  at  the  moment  of  fusion.  It  is  at  that  moment  of  fusion 
that  the  new  individual  begins  its  existence.  Any  influence  acting  upon  and 
modifying  it  after  this  moment  is  something  acquired  by  what  is  already  a 
separate  entity;  it  is  not  inherited. 

Starting  from  this  basis,  and  for  the  nonce  accepting  Virchow's  dictum 
that  every  departure  from  the  normal  in  the  individual  is  to  be  regarded 
as  a  pathological  condition,  we  are  led  to  classify  all  pathological  condi- 
tions (including  variations,  modifications,  and  actual  conditions  of  dis- 
ease) into: 

(1)  Inherited  conditions — 

a.  Derived  from  the  male  parental  stock. 

b.  Derived  from  the  female  parental  stock. 

c.  Due  to  fusion  and  interaction  of  the  two  nuclear  materials. 

(2)  Acquired  conditions — 

a.  Of  ante-natal  acquirement. 

b.  Of  parturient  acquirement. 

c.  Of  post-natal  acquirement. 


CONDITIONS   MISTAKENLY  REGARDED  AS  INHERITED. 

And  now  to  clear  the  ground.  It  is  obvious  from  the  above  that  many 
conditions  commonly  described  as  inherited  are  of  ante-natal  acquire- 
ment. Yet  other  conditions  presuppose  influences  at  work  on  the  nuclear 
matter  of  the  germ-cells  of  either  parent  which  by  no  mental  effort  we  can 
conceive  as  bringing  about  the  declared  results.  It  will  be  well  to  dismiss 
all  these  before  passing  on  to  consider  the  conditions  truly  inherited. 

Maternal  and  Paternal  Impressions.— The  belief  in  these  as  causes 
of  local  bodily  disturbances  has  not  wholly  died  out,  and  in  the  United 
States,  as  McMurrich  indicates,^  judging  from  the  relative  amount  of 
literature  on  the  subject,  it  dies  a  hard  death.  Even  could  we  accept  the 
view  that  through  the  influence  of  the  maternal  nervous  system — for  it 
could  under  the  circumstances  only  be  by  this — conditions  affecting  one 
area  of  the  maternal  organism  could  reproduce  themselves  upon  the 
corresponding  area  in  the  offspring,  the  overwhelming  majority  of  the 
cases  cited  are  clearly  not  examples  of  inheritance;  for  in  that  majority, 
studying  the  histories  given,  the  maternal  impression  has  occurred  after 
conception,  and  most  often  after  the  second  month  of  pregnancy;  i.e., 
the  period  when  the  offspring  passes  from  the  embryonic  to  the  foetal 
stage,  when  already  the  different  organs  have  received  their  outline  and 
are  recognizable  as  such. 

Of  maternal  and  paternal  impressions  stated  to  have  been  in  action 
prior  to  fertilization,  the  recorded  instances  are  few  and  far  between.  The 
locus  classicus  is  Jacob's  stratagem  to  increase  his  flock  of  ring-straked, 

^McMurrich:  The  Physician  and  Surgeon,  (Ann  Arbor,)  January,  1905.  For 
full  studies  of  this  subject  see  also  Tartuffi,  Storia  delta  Teratologia  Bologna;, 
1881-1894;    and  Ballantyne,  Trans.  Edin.  Obstetr.  Soc  ,  21,  1896. 


20  HEREDITY  AND  PREDISPOSITION 

spotted  and  speckled  sheep  and  goats  at  the  expense  of  Laban,  his  father- 
in-law.  The  most  recent  instance  that  has  come  to  our  notice  is  that  of  a 
well-known  Aberdeen  breeder  of  shorthorns,  who  is  convinced  that  his 
failure  during  a  recent  season  to  obtain  calves  having  the  proper  marking 
— all  those  cast  showing  a  patch  of  white  on  the  flank — was  due  to  the  fact 
that  instead  of  the  bull  serving  the  cow  in  the  obscurity  of  the  byre,  for  a 
time  service  was  conducted  in  the  yard  where  the  family  washing  was 
hung  out  to  dry.  The  cases  upon  record,  in  short,  are  so  rare,  and  the 
causes  adducecl  so  bizarre,  that  even  if  we  accept  the  histories  given,  it  is 
unnecessa-ry  to  discuss  possibilities.  The  cases  are  not  more  frequent  than 
would  occur  under  the  law  of  chance — a  law  too  often  neglected  in  seeking 
for  an  explanation  of  rare  conditions.  But  if  this  does  not  satisfy,  it  may 
be  asked  by  what  conceivable  means  can  a  visual  impression  affecting 
either  parent  at  the  time  of  conception,  influence  either  spermatozoon  or 
ovum,  when  both  have  become  free  cells,  liberated  from  organic  connec- 
tion with  the  parental  organisms?  There  is  this  difference  between  the 
domestic  animals  and  man,  that  in  the  latter,  conjugation  occurs  irrespec- 
tive of  periods  of  the  dehiscence  of  the  ova,  and  these,  therefore,  may  still, 
in  the  female,  have  loose  organic  connection  with  the  parental  organism. 
Even  then  it  maybe  asked,  how  can  preconceptional  nerve  stimuli  in  the 
mother  so  aiter  the  mole-cular  arrangement  of  the  nuclear  material  of  an 
individual  ovum  as  to  induce  a  minute  specific  difference  in  the  progeny? 

The  Non-inheritance  of  Mutilations. — It  is  obvious  from  the  prem- 
ises laid  down  that  gross  mutilations  of  the  limbs  or  trunk  of  either  parent 
cannot  reproduce  themselves  in  the  offspring;  and  as  a  matter  of  fact, 
every  experiment  made  with  due  regard  to  scientific  accuracy  demon- 
strates that  this  is  the  case.  One  may,  following  Weismann,  cut  off  the 
tails  of  twenty  successive  generations  of  long-tailed  mice — cut  them  off 
immediately  after  birth — cut  them  off  not  in  one  but  in  both  parents — 
and  the  twenty-first  generation  will  be  born  with  tails  as  long  and  with 
as  many  vertebrae  as  those  of  the  first. 

These  conclusions  have  been  violently  contested,  and  that  because  the 
Lamarckian  theory  of  evolution  is  based  upon  the  transmission  of  char- 
acters acquired  or  further  developed  by  the  parent— so  that  could  it  be 
found  that  gross  changes  in  the  paternal  and  maternal  organism  were  in- 
herited, it  would  have  to  be  conceded  that  changes  of  all  orders  are  sim- 
ilarly capable  of  inheritance.  Now  it  ic  worthy  of  note  that  not  a  single 
series  of  experiments  has  been  devised  by  the  Lamarckians  which  has 
demonstrated  this  inheritance  of  mutilations.  Individual  cases  they  have 
adduced  in  which  the  offspring,  through  one  or  more  generations,  have 
shown  defects  which  more  or  less  definitely  imitated  the  outcome  of  an 
injury  received  by  one  or  other  parent-member  of  an  earlier  generation. 
But  in  the  absence  of  absolute  experimental  proof,  which,  if  mutilations 
of  any  order  are  transmissible,  ought  to  be  forthcoming  without  difficulty, 
these  isolated  instances  must  again  be  regarded  as  coming  under  the  law 
of  chance. 

Circumcision,  we  know,  has  been  practised  from  time  immemorial  by 
certain  oriental  nations,  and  practised  shortly  after  birth  among  the  Jews, 
according  to  their  history,  for  at  least  six  score  generations;  but  the  males 
are  still  born  with  fully  developed  prepuces.  It  has  been  urged  recently 
as  evidence  of  the  inheritance  of  mutilations  that  a  greater  proportion  of 


INHERITANCE  AND  DISEASE  21 

Jews  are  born  with  shortened  foreskin  and  exposed  glans  than  is  found 
among  nations  which  have  not  practised  this  rite.  This,  however,  is  no 
argument.  The  only  vahd  proof  would  be  afforded  if  it  could  be  demon- 
strated that  the  number  of  naturally  circumcised  Jews  had  been  under- 
going a  steady  increase  during  the  last  thousand  years,  while  no  such 
increase  has  shown  itself  in  an  allied  race  of  the  uncircumcised.  It  may 
indeed  be  suggested  as  eminently  probable  that  circumcision  arose,  not 
primarily  as  a  religious  rite,  but  as  a  hygienic  measure  of  considerable 
importance  in  tropical  and  subtropical  regions,  and,  if  so,  it  must  have 
been  based  upon  not  an  occasional  observation,  but  upon  the  common 
experience  that  those  "naturally  circumcised"  escaped  the  troubles  to 
which  those  having  the  fully  developed  foreskin  were  subjected.  In 
other  words,  cases  of  shortened  foreskin  must  have  been  fairly  frequent 
in  those  races  before  circumcision  came  into  vogue. 

There  is  one  series  of  experiments  that  is  constantly  adduced  in  this 
connection — the  celebrated  observations  of  Brown-Sequard  upon  guinea- 
pigs  rendered  epileptic  by  sundry  injuries  to  the  nervous  system,  the  off- 
spring of  which  were  found,  some  of  them,  to  manifest  epileptic  and  other 
nervous  phenomena.  These  observations  have  been  confirmed  by  one 
group  of  observers  (Westphal  and  Obersteiner),  and  have  been  contra- 
dicted by  others  (Sommer  and  Binswanger).  There  is  no  need  to  enter 
fully  into  these  cases,  because  on  the  face  of  them  they  do  not  enter  into 
the  present  category.  Only  by  a  confusion  of  ideas  are  they  included  as 
evidence  of  the  transmission  of  mutilations  or  injuries.  Epilepsy  is  not  a 
specific  anatomical  injury;  it  is  the  expression  of  a  functional  irritation 
of  the  higher  nervous  centres,  set  up  often  by  injury  at  a  distance — in 
Brown-Sequard' s  cases  by  injury  to  the  sciatic  nerve,  etc.;  and  none  of 
those  who  adduce  these  cases  demonstrate  the  transmission  to  the  off- 
spring of  the  local  disturbances  which  in  the  parent  had  induced  the  epi- 
lepsy. At  most,  these  cases  come  under  the  heading  of  the  inheritance  of 
acquired  functional  modifications,  which  is  quite  another  matter  and  will 
be  discussed  subsequently. 

There  are,  however,  two  instances  recorded  by  Brown-Sequard  which 
have  a  bearing  in  this  controversy  and  cannot  be  passed  over  without 
notice.  He  noted  that  one  of  the  progeny  of  a  guinea-pig,  which  exhibited 
atrophy  of  a  hind  limb  following  upon  section  of  the  sciatic  nerve,  was  born 
with  an  ill-developed  hind  limb,  and  that  similarly  one  of  the  progeny  of 
another  guinea-pig  whose  eye  had  been  destroyed,  suffered  also  from  an 
imperfectly  developed  eye.  I  do  not  doubt  Brown-Sequard' s  veracity— 
that  would  be  absurd;  nor  will  I  pretend  to  explain  these  cases.  I  will  only 
say  that  they  are  at  variance  with  human  experience  and  that  I  cannot 
accept  them  as  examples  of  inherited  mutilations.  Whenever  the  father  or 
the  mother  has  lost  a  limb,  it  is  a  surely  ascertained  fact  that  the  children 
are  born  with  the  full  complement  of  limbs ;  and  similarly  the  accidental 
destruction  of  an  eye  in  man  is  known  to  be  without  effect  on  the  chil- 
dren. Neither  Brown-Sequard  nor  any  one  else  has  been  able  to  repeat 
these  observations  at  will,  or  to  show  how  these  results  can  be  repro- 
duced.    Again  I  must  class  them  as  chance  occurrences. 

Until,  therefore,  some  supporter  of  the  Lamarckian  theory  can  arise 
and  bring  forward  an  experimental  mutilation  upon  one  or  other  animal 
which  is  transmitted  and  reproduces  itself  not  as  an  exception  but  in  a 


22  HEREDITY  AND  PREDISPOSITION 

reasonable  proportion  of  the  offspring  of  the  mutilated  animals,  we  are 
forced  to  adhere  to  the  view  that  7/-t».v.s'  viuiilaiiun.s-  are  not  iransmiiied — and 
what  is  more,  must  urge  that  we  cannot  conceive  any  sucli  transmission. 

The  Non-inheritance  of  Specific  Infectious  Diseases.— Like  con- 
siderations indicate  that  it  is  impossible  for  there  to  be  inlicritance 
proper  of  infectious  diseases.  There  is  no  such  thing  as  inherited  small- 
pox,  inherited  tuberculosis,  or  hereditary  syphilis.  For  consider  what 
such  inheritance  necessitates.  All  infectious  disease,  we  admit  now- 
a-days,  is  brought  about  by  the  growth  of  pathogenic  microorganisms 
within  the  system.  It  is  by  the  nuclear  material  of  the  spermatozoon  and 
of  the  ovum  that  the  ])arental  pro])erties  are  conveyed  to  the  offspring; 
it  is  the  molecular  composition  of  that  nuclear  material  that  controls  the 
organism  of  the  develo})ing  individual.  Granted  that  the  inert  ovum  be- 
fore conception  could  take  up  pathogenic  bacteria — or,  what  is  still  more 
opposed  to  general  })rinciples,  that  the  bacteria  actually  made  their  way 
into  the  ovum;  granted,  again,  that  the  spermatozoon— a  mass  of  nuclear 
material  and  little  more — could  similarly  come  to  contain  a  pathogenic 
microbe :  in  not  one  of  these  cases  would  the  microbes  be  a  part  or  portion 
of  the  heritable  matter;  they  would  but  be  associated.  At  most  the  dis- 
ease would  be  transmitted  "from  parent  to  offspring  by  means  of  the 
germ-cells;  it  would  not  be  strictly  inherited. 

It  may  be  urged  that  this  is  a  refinement  of  logic;  that,  for  practical 
purposes,  it  matters  little  whether  we  have  to  deal  with  inheritance,  or 
transmission  through  the  germ-cells;  that  if  the  father  has  syphilis  and 
the  child  is  born  with  the  disease,  the  fact  stands  evident  that  syphilis  has 
passed  from  the  elder  .to  the  younger  generation;  and  most  assuredly  in- 
fectious diseases  do  thus  pass.  We  think,  however,  that  it  must  be  ad- 
mitted that  there  is  some  advantage  in  realizing  with  a  certain  amount  of 
precision  the  course  of  events  in  such  a  process  of  infection  —  a  certain 
advantage  in  the  correct  employment  of  terms — and  assuredly  the  more 
we  inquire  into  the  data  bearing  upon  the  conveyance  of  tuberculosis  or 
syphilis  from  the  parents  to  their  oft'spring,  the  more  it  is  borne  in  upon 
us  that  even  transmission  by  means  of  the  germ-cells  is  most  doubtful; 
the  facts  at  our  disposal  best  fit  in  with  an  antenatal,  intra-uterine  ac- 
quirement— an  infection  of  the  embryo  or  the  foetus  at  a  later  date. 

Transmission  of  microorganisms  by  the  egg  is  not  unknown  among 
lower  forms  of  life.  It  may  happen  that  the  hen's  egg  is  not  perfectly  ster- 
ile, and  this  in  eggs  that  are  freshly  laid;  the  eggs  of  the  silkworm  may  be 
infected  by  the  organism  of  pebrine  so  that  the  developing  caterpillars  in 
their  turn  are  found  to  exhibit  the  disease;  similarly  there  is  some  evi- 
dence that  the  eggs  of  the  tick  boophilus  carry  within  them  the  piro- 
plasma,  the  organism  of  Texas  fever.  Leaving  aside  the  possibility  in  these 
last  two  cases  that  infection  of  the  interior  of  the  egg  may  occur  at  a  late 
period,  the  germs  being  at  first  outside  the  egg-cases  and  only  subsequently 
gaining  entrance,  it  has  to  be  pointed  out  that  the  eggs  in  all  these  cases 
are  different  from  the  human  and  mammalian  ova.  All  the  above  have  a 
relatively  abundant  yolk  and  food  supply,  in  which  the  microbes  may 
multiply  without  at  first  affecting  the  embryo.  The  human  ovum,  on  the 
contrary,  is  devoid  of  yolk;  the  microbes,  if  present,  would  from  the  first 
be  within  the  cells  of  the  young  embryo,  and  is  it  difficult  to  conceive  such 
intra-cellular  microbes  lying  inert;   difficult  to  imagine  that  they  would 


INHERITANCE  AND  DISEASE  23 

not  set  up  so  serious  a  perversion  of  metabolism  that  if  they  did  not  rap- 
idly destroy  the  embryo,  at  least  they  would  induce  dcveloj)mental  anom- 
alies incompatible  with  eventual  continued  existence.  Baumgarten  and 
others  believing  in  germinal  infection  have  found  it  necessary  to  predi- 
cate a  latency,  or  lying  latent,  of  the  pathogenic  organisms.  When  we 
find  that  the  post-natal  tuberculosis  of  early  infancy  is  characterized  in 
general  by  a  much  more  rapid  infection  and  generalization  than  occur  in 
the  adult,  the  likelihood  that  at  a  yet  earlier  period  the  tubercle  bacillus 
is  arrested  in  its  activities  is  at  most  extremely  slight.^ 

The  observations  of  Schaudinn^  upon  trypanosomes  (halteridium)  and 
leukocytozoa  (spirochsetes)  of  the  stone-owl,  may  possibly  oppose  what  is 
here  said,  for,  according  to  him,  both  these  forms  of  parasitic  protozoon 
may  make  their  way  into  the  eggs  of  their  hosts  (mosquitos) ;  and,  as  re- 
gards the  former,  he  lays  down  that  they  rest  during  the  development  of 
the  young  gnat,  becoming  active  when  the  latter  is  adult  and  begins  to 
suck  blood.  In  both  these  protozoon  forms  the  conditions,  so  far  as  we 
may  see,  differ  from  what  obtains  with  tubercle  bacilli.  In  them  we  are 
dealing  with  species  presenting  a  pronounced  alteration  of  generations, 
and  so  accustomed  to  long  periods  of  rest  before  circumstances  are  favor- 
able for  transmission  to  another  host.  In  the  absence  of  spores  the  exis- 
tence of  anything  like  a  resting-stage  in  the  tubercle  bacillus  is  still 
regarded  as  doubtful,  although,  not  to  be  partial,  it  has  to  be  noted  that  cer- 
tain modern  authorities  describe  minute  gonidial  forms  of  the  bacilli,  and 
these  might  possess  the  property  of  latency.  The  saner  view  is  that  in 
man,  the  infection  of  the  offspring  from  the  mother  is  placental,  and  this 
view  is  supported  by  (1)  the  analogy  of  the  acute  exanthemata;  (2)  the 
absence  of  any  constant  stage  of  tuberculosis  or  syphilis  manifested  at 
birth;  (3)  the  frequent  evidence  of  placental  infection;  and  (4)  the  gen- 
eral nature  of  the  lesions  in  the  offspring.  Acute  exanthemata  attacking 
the  mother  in  the  last  days  of  pregnancy  can  affect  the  child,  which  is 
born  showing  the  acute  lesions  of  the  disease;  here  there  can  be  no  ques- 
tion of  germinal  infection.  Infants  may  be  born  showing  generalized 
and  advanced  syphilis  or  tuberculosis,  or,  on  the  contrary,  may  present 
indications  only  a  week  or  more  after  birth:  this  very  inconstancy  indi- 
cates irregularity  in  the  period  of  infection.  Regarding  the  existence  of 
infective  lesions  of  the  placenta  we  need  say  nothing  here ;  no  one  denies 
their  existence.  Lastly,  as  regards  the  nature  of  the  lesions,  syphilis 
presents  a  specially  instructive  picture.  In  syphilis  of  postnatal  acquire- 
ment the  liver  is  infrequently  involved;  in  11,629  autopsies  at  St. 
George's  Hospital,  extending  over  forty-two  years,  J.  L.  Allen  found 
only  37  cases  of  undoubted  hepatic  gummata,  and  27  cases  in  which 
cicatrices  alone  were  present.  Flexner,  including  also  cases  of  syphilitic 
fibrosis,  found  in  Philadelphia  altogether  88  cases  of  hepatic  syphilis 
in  5,088  autopsies.     In  congenitaP  syphilis  the  liver,   of  all  internal 

^Von  Behring's  recent  theory  that  most  tuberculosis  in  man  is  acquired  in 
infancy  from  cow's  milk,  also  demands  a  similar  latency  of  the  tubercle  bacilli. 
The  basis  of  this  theory  has  been  completely  shattered  by  Kitasato's  full  statis- 
tical study  of  conditions  in  Japan.  There  tuberculosis  at  all  ages  is  as  common  as 
in  Europe  and  North  America;  but,  in  the  first  place,  the  native  cattle  are  im- 
mune to  tuberculosis;  in  the  second,  infants  are  not  brought  up  on  cow's  milk. 

^Arb.  a.  d.  Kaiserl.  Gesundheitsamte,  Berlin,  xx,  1904,  pt.  3. 

^  I  have  so  far  refrained  from  using  this  term,  which,  though  strictly  correct  as 


24  HEREDITY  AXD   PREDISPOSITION 

organs,  is  that  most  frequently  involved.  Aeeording  to  Chiari,  out  of  132 
S}TDhilitic  infants  examined,  119  showed  hepatic  involvement.  This  is 
scarce  to  be  explained  on  the  theory  of  germinal  infection;  it  is  exactly 
what  we  should  expect  from  placental  infection,  and  this  because  the 
blo(xl  of  the  umbilical  vein  passes  first  to  the  liver,  which  thus  bears  the 
brunt  of  the  infection:  it  is  here  that  the  microbes  of  the  disease  are  liable 
to  be  arrested.  Yet  another  method  of  uterine  infection,  through  the  am- 
nion and  anmiotic  fluid,  has  also  to  be  taken  into  account. 

With  reference  to  germinal  infection  through  the  spermatozoon  and  its 
unlikelihood,  the  following  observations  of  Gartner^  deserve  consider- 
ation. 

As  Wyssokowicz  has  demonstrated,  the  minimal  number  of  tubercle 
bacilli  which  will  set  up  peritoneal  infection  in  the  guinea-pig  is  eight. 
Gartner,  obtaining  with  every  precaution  the  ejaculations  from  guinea- 
pigs  rendered  tuberculous  by  intra-tracheal  injections,  found  that  only 
five  out  of  thirty-two  ejaculations  contained  a  sufficient  number  of  bacilli 
to  set  up  peritoneal  tuberculosis  in  other  guinea-pigs.  Rohlff,  taking  se- 
men from  the  bodies  of  men  succumbing  to  pulmonary  phthisis,  did  not 
once  succeed  in  rendering  rabbits  tuberculous.  (To  set  up  peritoneal  in- 
fection in  the  rabbit  a  minimum  of  twenty-four  to  thirty  tubercle  bacilli 
must  be  present.)  From  these  and  other  considerations,  Gartner  was  led 
to  the  conclusion  that  the  semen  of  the  advanced  phthisical  patient,  with- 
out direct  tuberculosis  of  the  genital  organs,  does  not  on  the  average 
contain  as  many  as  ten  bacilli. 

A  careful  computation  of  twenty-four  cases  has  shown  that  the  aver- 
age human  seminal  ejaculation  contains  more  than  two  hundred  and 
twenty-six  millions  spermatozoa.  (The  number  appears  extraordinary, 
but  is  comprehensible  Avhen  we  remember  that  a  cubic  millimeter  of 
blood  contains  five  million  erythrocytes.)  Thus,  says  Gartner,  if  the 
semen  contained  not  ten  but  one  hundred  bacilli,  the  chances  that  an 
individual  spermatozoon  fertilizing  an  ovum  should  have  with  it  a  tuber- 
cle bacillus,  and  so  cause  germinal  infection,  are  as  1  to  2,260,000. 
Even  did  the  semen  contain  1,000,000  bacilli  the  chances  would  be  as 
1  to  226.  He  pursues  the  argument  further  by  showing  that  on  the 
average  only  1  out  of  about  85,000,000,000  spermatozoa  has  the  chance 
of  fertilizing  an  ovum.  Suffice  to  say  that  the  chance  of  germinal 
infection  through  the  conveyance  of  tubercle  bacilli  by  the  spermatozoon 
is  so  absurdly  minute  that  it  must  be  neglected. 

Infection  of  the  offspring  in  utero  by  the  father,  when  it  occurs — as  we 
know  it  does  occasionally,  and  that  without  apparent  infection  of  the 
mother — must  happen  at  a  later  period,  and  two  possibilities  present 
themselves:  namely,  it  is  possible  that  there  may  be  purely  local  infec- 
tion of  the  womb,  and  more  particularly  of  the  placental  area,  from  the 
seminal  fluid  of  the  male  parent;  or,  without  direct  infection  of  the 
womb,  there  may,  at  a  later  period,  be  conveyance  of  pathogenic  microbes 
from  the  uterine  cavity  through  the  amnion  into  the  amniotic  fluid. 
Without  discussing  these  possibilities,  it  is  here  only  necessary  to  state 
that  it  has  been  positively  demonstrated  that  tubercle  bacilli  introduced 

embracing  the  conditions   of  ante-natal  disease,  is  so  frequently  regarded  as 
synonomous  with  "hereditary"  that  to  employ  it  is  apt  to  confuse. 
'Zeilchr  f.  Hygiene,  13,  1893,  101. 


INHERITANCE  AND  DISEASE  25 

into  the  uterine  cavities  of  pregnant  animals  may  later  be  detected  in  the 
amniotic  sacs. 

To  repeat,  we  are  forced  to  conclude  that  specific  injections  are  not  in- 
herited, hut  are  of  post-conceptional  acquirement.  This,  however,  is  not  the 
same  as  stating  that  no  inheritance  of  any  order  can  occur  in  connection 
with  specific  diseases.  To  this  latter  possibility  we  shall  return  later. 

CONDITIONS   TRULY  INHERITED. 

We  have  now  cleared  the  ground,  and  it  may  seem  that  very  little  of 
the  nature  of  disease  is  left  which  can  be  inherited.  Of  actual  dis- 
ease, it  is  true,  very  little  is  left;  of  morbid  conditions — of  departures  from 
the  normal  (variations),  and  morbid  tendencies  (diatheses), — much  re- 
mains to  be  said:  so  much,  indeed,  that  it  is  difficult  to  know  where  to 
stop;  for  to  discuss  these  subjects  adequately  demands  a  study  of  the 
whole  theory  of  inheritance. 

But  first,  in  order  to  think  clearly  over  these  matters,  it  is  well  to  treat 
apart  as  far  as  possible  two  broad  groups  of  cases;  namely,  the  cases  in 
which  we  have  to  deal  with  the  inheritance  of  conditions  which  have 
passed  down  from  earlier  generations  (and  dealing  with  that  we  will  for 
the  time  leave  out  of  consideration  how  these  departures  from  the  normal 
gained  origin);  and,  secondly,  those  cases  in  which  abnormal  conditions 
have  manifested  themselves  first  in  one  or  other  parent.  It  is  when  dis- 
cussing these  that,  to  gain  a  grasp  of  their  meaning  and  extent,  we  shall 
have  to  inquire  into  their  origin  and  strive  to  establish  an  adequate 
theory  of  inheritance.  We  arrive  at  the  same  result  by  classifying  the 
truly  inherited  morbid  conditions  into:  (1)  Ex  specie,  or  specific;  (2) 
racial;  (3)  familial;  and  (4)  individual.  We  may  rapidly  run  over  ex- 
amples of  the  first  three  classes;  it  is  the  fourth  that  we  shall  have 
specially  to  study. 

1.  Ex  Specie. — The  fixity  with  which  specific  properties  are  inherited, 
as  compared  with  familial  or  even  racial  peculiarities,  affords  the  most 
patent  example  of  the  working  of  the  law  that  those  features  which  have 
for  the  longest  period  been  possessed  by  a  given  stock  are  the  features 
most  impressed  on  that  stock,  and  least  easily  lost.  It  is  in  the  broad 
study  of  species  that  the  existence  of  heredity  is  most  emphasized.  Con- 
ditions which,  we  must  assume,  had  originated  as  variations  or  as  muta- 
tions have  ceased  to  be  pathological  and  have  become  attributes  of  the 
species.  In  the  majority  of  these  specific  variations  we  have  to  see  a  defi- 
nite advantage;  following  the  present  trend  of  evolutional  thought  we 
recognize  an  inherent  probability  that  it  is  those  features  of  advantage  to 
the  stock  that  are  retained,  while  valueless  variations  tend  to  disappear. 
Bland  Sutton  has  suggested  that  this  is  not  always  the  case;  that  a  useless 
variation  in  one  part  of  the  organism  may  show  itself  along  with  a  variation 
of  advantage  in  another  part,  and,  being  coincident,  both  may  tend  to  be 
perpetuated.  He  cites  the  "castors"  situated  on  the  inner  side  of  either 
foreleg  of  the  horse — horny  cutaneous  overgrowths  unconnected  with 
the  bone.  The  only  suggestion  that  he  can  make  is  that  these  have  shown 
themselves  primarily  as  a  correlated  variation  along  with  others  more 
valuable   in   some  prepotent  ancestor.    Another  remarkable  example. 


26  HEREDITY  AND  PREDISPOSITION 

apparently  of  this  class,  is  seen  in  that  strange  fish,  the  chietodon,  with  its 
osteomatoid  enlargements  of  sundry  bones. 

There  are  more  easily  recognized  functional  morbid  inheritances. 
Notably,  the  ditferent  species  show  strongly  defined  differences  in  suscep- 
tibility to  various  diseases.  Thus  each  species  harbors  one  or  more 
forms  of  the  grosser  parasites  which  are  peculiar  to  it,  and  the  same  may 
largely  be  said  with  regard  to  niicrobic  parasites.  We  need  but  suggest 
that  typhoid,  gonorrhoea  and  syjjhilis  appear,  under  natural  conditions, 
to  be  limited  to  the  hunum  species. 

2.  Racial. — Dealing  with  races  we  observe  numerous  minor  anatomical 
varieties,  nor  can  we  in  every  case  comprehend  their  development,  save 
as  "sports"  which  have  appeared  in  some  ancestor  of  the  race  and  have 
been  perpetuated.  Without  going  far  afield  abundant  examples  may  be 
called  to  mind:  the  lack  of  development  of  the  nasal  bones  in  pug  dogs; 
the  existence  of  horned  and  hornless  races  of  domestic  cattle;  the  ab- 
sence of  tails  in  certain  races  of  sheep  and  cats,  etc.;  while,  coming  to 
man  himself,  we  observe  pronounced  differences  in  the  quality  of  the 
hair  and  the  pigmentation  of  the  skin  of  the  different  races,  not  to  men- 
tion deeper  structural  peculiarities  such  as  the  symmetrical  exostoses  of 
the  malar  bones  among  the  Akim  (or  horned  men)  of  Africa,  and  the 
penile  bone  present  in  yet  other  African  races.  There  are  among  the 
different  races  of  animals,  as  of  man,  different  susceptibilities  to  infectious 
diseases.  The  native  cattle  of  Japan,  as  again  the  "Buft"el"  or  native 
cattle  of  Austro-Hungary,  are  relatively  insusceptible  to  tuberculosis;  a 
race  of  Algerian  sheep  shows  a  similar  relative  insusceptibility  to  anthrax, 
whereas  sheep  in  general  are  highly  susceptible.  As  between  human 
races  these  differences  in  susceptibility  are  well  marked.  We  need  but 
cite  the  relative  susceptibility  of  Melanesians  to  measles,  of  Negroes  to 
tuberculosis,  of  Malaysians  and  other  oriental  races  to  beri-beri,  of 
those  of  European  descent  to  yellow  fever. 

3.  Familial. — Taking  man  alone  into  consideration  the  instances  of 
familial  inheritance  of  abnormal  conditions  are  so  numerous  that  it  is 
impossible  within  the  limits  of  this  article  to  attempt  anything  approach- 
ing a  complete  record.  As  we  have  indicated  elsewhere,  they  may  roughly 
be  divided  into: 

(A).  Gross  Anomalies. — There  are  abundant  instances  of  the  inher- 
itance by  successive  generations  of  one  family  of  such  conditions  as 
Polydactyly,  syndactyly,  abnormal  shortness  of  one  or  more  phalanges,  hy- 
pospadias, phimosis,  etc.  So  marked,  indeed,  is  this  inheritance  that 
there  is  recognized  a  tendency  for  those  possessing  such  anomalies  to  be 
prepotent;  i.  e.,  the  majority  of  the  progeny  of  these  individuals  mated 
with  more  normal  individuals  exhibit  the  like  anomaly,  whether  in  the 
one  sex  only  or  in  both. 

(B).  Probable  Anomalies  of  Defect. — Such  are  haemophilia  (exhibited 
more  particularly  in  the  males,  but  descending  through  the  female  line), 
albinism,  Daltonism,  myopia,  strabismus,  ichthyosis. 

(C).  Susceptibility  to  Specific  Infections. — Certain  families  are  notor- 
iously more  prone  to  certain  infections  than  is  the  generality  of  the  com- 
munity. This  is  especially  marked  in  connection  with  tuberculosis,  and 
this  when  due  deductions  are  made  for  house  infection,  subjection  to 
similar  environment,  etc.     We  recognize,    in   short,    a  tuberculous  dia- 


tNlJERITANCE  AND  DISEASE  27 

thesis.  In  other  famiUes  the  exanthemata,  such  as  measles  and  scarlet 
fever,  are  specially  apt  to  take  a  severe  form. 

(D).  Diathetic. — Other  conditions,  due,  it  would  seem,  to  disturbances 
of  metabolism,  underlying  which  may  very  possibly  be  finer  anatomical 
variations,  have  for  long  been  noted  as  tending  to  be  inherited;  such  are 
obesity,  diabetes,  gout,  and  chronic  rheumatism  (though  all  of  them  as- 
sume also  a  racial  aspect) .  Upon  further  consideration  it  will  be  seen  that 
this  and  the  preceding  class  are  doubtfully  to  be  separated;  the  essential 
feature  common  to  both  is  an  inherited  habit  of  body  or  vice  of  organiza- 
tion— a  constitutional  weakness  in  one  or  the  other  direction.  In  all  these 
cases  we  are  apt  to  observe  a  form  of  "homochronous  inheritance;"  i.  e., 
the  disturbance  is  apt  to  manifest  itself  at  or  about  the  same  life-period 
in  the  offspring  as  in  the  parent. 

(E).  Nervous. — More  and  more  attention  has  been  paid  of  late  years  to 
familial  nervous  disturbances,  of  which  two  groups  may  be  recognized, 
the  homeomorphic  and  the  heteromor'phic.  In  the  former  the  offspring 
show  the  same  lesions  and  symptoms  as  did  the  parent.  These  are 
cases  more  particularly  of  lack  of  development  or  premature  atrophy  of 
certain  groups  of  nerve-cells,  and  among  them  are  to  be  included  familial 
palsies,  pseudohypertrophic  and  amyotrophic  paralyses,  Friedreich's 
disease,  Thomsen's  disease,  etc.  It  is  noteworthy  that  the  more  these 
conditions  are  being  studied,  the  greater  is  the  number  of  strictly  local- 
ized familial  diseases  that  is  being  determined,  each  group  affording  a 
particular  syndrome. 

The  heteromorphic  disturbances  embrace  a  series  of  cases  in  which, 
the  parent  suffering  from  one  form  of  nervous  disease,  the  progeny  may 
individually  exhibit  one  or  more  of  a  group  of  other  nervous  disturb- 
ances. Broadly  speaking,  it  would  seem  that  here  we  have  to  deal  not 
so  much  with  lack  of  development  and  atrophy  of  particular  groups  of 
nerve-cells  as  with  lack  of  the  highest  development  of  the  higher  centres 
as  a  whole;  there  is  wanting  perfect  stability  and  coordination  of  various 
parts,  so  that  according  to  the  strains  to  which  the  individual  members 
of  the  family  are  subjected,  now  one,  now  the  other  series  of  centres  may 
show  itself  unable  to  respond  adequately,  and  one  or  other  form  of 
mental  disturbance  and  nervous  disease  may  result.  Here  are  to  be  in- 
cluded conditions  of  insanity,  familial  epilepsy,  hysteria,  and  the  neu- 
roses. 


INDIVIDUAL   INHERITANCE. 

Strictly  speaking,  every  property  possessed  by  the  individual  which  is 
not,  or  cannot  be,  ascribed  to  intra-uterine  influences  and  postnatal 
acquirement,  is  the  individual  inheritance.  It  has  reached  him  through 
the  parental  germ-plasm;  thus,  specific,  racial,  and  familial  traits  be- 
come the  individual  property.  For  practical  purposes,  however,  all  of 
these  may  for  the  moment  be  neglected,  and  merely  those  properties  taken 
into  consideration  which,  (1)  peculiar  to  the  parents  as  distinct  from  the 
family,  reappear  in  the  progeny;  or,  (2)  not  observable  in  either  parent 
or  parental  stock,  can  only  be  ascribed  to  the  interaction  of  the  two  paren- 
tal germ-plasms.    We  have  here,  in  short,  to  deal  with  variation,  w-hether 


28  HEREDITY  AND  PREDISPOSITION 

first  appearing  In  the  parent  or  in  the  ofl'spring,  and  must  of  necessity 
inquire  into  the  factors  bringing  about  incUvidual  variation. 

This  inevitably  demands  an  inquiry  whether  conditions  acquired  by  the 
parent  can  be  transmitted  to  the  otispring.  ^Ye  approach  the  crucial 
point  of  the  whole  debate.  If  influences  telling  on  the  ])arent  modify  the 
constitution  of  the  offspring,  then  not  merely  do  we  gain  an  insight  into 
the  ultimate  causation  of  individual  variation,  and,  what  is  more,  an  in- 
sight into  the  meaning  of  the  evolution  of  the  species,  but  also  to  some  ex- 
tent approach  the  Lamarckian  stand})oint.  I  say  "approach"  because  the 
full  Lamarckian  doctrine  demands  that  the  identical  change  acquired  by 
the  parent  become  transmitted — that  if,  for  example,  the  giraffe  by  strain- 
ing towards  higher  things  adds  a  cubit  to  his  stature,  the  little  giraffe  is 
born  with  larger  forelegs  and  longer  neck  than  are  possessed  by  his  cous- 
ins. What  we  have  said  regarding  the  non-inheritance  of  mutilations 
will  have  indicated  that  we  cannot  see  how  this  extreme  doctrine  is  to  be 
accepted. 

We  must  deny  the  inheritance  of  acquired  gross  structural  modifica- 
tions, and  if  this  is  the  essence  of  Lamarckianism,  then  Lamarckianism  we 
cannot  entertain.  Wliat  we  here  refer  to  is  the  possibility  that  the  molec- 
ular constitution  of  the  germ-plasm  may  be  modified  in  one  or  other 
direction  by  influences  acting  upon  the  parental  organism,  with  the  result 
that  the  offspring  varies  in  one  or  other  direction  according  to  the  nature 
of  this  influence.  Variations  so  produced  would  not  be  identical  with  the 
modification  acquired  by  the  parent,  but  might  be  specific  to  this  extent, 
that  a  given  influence  acting  on  the  parent  would  tend  to  variation  in  the 
offspring  along  certain  definite  lines.  If  this  is  found  not  to  be  the  case 
there  is  but  the  alternative  that  each  parent  hands  down  to  the  offspring 
a  fixed  germ -plasm;  that  the  molecules  constituting  this  germ-plasm  in 
the  ovum  and  spermatozoon  respectively  are  not  of  identical  composition 
and  arrangement;  and  that  consequently  it  is  to  the  amphimixis  or  com- 
mingling and  interaction  of  the  two  unlike  parental  germ-plasms  that 
variations  are  due.  According  to  this  view  the  laws  governing  variation 
are  akin  to  the  laws  determining  the  pictures  presented  by  the  pieces  of 
glass  in  the  kaleidoscope. 

It  may  seem  that  here  we  approach  matters  too  intricate  for  solution 
— matters  altogether  too  deep  and  removed  from  medical  practice  to  re- 
quire treatment  in  a  work  of  this  nature.  And  yet  a  little  thought  will 
show^  that  for  medical  men  here  also  is  the  crux.  Upon  our  answer  to  this 
question  depends,  if  not  our  whole  outlook  over  the  inheritance  of  disease, 
at  least  our  attitude  towards  the  one  problem  of  heredity  regarding  which 
our  advice  is  most  often  sought.  If  the  germ-plasm  is  fixed  and  variation 
is  due  simply  to  amphimixis,  then  disease  in  the  father  should  have  no  ef- 
fect upon  his  children,  save  and  except  that  disease  be  conveyed  by  him 
to  the  mother  and  so  tell  upon  the  intra-uterine  nutrition  of  the  foetus ;  or, 
more  remotely,  be  conveyed  by  him  to  these  children  after  birth.  If,  on 
the  contrary,  parental  disease  not  directly  affecting  the  ovaries  or  testes 
can  nevertheless,  by  the  toxins  generated  elsewhere  and  circulating  in  the 
blood,  deleteriously  influence  and  modify  the  nuclear  material  of  the  ovum 
or  spermatozoon,  just  as  it  may  modify  the  other  cells  of  the  body  and 
their  nuclear  material,  then,  obviously,  the  molecular  constitution  of  the 
individual  developed  from  the  germ-cell  must  vary  from  the  normal;  or 


INHERITANCE  AND  DISEASE  29 

otherwise  parental  disease  is  liable  to  affect  the  offspring  very  materially. 
It  will  be  seen  that  everything  leads  me  to  accept  the  latter  view.  It 
will,  however,  aid  our  understanding  of  the  problems  presented  if  first  we 
endeavor  to  classify  individual  variations  and  collect  certain  data  bear- 
ing upon  individual  inheritance  in  general. 

The  Different  Forms  of  Individual  Inheritance.— As  regards  any 
one  property,  structural,  constitutional,  or  mental,  the  individual  may 
exhibit  the  following  forms  of  individual  heredity : 

1.  Inheritance  to  an  Extent  Intermediate  Between  What  Has  Ob- 
tained in  the  Parents. — The  blended  is  the  commonest  type  of  inherit- 
ance, and  would  seem  to  indicate  an  equality  of  influence  on  the  part  of 
the  respective  germ-plasms.  The  broad  tendency  of  sexual  conjugation 
is  to  preserve  the  mean  and  perpetuate  the  type,  rather  than  to  induce 
extreme  varieties  and  develop  new  species. 

2.  Mosaic  Inheritance. — This  form  is  rarely  to  be  made  f  ut  dis- 
tinctly. It  may  well  be  more  frequently  in  action  than  we  can  recog- 
nize. It  is  best  exhibited  in  cases  of  piebald  animals,  the  offspring  of 
parents  of  different  colors.  Here  the  two  colors  do  not  blond  in  the 
offspring,  but  both  are  represented  independently  in  different  areas. 
It  is  thus  a  form  of  particulate  inheritance  though  not  of  exclusive. 

3.  Reproduction  of  the  Condition  Found  in  the  One  Parent  to  the 
Exclusion  of  That  Seen  in  the  Other. — This  form  of  particulate  inherit- 
ance is  specially  noted  in  connection  with  certain  properties.  Thus 
where  one  parent  has  blue  eyes,  the  other  dark  brown,  the  children  have 
either  blue  or  brown  eyes,  rarely  those  of  an  intermediate  color.  What 
is  more,  as  shown  well  by  Mendel  in  his  studies  upon  hybridization,  and 
fully  confirmed  by  numerous  biologists  during  the  last  few  years,  while 
in  general  the  properties  of  the  hybrid  are  apt  to  be  intermediate  be- 
tween those  of  the  two  parents,  certain  properties  are  apt  to  be  dominant. 
The  "hybrid  character"  resembles  that  of  one  of  the  parental  forms  so 
closely  that  the  other  either  escapes  observation  completely  or  cannot  be 
detected  with  certainty.  But  the  character  not  exhibited  by  the  hybrid 
is  not  of  necessity  entirely  lost — only  recessive.  In  studying  plant  hybrids, 
which  manifest  this  exclusive  inheritance,  as  the  result  of  self-fertilization 
of  the  hybrids,  the  recessive  character  has  been  found  to  reappear  in  a 
certain  definite  proportion  of  the  plants  of  the  next  generation.  Grow- 
ing these  hybrids  and  their  offspring,  (the  result  in  each  case  after  the 
first  of  self-fertilization,)  it  has  been  found  that  each  plant  presenting  the 
hybrid  characters  may  give,  as  regards  any  one  pair  of  exclusive  char- 
acters in  the  original  species  (length  or  shortness  of  stem,  inflated  or 
constricted  seed-pods,  axial  or  terminal  flowers,  etc.),  a  remarkably 
definite  proportion  of  offspring.  If  D  be  the  dominant  and  R  the  re- 
cessive character,  the  proportion  of  forms  produced  from  the  hybrid 
parents  is  expressed  by  the  formula:   (DD+2D[R]^+RR.) 

Two  hybrids,  though  of  the  dominant  type,  are  produced  to  any  one 
plant  that  has  the  dominant  character  fixed  and  every  one  that  has  the 
recessive  character  fixed.  Henceforth  plants  of  the  pure  D  type  will  by 
self-fertilization  produce  only  offspring  of  that  type,  with  no  reversion 

^Following  Castle,  we  place  the  Rin  brackets  to  indicate  that  the  recessive 
character,  while  possessed  by  the  germ-cells,  does  not  show  itself  in  the  individual 
To  external  appearance  the  progeny  consists  of  3D  +  R. 


30  HEREDITY  AXD  PREDISPOSITION 

to  the  R  features;  and  so  with  parents  possessing  the  R  character.  The 
hybrids  D  [R],  however,  in  each  subsequent  generation  produce  the  defi- 
nite proportion  of  dominants,  hybrids,  and  recessives. 

When  the  species  differ  in  several  pairs  of  features,  the  result,  though 
following  the  same  lines  as  regards  each  individual  pair,  becomes  much 
more  complicated,  although  eventually,  after  several  generations,  individ- 
uals of  the  pure  ])arent  types  are  reproduced  In  other  words,  by  this  ex- 
clusive inheritance  the  results  of  a  m(f>salliance  in  the  pedigree  may  be 
completely  cast  out  and  the  stock  become  once  more  pure.  Castle  and 
Allen  have  demonstrated  the  existence  of  the  same  law  in  animals — 
mice — in  regard  to  coat  color. 

4.  Production  of  New  Features  and  a  New  Strain  by  Cross-Breed- 
ing. — There  is  shown,  it  may  be  added,  an  equal  likelihood  that  the 
mating  of  two  individuals  which,  as  regards  two  pairs  of  contrasted 
characters  (or  aUelomorpJis),  exhibit  each  reversely  a  dominant  feature 
as  regards  the  one  and  a  recessive  as  regards  the  other  will  result  in  the 
development  of  definite  proportions  of  individuals  resembling  neither 
stock  but  showing  a  commingling  of  two  dominant  or  two  recessive  fea- 
tures. If  cither  of  these  new  forms  be  mated  strictly  with  other  individ- 
uals of  the  same  type  there  results  a  new  strain  or  variety  breeding  true 
and  distinct  from  cither  ancestral  stock.  Thns,  to  quote  Bateson,  if  a 
red  variety  of  some  plant,  say  a  stock,  be  crossed  with  a  cream-colored 
variety,  while  the  hybrids  of  the  first  generation  are  red  (red  being  domi- 
nant) ,  in  the  second  generation  a  small  proportion  (three-sixteenths  of 
the  total  progeny)  of  plants  may  appear  v/ith  flowers  neither  yellow  nor 
red  but  tvhite,  and  these  white-flowered  forms,  if  crossed  among  them- 
selves or  allowed  to  undergo  self-fertilization,  yield  a  permanent  white 
strain.  The  explanation  here  is  that  the  one  ancestral  form  has  red 
sap  (D)  with  colorless  corpuscles  (R)  floating  in  it,  the  other,  colorless 
sap  (R)  with  cream-colored  corpuscles  (D).  In  this  way  some  of  the 
second  generation  come  to  possess  a  mingling  of  the  characters,  color- 
less corpuscles  and  colorless  sap.  This,  it  may  be  noted,  is  the  basal 
principle  underlying  the  production  of  new  strains  or  varieties  by  the 
horticulturist  and  undoubtedly  helps  to  explain  the  production  of  one 
order  of  the  "sports"  to  which  we  refer  in  a  later  paragraph.  Interesting 
as  it  is,  we  shall  not  here  enter  into  a  detailed  account  of  the  Mendelian 
doctrine,  wliich  has  provided  keen  activity  of  late,  more  particularly 
among  English  and  American  biologists;  to  discuss  it  adequately  would 
demand  many  pages.  A  consideration  of  its  bearings  upon  the  inherit- 
ance of  morbid  conditions  is  given  by  Bateson,  the  leader  of  the  school, 
in  a  lecture  to  the  Neurological  Society  of  London.^ 

In  the  human  race,  where  not  only  there  is  no  self-fertilizing  but  con- 
jugation between  those  of  the  same  stock  is  largely  prohibited,  and 
where,  again,  the  number  of  points  of  difference  between  the  individuals 
is  extraordinarily  great,  Mendel's  law  can  rarely  be  brought  to  apply,  save 
in  the  most  general  terms.  In  any  case  it  does  not  explain,  any  more 
than  does  the  law  of  gravitation.  It  helps  us,  however,  to  harmonize  data 
otherwise  not  a  little  confusing — to  recognize  dominant  features  in  the 
members  of  a  family  (such  as,  for  example,  the  well-known  Hapsburg 

^  British  Medical  Journal,  1906,  ii,  61 


INHERITANCE  AND  DISEASE  31 

lip),  the  appearance  of  recessive  features  in  a  certain  number  of  the  mem- 
bers of  a  later  generation,  etc.  When  in  gout  and  haemophilia  a  given 
diathesis  skips  a  generation  we  realize  that  we  are  dealing  not  with 
isolated  phenomena  but  with  conditions  subservient  to  law.  Where  one 
parent  has  a  neurotic  or  alcoholic  heredity  we  realize  that  it  is  not  essen- 
tial that  all  of  the  progeny  be  neurotic  or  show  stigmata  of  degeneration, 
though  at  the  same  time  we  are  bound  to  realize  that  while  the  parents 
themselves  may  show  no  vice  of  organization,  yet,  if  either  comes  from  an 
unsound  stock,  there  is  the  possibility  that  in  them  the  particular  inheri- 
tance of  morbid  state  is  merely  in  abeyance  (recessive) — that  it  may  show 
itself  once  more  in  some  of  their  offspring.  There  is  the  lesser  possibil- 
ity that  by  fortunate  mating  it  may  be  wholly  cast  out  not  to  reappear. 
In  these  instances  we  are  dealing  with  true  atavism  {atavus,  a  grand- 
father), or — 

5.  Reproduction  of  a  Condition  Seen  in  Generations  Nearly  Pre- 
ceding the  Parental. 

6.  Reversion. — The  reproduction  of  remote  ancestral  conditions. 
Atavism  must,  we  hold,  be  regarded  as  distinct  from  the  next  condi- 
tion which  may  show  itself,  namely,  reversion.  In  atavism  there  is  no 
necessary  degeneration;  the  return  may  be  to  a  better  type.  By  rever- 
sion is  meant  at  least  loss  of  properties  common  to  the  stock  or  race  and 
the  reproduction  of  the  characteristics  of  the  lower  type  in  the  line  of 
descent.  If  ontogeny  be  an  abbreviated  phylogeny,  then  by  reversion  we 
understand  the  development  of  the  individual  up  to  some  point  short  of 
the  completed  phylogeny. 

This  again  is  well  exemplified  by  certain  studies  in  hybridism.  Some 
of  the  latest  are  those  of  von  Guaita,^  who  found  that  breeding  together  a 
tame  albino  mouse  with  a  piebald  Japanese  waltzing  mouse  the  progeny 
was  a  "wild  gray  mouse."  The  color  and  general  configuration  here 
were  not  those  of  either  parent :  they  were  those  of  the  presumptive  wild 
ancestor  from  which  both  strains  had  their  origin  long  generations  pre- 
viously. Even  more  remarkable  is  Darwin's  famous  case.^  The  ancestors 
of  our  domestic  pigeons  were  probably  eastern  birds;  it  is  known  that  for 
now  some  centuries  the  leading  varieties  have  been  bred  in  Europe,  for  still 
longer  centuries  in  India  and  the  East;  and  everything  indicates  that  their 
ancestors  were  the  wild  blue-rock  pigeon  {Columba  livia).  Crossing  a 
barb-fantail  female  with  a  barb-spot  male,  Darwin  produced  a  bird 
"which  was  hardly  distinguishable  from  the  wild  Shetland  species"  (of 
blue-rock).  Weismann  has  supposed  that  in  Darwin's  case  the  similarity 
was  purely  in  the  color  and  the  bars  on  the  wings.  Ewart,^  crossing 
an  absolutely  white  fantail  with  thirty  feathers  in  its  tail  with  an  owl- 
archangel  hybrid,  (the  owl  was  powdered  blue,  with  a  short  beak;  the 
archangel  copper-colored,  with  well-developed  crest)  obtained  a  bird 
which  in  measurement  was  almost  identical  with  the  blue-rock,  while  in 
color  and  markings  it  showed  complete  reversion  to  the  checkered  blue- 
rock  of  India,  and,  like  that,  had  only  twelve  tail-feathers. 

In  this  "harking  back"  we  seem  to  have  what  may  be  termed  a 
"greatest-common-measure"  action.     In  this  fusion  of  the  germ-plasms 

^  Bericht  d.  Naturf.Gesamml,  Freiburg  10,  1898,  317;    and  11,  1900,  131. 
^  Animals  and  Plants  Under  Domestication,  I.,  p.  204. 
^The  Penycuik  Experiments,  1899,  p.  xxvi. 


32  HEREDITY  AND  PREDISPOSITION 

those  *' constituents,"  if  we  may  so  express  it  for  the  moment,  which  had 
controlled  the  racial  differences  in  the  respective  parents  antagonize  one 
another,  and  the  older  constituents  common  to  the  two  germ-plasms 
alone  control  the  development  of  the  offspring.^ 

Such  a  cutting  off,  or  inactivity,  is  liable  to  occur  generally  when  widely 
separated  stocks  are  mated — until  the  ])oint  is  reached  when  no  result  is 
obtained,  the  union  being  sterile.  The  cutting  oft'  is  of  the  recessive 
type  and  not  absolute,  for  later  generations  may  furnish  individuals 
returning  again  to  either  primary  parental  type.  DeVries  nevertheless 
lays  down  that  Mendel's  law  does  not  hold  satisfactorily  in  connection 
with  other  racial  properties. 

7.  Degeneration  and  Degenerates.  —  Herein  we  have  a  condition 
allied  in  its  results  to  the  reversion  just  described,  but  differing  in  this, 
that  the  parents  belong  to  the  same  stock.  Although  in  externals  they 
may  or  may  not  apjiear  to  be  normal,  their  offspring  are  of  low  type,  the 
cranial  ca])acity  less  than  normal  and  reversionary  in  character,  and,  more 
particularly,  the  intellectual  and  moral  properties  approximate  toward 
those  of  the  uncivilized  and  lower  types  of  mankind.  We  shall  have 
later  to  discuss  the  causes  of  such  degeneration.  Here  I  would  only  state 
that  under  this  heading  must  be  included  certain  less-pronounced  con- 
ditions of  defect — conditions  in  which  it  may  be  that  only  one  system, 
notably  the  nervous  system,  shows  signs  of  defective  development;  or, 
again,  in  which  no  positive  structural  defect  may  be  made  out,  but  the 
constitution  is  feeble  and  the  natural  resistance  to  disease  possessed  by 
the  race  is  characteristically  lowered. 

8.  Excess  of  Development  of  a  Property  Over  What  Obtains  in 
Either  Parent.  —  Mendel  noted  forty  years  ago  that  in  hybridization 
the  cross-fertilization  of  a  tall-stemmed  (4  to  5  foot)  variety  or  species  of 
pea  with  a  short-stemmed  species  (1^  to  2  feet),  regularly  led  to  the 
production  of  hybrids  taller  (6  to  7  feet)  than  the  taller  parents.  Within 
certain  limits  the  cross-fertilization  of  distinct  stocks  leads  to  progeny 
exhibiting  greater  vigor  of  growth  than  either  parent.  It  is  a  familiar 
observation  in  Canada  that  the  offspring  of  mixed  Anglo-Saxon  and 
French  marriages  tend  to  be  of  better  build,  brighter,  and  more  active, 
than  the  rest  of  the  community  whether  French  or  Anglo-Saxon.  The 
same  was  noted  of  the  Normans  centuries  ago. 

9.  Sports. — Mutations. — The  abrupt  appearance  of  conditions  neither 
parental  nor  ancestral. 

Certain  gross  anomalies  are  clearly  reversionary;  although  appearing 
abruptly  in  the  line  of  descent,  they  reproduce  obviously  organs  or  parts 
well  developed  in  some  ancestor.  Such  for  example  are  various  persistent 
ducts  and  cysts  developing  along  the  course  of  such  ducts — the  majority 
of  the  cardiac  anomalies,  cleft  palate,  supernumerary  nipples,  etc.  The 
list  can  be  greatly  extended,  although,  as  will  be  noted  later,  it  is  not  al- 
ways possible  to  distinguish  between  the  inherited  and  the  acquired  con- 
ditions of  this  order;  by  which  we  mean  that  everything  points  to  the 
fact  that  a  considerable  number  of  anomalies  are  due  to  influences  acting 
on  the  embryo.    Wholly  apart  from  these  is  another  series  of  appearances. 

*This  explanation  of  "  harking  back  "  appears  to  possess  greater  inherent  prob- 
ability than  Bateson's  "meeting  of  two  complementary  elements  which  have 
somehow  been  separated  by  variation." 


INHERITANCE  AND  DISEASE  33 

Once  again  to  take  a  botanical  example:  in  a  bed  of  single  tulips  a  rare 
flower-head  may  show  only  five  petals;  another  may  show  seven.  The 
liliacese,  to  which  the  tulips  belong,  are  throughout  characteristically  six 
partite,  and  if  one  of  these  variations  is  reversionary  to  an  ancestral  con- 
dition, the  other  cannot  be.  From  the  fact  that  in  neither  case  is  the 
general  character  of  the  tulip  greatly  altered,  the  probability  is  that 
neither  condition  represents  a  reversion,  and  that  both  are  sports.  The 
four-leaved  shamrock  is  of  the  same  order.  We  owe  to  the  great  Belgian 
botanist  de  Vries  the  fullest  study  and  recognition  of  this  production  of 
'mutations.'^  Cultivating  the  plant  (Enothera  Lamarckiana  over  a  long 
series  of  years — in  fact  since  1886 — he  observed  the  appearance  from 
time  to  time  of  individuals  which  definitely  varied  from  the  parents,  and, 
what  is  more,  when  fertile,  were  true  to  seed.  Thus  in  1895,  to  quote 
an  instance,  there  appeared  the  relatively  huge  (Enothera  gigas,  and  that 
not  by  gradual  variation  but  by  a  sudden  jump.  Subjected  to  self-ferti- 
lization this  single  plant  afforded  seeds  giving  origin  to  plants  (several 
hundreds)  of  the  gigas  type.  At  a  bound  therefore  a  new  species  was 
seen  to  develop.  As  de  Vries  points  out,  we  have  here  an  example  of 
discontinuous  and  not  of  gradual  evolution,  and  he  holds  that  in  all 
cases  evolution  must  be  of  this  discontinuous  type.  In  this  as  supporting 
a  physico-chemical  theory  of  inheritance  we  cannot  but  agree  with  him. 
To  quote  Jacques  Loeb,^  "If  the  (determinants)  are  comparable  to  a 
series  of  compounds,  e.  g.,  of  alcohols,  there  is  no  more  a  transition 
possible  between  two  species  separated  by  a  difference  in  only  one 
determinant  than  there  is  a  transition  possible  between  two  neighbour- 
ing alcohols  of  the  same  series."  We  meet  with  similar  conditions  in 
animals.  Thus  it  is  known  that  the  celebrated  royal  strain  of  cream- 
white  horses  at  Hanover  originated  by  careful  inbreeding  from  a  single 
sport — a,  white  horse  which  appeared  fortuitously  in  a  breed  that  had 
previously  shown  no  tendency  to  throw  white  horses.  Certain  breeds 
of  merino  sheep  are  also  traceable  back  to  a  single  sport  possessing  silky 
hair  in  place  of  the  ordinary  wool;  and  so  on.  In  man  we  occasionally 
encounter  the  same,  though  it  has  to  be  admitted  that  well-authenticated 
family  histories  are  rare,  and  we  cannot  always  assure  ourselves  that  a 
given  sport  has  appeared  in  a  given  family  for  the  first  time;  i.  e.,  that  it 
is  not  an  inheritance.  The  most  frequent  examples  are  what  Bateson  has 
called  meristic — alterations  in  the  number  of  parts  in  series.  Such  are  in- 
crease or  diminution  in  the  number  of  the  teeth,  vertebrae,  ribs,  fingers, 
toes,  etc.  It  is  difficult  to  speak  with  precision  of  internal  organs,  but 
probably  some  cases  at  least  of  double  kidneys  and  ureters,  accessory 
ovaries  and  testicles,  etc.,  come  under  this  group.  In  addition  there  are 
what  may  be  termed  metabolic  sports — conditions  of  albinism,  ichthyo- 
sis, etc.  It  is  common  to  class  most  of  the  examples  of  the  first,  meristic, 
class  as  instances  of  reversion;  but  the  more  one  studies  them  the  more 
evident  it  is  that  they  must  in  general  be  included  as  sports.  They  occur 
most  often  in  those  who  present  no  other  signs  of  reversion,  and,  as  al- 
ready stated,  if  numerical  increase  is  an  instance  of  reversion,  numerical 
decrease  cannot  be;  and  vice  versa.    Supernumerary  digits  crop  up  in  no 

^Die  Mutationstheorie,  1901. 

■  The  Dynamics  of  Living  Matter,  New  York;  MacMillan,  1906,  225. 
3 


34  HEREDITY  AND  PREDISPOSITION 

particular  position ;  they  may  show  themselves  at  either  end  of  the  series, 
or  as  a  reduplication  of  the  index  or  the  middle  finger.  When  a  super- 
numerary mammary  gland  appears  in  the  line  between  the  outer  end  of 
the  clavicle  and  the  pubic  symphysis  (the  line  along  which  the  mammary 
glands  are  arranged  in  animals  possessing  multiple  pairs),  there  is  some 
force  in  the  argument  that  they  arc  reversionary,  although  it  has  not  been 
shown  what  direct  ancestors  of  man  possessed  multiple  mammjie.  When, 
as  occasionally  happens,  the  su])ernumcrary  gland  occurs  on  the  shoulder 
or  the  hip,  to  speak  of  reversion  is  absurd;  this  can  only  be  a  sport. 
What  is  very  marked  is  that  sports  as  a  rule  arc  curiously  dominant; 
once  they  appear  they  may  reappear  through  several  generations;  they 
may  skip  one  or  more  generations;  they  may  affect  alternate  generations. 
Hey^  has  afforded  a  good  instance  of  this  recently,  in  which  the  existence 
of  supernumerary  digits  was  first  noted  in  the  great-grandfather,  was  ab- 
sent in  the  next  two  generations,  affected  one  of  the  seven  children  of  the 
grandfather,  and  aft'ected  six  children,  the  offspring  of  three  of  the  above 
seven.  Whereas  in  the  earlier  generations  the  toes  were  affected,  in  the 
last,  in  some  individuals  the  toes,  in  others  the  fingers,  were  supernu- 
merary, 

I.  Supernumerary  toes 

II.  normal 

III.  normal 


IV.      S.  toes      normal      normal      normal     normal     normal     normal 


V.        S.  toes  S.  toes  S.  toes    S.  fingers    S.  toes    S. fingers 

It  is  almost  needless  to  call  attention  to  the  pronounced  inheritance, 
often  alternate,  of  albinism  and  haemophilia,  which  may  both  be  placed 
in  the  category  of  metabolic  sports. 

If  now  we  attempt  to  sum  up  the  various  forms  of  individual  inheri- 
tance brought  about  by  fusion  of  the  germ-plasms  of  the  two  parents  we 
make  out  the  following  points : 

I.  Inheritance  of  a  property  or  group  of  properties  may  be  either 
blended  or  particulate. 

II.  There  are  various  grades  of  blended  inheritance: 

(a)  Intermediate,  the  commonest,  with  on  the  one  hand  the  sub-groups: 
(6)  Cumulative,  the  blend  producing  a  quality  superior  to  that  possessed  by 
either  parent. 

(c)  Progressive  sport  'production  (sports  of  excess),  the  blend  inducing  ad- 
ditional properties  in  the  offspring  not  possessed  by  either  parent. 

And  on  the  other  hand — 

id)  Antagonistic,  certain  properties  in  the  two  germ-plasms  antagonizing  one 
another  and  leading  the  offspring  to  have  qualities  inferior  to  those  possessed  by 

^Pey:  British  Medical  Journal,  May  28,  1904. 


INHERITANCE  AND  DISEASE  35 

either  parent,  and  so  to  revert  toward  an  earlier  stage  in  the  ontogeny  or  phylog- 
eny.     We  can  distinguish  the  following  varieties: 
Atavistic. 
Reversionary. 
(e)  Regressive  sport  production  (sports  of  defect),  the  blend  leading  to  defects 
not  to  be  explained  by  phylogenetic  considerations. 

III.  With  regard  to  partindate  inheritance  this  may  well  be  only  a  par- 
ticular case  of  what  we  have  termed  antagonistic  blended  inheritance.  For 
the  present  it  is  perhaps  well  to  treat  it  as  distinct.     It  may  be  either — 

(o)  Mosaic — One  property  in  which  the  two  parental  stocks  differ  being  con- 
veyed to  and  effective  in  the  germ-plasm  from  which  the  offspring  originates  so 
that  in  part  the  offspring  exhibits  the  dominance  of  the  property  conveyed  from 
the  one  parent,  in  part  the  property  conveyed  from  the  other. 

(b)  Dominant — The  germ-plasm  of  the  one  parent  dominating  the  offspring  as 
regards  one  or  more  properties;  that  of  the  other  not  being  wholly  neutralized 
but  merely  recessive,  being  contributed  also  to  the  germ-plasm  of  the  offspring 
so  that  in  its  turn  the  property  may  reappear  in  a  later  generation. 

(c)  Exclusive — Certain  "'constituents"  of  the  germ-plasm  of  the  one  parent 
wholly  replacing  or  casting  out  the  corresponding  constituents  of  the  other,  so 
that  the  peculiar  features  of  that  other  parent  are  not  reproduced  in  any  subse- 
quent generation. 

Are  all  these  various  forms  of  inheritance  the  results  of  chance  combina- 
tions of  the  constituents  of  the  maternal  and  paternal  germ-plasms,  or  can 
we  discern  certain  underlying  laws  ?  It  is  clear  that  we  are  not  dealing 
with  mere  chance,  even  though  chance  also  has  its  law.  Certain  phenom- 
ena appear  with  such  regularity  (when  large  series  are  taken  into  con- 
sideration) that  clearly  they  have  law^s  specially  influencing  them.  One 
of  these  laws  I  have  already  indicated;  namely,  that  of  Mendel  on  cross- 
breeding. There  are  still  those  biologists  who  attack  it;  but  the  more 
it  is  studied  the  more  cases  are  found  to  harmonize  therewith.  This  bears 
on  particulate  heredity,  and  it  may  well  be  that  the  apparent  exceptions 
are  cases  of  other  phases  of  what  above  I  have  termed  "antagonistic 
blended  inheritance."  Bearing  more  particularly  upon  blended  inheri- 
tance we  have  another  law,  that  of  Francis  Galton,  recently  modified  by 
Karl  Pearson.  The  latter  unfortunately  has  not  troubled  to  translate  his 
law  out  of  an  algebraic  equation  into  English,^  and  so  the  ordinary  reader 
would  be  unable  to  follow  it.  Pearson  accepts  Galton's  general  principle 
but  holds  that  the  terms  of  the  series  are  different,  the  contribution  of  the 
different  generations  being  greater  than  held  by  Galton.  Herein  our  own 
line  of  argument  leads  us  to  believe  that  he  is  right.  For  general  purposes, 
however,  Galton's  law  is  near  enough  for  purposes  of  expression.  It  is  that 
the  two  parents  contribute  one-half  (or  each  one-quarter),  the  four  grand- 
parents one-quarter  (or  each  one-sixteenth),  and  so  on.  The  series  |+J 
+5+^,  etc.=l;    i.  e.,  equals  the  total  inheritance. 


THEORIES  OF  INHERITANCE. 

Based  upon  and  deduced  from  the  study  of  long  series  of  cases  these 
laws  are  of  distinct  value.  They  do  not,  however,  explain  what  is  the 
nature  of  heredity  that  these  laws  should  be  in  action.    In  seeking  to  answer 

^The  formula  is  discussed  in  Pearson's  Grammar  of  Science  (2d  edit.),  Lon- 
don: 1900. 


36  HEREDITY  AND  PREDISPOSITION 

this  we  immediately  proceed  into  the  realm  of  hypothesis.  There  have  of 
late  years  been  abundant  theories  brought  forward,  but  none  has  attracted 
greater  attention  than  that  of  Weismann,  none  has  been  so  fully  worked 
out;  and  as  the  distinguished  author  of  the  theory  in  the  evening  of  his 
life  has  given  us  this  theory  in  a  rounded  and  complete  form  which  has, 
further,  been  admirably  translated/  it  will  be  well  to  take  this  as  a  basis. 

Weismann  accepts,  as  indeed  he  was  one  of  the  first  to  emphasize,  that 
inheritance  is  conveyed  by  germ-cells  which  have  from  the  first  been  set 
apart  for  reproductive  purposes.  These  germ-cells  as  such  take  no  part 
in  the  building  up  of  the  parental  individual  of  whose  organism  they  form 
a  part;  only  when  liberated  and  fertilized  do  they  proceed  to  multiply, 
giving  rise  to  one  set  of  cells  which  form  the  body  as  a  whole,  and  to 
another  smaller  set — the  germ-cells.  In  other  words,  he  holds  that  the 
germ-cells  contain  within  them  two  constituents,  the  somatic-  or  body- 
plasm  and  the  germ-plasm.  The  tissues  built  up  by  the  somatic-plasm 
are  mortal,  subject  to  death;  the  germ-plasm  is  potentially  eternal — it  is 
carried  onward  from  generation  to  generation.  Here  is  the  first  Aveak 
point  in  Weismann's  argument — a  false  conception  which  vitiates  the 
whole  subsequent  train  of  thought.  The  germ-plasm  is  not  potentially 
eternal.  If,  as  already  indicated,  the  individual  human  being  derived 
from  a  solitary  spermatozoon  and  a  solitary  ovum  can  produce  on  the 
average,  as  already  indicated,  85,000,000,000  other  spermatozoa  each 
resembling  the  primordial  spermatozoon  in  size  and  properties,  it  is  clear 
that — leaving  the  body-cells  out  of  account — the  germ-plasm  contained  in 
that  primordial  spermatozoon  has  multiplied  itself  several  thousands  of 
millions  of  times ;  or  otherwise  it  has  in  the  process  of  growth  assimilated 
vast  quantities  of  other  material  to  itself,  and  rearranged  it  so  that  that 
new  material  has  come  to  possess  the  same  constitution,  and,  with  this, 
the  same  properties  as  itself.  With  growth  there  is  constant  new  forma- 
tion of  molecules  forming  the  individual  cells.  In  other  words,  the  germ- 
plasm  is  not  eternal;  it  is  constantly  being  renewed.  What  are  the  nearest 
to  being  potentially  eternal  are  the  chemical  and  physical  properties  of  the 
germ-plasm;  and  this  very  fact,  that  growth  implies  constant  rearrange- 
ment and  assimilation  of  constituent  molecules,  makes  the  chemical 
composition  "eternal"  only  so  long  as  the  assimilable  material  remains 
the  same.  To  this  I  shall  revert.  Weismann,  it  is  true,  admits  that  there 
is  growth;   he  does  not,  however,  realize  all  that  this  necessitates. 

He  next  demonstrates  very  clearly  that  this  heritable  germ-plasm  is 
contained  in  the  nuclei  of  the  conjugating  ovum  and  spermatozoon,  (vide 
p.  18),  and  regards  as  a  proved  proposition  that  the  nuclear  chromatin  is 
the  hereditary  substance.  This  is  present  in  the  germ-cells  of  every 
species  in  the  form  of  a  definite  number  of  chromosomes  which,  in  cells 
destined  for  fertilization,  is  reduced  to  one-half  the  number;  so  that  the 
single  nucleus  —  the  segmentation  nucleus — of  the  fertilized  ovum  con- 
tains the  number  of  chromosomes  characteristic  of  the  cells  of  the  indi- 
vidual of  any  particular  species.  The  hereditary  substance  of  the  child  is 
therefore  formed  half  from  the  maternal,  half  from  the  paternal  sub- 
stance, and  as,  at  each  succeeding  cell-division,  each  of  the  paternal  and 

>  August  Weismann:  The  Evolution  Theory;  translated  by  J.  Arthur  Thom- 
son and  Margaret  R.  Thomson.     London  Ed.,  Arnold:  1904. 


INHERITANCE  AND  DISEASE 


37 


maternal  chromosomes  doubles  by  dividing,  each  cell  of  the  individual 
contains  hereditary  material  derived  from  both  father  and  mother. 

This  very  fact  of  reduction,  he  points  out,  indicates  that  half  the  chro- 
mosomes contain  all  the  essential  primary  hereditary  constituents,  or, 
otherv^^ise,  that  it  is  not  the  chromatin  as  a  whole  that  conveys  hereditary 
properties.  The  rather,  this  must  be  made  up  of  a  series  of  constituents 
or  ids,  each  of  which  is  representative  and  capable  of  conveying  all  the 
paternal  or  maternal  properties. 

Let  us  pass  back  a  generation.  The  germ-cells  of  the  parent  are 
similarly  formed  by  a  combination  of  chromosomes  from  the  two 
grandparents.  These  must  be  represented,  as  indeed  must  also  be  the 
chromosomes  of  the  great -grandparents,  etc.  What  is  more,  in  the  pro- 
cess of  reduction  he  holds  that  certain  chromosomes  derived  from  certain 
ancestors  are  cast  out,  others  retained,  and  that  it  is  the  variation  in  the 
series  of  retained  chromosomes  that  in  the  main  determines  the  varia- 
tions between  the  members  of  the  same  generation.  The  hereditary  sub- 
stance in  the  fertilized  ovum  thus  consists  of  several  complexes  of  primary 
constituents  contained  in  the  chromosomes,  or  "idants,"  each  of  which 
complexes  (an  "id")  comprises  within  itself  all  the  primary  constituents 
of  a  complete  individual. 

Fig.  1. 


Each  "id"  Weismann  conceives  as  being  composed  of  a  mass  of  differ- 
ent kinds  of  parts,  each  of  which  bears  a  relation  to  a  particular  part  of  the 
perfect  animal,  and  so  to  some  extent  represents  its  primary  constituents, 
although  there  may  be  no  resemblance  between  these  "Anlagen"  and  the 
finished  parts.  These  representatives  of  individual  parts  contained  in 
each  "id"  he  terms  "determinants"  (Bestimmungsstucke).  In  each  "id," 
therefore,  there  must  be  as  many  determinants  as  there  are  regions  in  the 
fully  formed  organism  capable  of  independent  and  transmissible  varia- 
tion at  all  stages  of  development — for  the  caterpillar  stage,  for  example, 
as  well  as  for  the  butterfly;  determinants  even  for  the  egg,  because  eggs, 
caterpillars  and  butterflies  are  seen  to  vary  independently.  If,  as  has 
been  noted,  the  individual  hairs  on  the  antennae  of  insects  are  capable  of 
transmissible  variation,  and  if,  in  man,  the  conformation  of  particular  teeth 
is  inheritable,  then  determinants  there  must  be  for  these  indi^^Ldual  hairs 
and  teeth.  If  a  little  patch  of  scales  on  the  butterfly's  wing  is  peculiar  to 
one  variety,  for  those  few  scales  there  must  be  a  determinant. 

And  lastly,  each  individual  determinant  must  be  made  up  of  molecules 
of  living  matter,  or  biophores.  Such  biophores,  he  holds,  must  be  larger 
than  any  chemical  molecule;   they  must  consist  of  groups  of  molecules, 


38  HEREDITY  AND  PREDISPOSITION 

some  large  and  complete,  others  simpler  and  more  minute;  so  that  ulti- 
mately it  is  the  interaction  of  these  biophores — the  casting  out  of  some 
from  one  parental  stock,  the  retention  of  others  in  their  containing  deter- 
minants and  ids — that  determines  variation.  No  two  individuals  contain 
identical  groups  of  detenninants  and  identical  ids,  and,  as  these  control 
development,  therefore  no  two  individuals  are  identical.  If  in  reversion 
the  characters  of  an  ancestral  form,  it  may  be  hundreds  of  generations 
back,  are  reproduced,  this  is  because  in  the  process  of  reduction,  followed 
by  fusion,  of  the  two  parental  germ-plasms,  the  ancestral  ids  come  to 
predominate  to  the  exclusion  or  casting  out  of  the  ids  of  more  recent  gen- 
erations. Why  this  should  tend  to  happen  in  a  special  order  of  cases  the 
theory  does  not  venture  to  explain. 

The  reader  from  these  data  should  be  able  to  apply  the  theory  to  par- 
ticular cases.  It  has  also  to  be  added  that  Wcismann  holds  that  the 
development  of  the  individual  from  the  ovum  proceeds  in  such  a  way  that 
by  nuclear  division  it  is  brought  about  that  the  germ-cells  are  assured  of 
possessing  a  complete  set  of  ids,  whereas  the  body-cells  do  not  gain  this 
complete  set.  There  is  a  qualitative  differentiation  of  the  chromatin 
passing  to  what  are  to  be  the  eventual  tissues  of  one  or  other  order,  so 
that  ultimately  the  particular  determinants  find  themselves  in  control  of 
particular  groups  of  cells,  destined  to  produce  specific  tissues  or  parts  of 
tissues. 

There  is,  we  confess,  something  that  savors  of  medieval  scholasticism  in 
this  conception, — something  remote  from  our  general  conception  of  the 
order  of  natural  events,  and,  as  a  matter  of  fact,  the  whole  edifice  of  ids, 
determinants  and  biophores  collapses  when  confronted  with  the  findings 
of  physical  science.  Weismann's  biophores,  in  brief,  composed  as  he  im- 
agines them  of  numerous  molecules,  some  of  them  complex  and  of  large 
size,  must  be  smaller  than  are  individual  atoms!  We  can  in  certain 
nuclei  recognize  rows  of  granules  forming  the  individual  chromosomes — 
little  bodies  0.5  /i  or  less  in  diameter, — bodies  considerably  smaller 
than  the  micrococci  of  suppuration.  These  Weismann  regards  as  the 
individual  ids.  Each  id  is,  he  postulates,  made  up  of  determinants,  of 
which,  as  each  region  capable  of  variation  is  supposed  to  be  represented 
by  a  separate  determinant,  there  must  in  the  human  id  be  thousands 
rather  than  hundreds.  Each  determinant  is  made  up  of  biophores  or 
ultimate  units  of  living  matter;  each  biophore,  according  to  him,  consists 
of  a  group  of  molecules.  Each  molecule  is,  we  may  add,  composed  of 
numerous  atoms.  Now  Lord  Kelvin,  in  his  convincing  investigation 
into  the  size  of  the  molecule  of  water  (by  a  study  of  the  thinnest  possible 
films  of  a  bubble),  has  proved  that  in  a  line  0.5  fx  in  length  there  could  be 
only  about  150  molecules  of  water.  Let  us  be  generous  and  compute  the 
ids  as  being  not  on  the  average  0.5  but  1.0  /x  in  diameter,  and,  again  being 
generous,  let  us  compute  the  ultimate  molecule  of  living  matter  as  being 
only  thirty  times  the  size  of  the  molecule  of  water — from  every  considera- 
tion an  absurd  underestimate.  It  will  be  seen  upon  calculation  that  the 
id  (supposing  it  to  be  spherical)  can  contain  only  about  as  many  molecules 
as  presumably  Weismann  requires  for  one  or  two  biophores,  or  at  the 
most  economical  rate  for  a  single  representative  determinant;  and  not 
one,  or  tw^o,  or  three,  but  several  hundreds  of  determinants,  ought  to  be 
compressed  into  a  respectable  id. 


INHERITANCE  AND  DISEASE  39 

We  have,  in  short,  the  reductio  ad  ahsurdum  of  Weismann's  theory. 
But  if  "idants,"  "ids"  and  "determinants"  be  swept  away  and  we  accept 
the  existence  of  biophoric  molecules — of  individual  molecules  of  living- 
matter;^ — if,  that  is,  we  very  largely  dismiss  the  latter  part  of  the  theory, 
and,  in  place  of  this  purely  morphological  conception  of  heredity,  build 
upon  a  chemical  basis,  we  can  safely  utilize  much  of  Weismann's  super- 
structure of  carefully  collected  facts  and  develop  a  theory  which  satisfies. 
And  it  is  the  work  accomplished  of  recent  years  by  the  pathologist,  the 
bacteriologist,  and  the  physiological  chemist,  that  indicates  the  lines  such 
a  theory  must  take.  Space  forbids  that  in  these  pages,  that  theory  be 
fully  developed.    We  can  but  indicate  its  broad  outlines. 

A  Physico-Chemical  Theory  of  Inheritance. — 1.  The  studies  of  the 
physiologist  and  physiological  chemist  abundantly  indicate  that  all  vital 
activities  are  ultimately  the  expression  of  molecular  rearrangements  and 
combinations.  Life  is  therefore  the  expression  of  a  series  of  chemical 
changes,  and  the  material  endowed  with  life  must  be  of  such  a  nature  that 
it,  itself,  is  composed  of  molecules  which  react. 

2.  So  many  are  the  vital  reactions  even  of  the  simplest  microorgan- 
isms known  to  us  that,  employing  current  chemico-physical  concepts, 
we  must  regard  the  individual  molecule  endowed  with  vital  properties 
— the  biophore  (to  utilize  Weismann's  term) — as  of  relatively  great 
size  and  complexity.  We  best  conceive  it  as  a  central  ring,  resembling 
the  benzol  ring,  of  associated  carbon-containing  molecules  of  which  each 
member  has  side-chains  capable  of  being  satisfied,  the  peculiar  feature  of 
the  vital  system  being  that  as  a  whole  it  is  never  satisfied  and  so  is  con- 
stantly interacting,  and  has  the  capacity  to  act  upon  and  be  acted  upon 
by  the  surrounding  medium.  When  the  unsatisfied  molecules  forming  a 
side-chain  attach  to  themselves  other  atoms  or  radicals  from  the  sur- 

FiG.  2. 


rounding  medium  and  become  satisfied,  they  tend  to  form  an  independent 
simpler  system,  which  breaks  off,  leaving  once  more  an  unsatisfied  affinity 
in  the  main  system,  and  so  long  as  the  surrounding  medium  is  otherwise 

^  It  will  be  seen  that  our  conception  of  the  biophore  differs  a  little  from  that  of 
Weismann.  We  regard  it  as  the  unit  molecule  of  living  matter;  Weismann  makes 
it  his  unit  of  living  matter  but  composed  of  several  molecules.  We  employ  this 
self-explanatory  term  rather  than  commit  the  crime  of  adding  one  more  name 
to  the  long  list  of  those  intended  to  convey  what  is  practically  the  same  idea. 


40  HEREDITY  AND  PREDISPOSITION 

unaltered,  similar  atoms  or  radicals  are  once  more  attracted  or  attached, 
and  the  process  is  repeated. 

3.  The  dominant  vital  activity  is  growth  or  increase  in  the  amount  of 
living  matter;  all  the  other  proj^erties  of  living  matter  lead  up  to  and  sub- 
serve this.  With  the  conception  above  stated  of  the  nature  of  living 
matter  we  are  forced  to  recognize  that  growth  is  brought  about  by  a  pro- 
cess of  satisfaction  of  side-cnalns  in  such  a  way  that  in  connection  with 
any  given  biophoric  molecule  there  is  attracted  and  built  up  an  arrange- 
ment of  atoms  and  radicals  identical  with  those  of  the  central  ring,  which, 
when  completed,  breaks  off  as  above  indicated.  The  accompanying  figure 
(on  page  39)  diagrammatically  represents  the  process  here  suggested. 

Having  the  same  structure,  this  newly  formed  molecule  must  possess 
the  same  properties.  In  other  words,  by  such  a  process  of  identical  aggre- 
gation we  can  conceive  the  development  of  two  biophoric  molecules  in 
place  of  one. 

4.  In  such  a  system,  so  long  as  the  medium  and  the  physical  environ-, 
ment  remain  the  same,  for  so  long  will  the  constitution  and  properties  of 
the  biophoric  molecules  remain  unaltered.  There  will,  it  is  true,  be  a 
continual  "come  and  go"  of  side-chains,  so  that  at  any  particular  moment 
the  molecule  as  a  whole  will  vary  in  weight,  number  of  combined  carbon 
and  other  atoms,  etc.,  from  its  constitution  the  moment  before;  but  the 
average  composition  will  remain  unchanged. 

5.  Alteration  in  environment,  by  inducing  alteration  in  the  nature  and 
proportional  amounts  of  the  atoms  and  ions  in  the  surrounding  medium, 
must  in  such  an  unstable  system  bring  about  alteration  in  the  composition 
of  the  molecule,  provided  always  that  there  exists  a  positive  affinity  be- 
tween the  atoms  or  radicals  of  a  new  order  entering  the  medium  and  the 
unsatisfied  side-chains;  the  side-chain  affinities  must  become  satisfied  in 
a  different  manner,  and,  as  the  form  and  properties  of  the  individual  are 
the  expression  of  the  composition  of  these  biophoric  molecules,  the  form 
and  properties  must  inevitably  undergo  variation. 

6.  So  long  as  a  given  alteration  of  medium  persists,  for  so  long  will  the 
form  and  properties  of  the  individual  present  a  particular  alteration. 

Variation  must  tlius  he  regarded  as  prirnarily  introduced  by  alteration  in 
enviromnent.  This  woidd  seem  to  be  the  only  factor  causing  variation  in 
organisms  in  which  sexual  conjugation  has  not  been  developed;  i.  e.,  in 
asexual  protozoa. 

7.  Studying  such  organisms,  notably  the  bacteria,  another  property 
of  the  biophoric  substance  becomes  obvious,  the  property  which  alone, 
with  molecular  change  due  to  alteration  of  environment,  has  made  possible 
the  evolution  of  species.  The  longer,  or  the  more  intensely,  a  given  altera- 
tion of  environment  acts  upon  bacteria,  the  longer  it  is  before  there  is  a 
return  to  the  original  characters  when  these  bacteria  are  restored  to  their 
usual  habitat.  We  can  take  a  chromogenic  microbe  like  the  microba- 
cillus  prodigiosus,  and  grow  it  for  a  short  period  at  30°  C.  or  thereabouts, 
when  it  will  produce  colorless  colonies;  brought  back  to  the  room  tem- 
perature and  more  normal  environment,  and  the  new  colonies  will  rapidly 
resume  the  power  of  pigment  formation.  If  the  microbe  be  grown  for 
weeks  at  a  temperature  just  below  the  maximum,  or  be  subjected  for  five 
minutes  to  a  temperature  which  in  ten  minutes  would  surely  kill  every 
microbe  in  the  test-tube,  then  it  will  be  long  weeks,  and  hundreds,  not  to 


INHERITANCE  AND  DISEASE  41 

say  thousands,  of  generations,  before  the  power  of  pigment  production  is 
regained.  Roux  and  Nocard  cultivated  for  years,  under  the  ordinary 
conditions  of  the  laboratory,  races  of  non-spore- bearing  anthrax  bacilli, 
in  which  the  power  to  produce  spores  had  been  removed  by  temporary 
growth  of  the  parent  stock  in  solutions  of  carbolic  and  chromic  acid  just 
not  powerful  enough  to  destroy  the  organisms.  Or  otherwise  altered  en- 
vironment does  not  of  necessity  merely  alter  the  side-chains  of  the  bio- 
phoric  molecules  during  the  period  in  which  it  acts  upon  the  molecules; 
it  may  impress  upon  the  general  constitution  of  the  molecules  such  an 
alteration  of  constitution  that  this  is  retained  after  reversion  to  the  pre- 
vious environment.  That  is  to  say,  the  affinities  of  the  molecules  may  be 
more  or  less  permanently  altered.  We  can  in  this  way  not  merely  take 
away,  but  add  properties  to  bacteria;  we  can,  as  Vincent  has  shown, 
render  non-pathogenic  bacteria  actively  pathogenic.  It  is  only  a  matter 
of  degree,  not  of  kind,  between  the  loss  of  these  acquired  pathogenic 
properties,  when  such  bacteria  are  once  more  grown  under  ordinary 
laboratory  conditions,  and  the  loss  of  pathogenicity  shown  by  definitely 
pathogenic  species  such  as  the  bacillus  typhosus  when  grown  outside  the 
body. 

The  work  of  the  last  few  years  in  physiologicpl  chemistry  indicates 
more  and  more  clearly  that  when  food-stuffs  are  assimilated,  they  are  not 
taken  up  in  an  unaltered  form  and  directly  combined  into  the  cytoplasm, 
but,  on  the  contrary,  undergo  a  disintegration  into  more  elementary  con- 
stituents, and  these  it  is  that,  present  within  the  cell  and  diffused  in  the 
spaces  of  the  cell-substance,  form  the  matter  from  which  the  biophoric 
molecules  attract  and  combine  the  atoms  and  radicals  which  become  built 
up  into  their  substance. 

Variation  and  the  assumption  of  new  properties  indicate,  therefore, 
that  under  the  influence  of  altered  environment  the  biophoric  molecules 
gain  the  power  of  attracting  new  combinations  of  atomc  and  of  forming 
side-chains  of  altered  type.  We  are  forced  to  realize  that  once  the  bio- 
plasmic  molecule  has  formed  a  new  side-chain  it  tends  to  continue  to  form 
that  particular  form  of  side-chain  by  attracting  particular  orders  of  atoms 
and  radicals  from  the  surrounding  medium,  even  when  the  old  environ- 
ment is  again  set  up,  and  what  is  more,  that  sooner  or  later  the  new 
biophores  built  up  from  the  side-chain  materials  come  to  differ  in  their 
constitution  from  .the  old. 

The  conception  of  properties  of  this  nature  on  the  part  of  a  chemical 
substance  may  seem  revolutionary.  It  appears  to  demand  at  first  sight 
that  a  particular  "ring"  which  at  one  time  attracted  as  side-chains  one 
particular  group  of  atoms,  obtains  the  habit  of  attracting  another  group, 
and  this  despite  the  fact  that  components  of  the  former  group  are  still  in 
its  immediate  vicinity.  But  in  imagining  this  we  fall  into  the  same  error 
as  did  Weismann  with  his  eternity  of  the  germ-plasm.  It  is  not  the  old 
"rings"  that  have  taken  on  the  new  properties,  but  newly  formed  rings, 
developed  primarily,  it  is  true,  according  to  our  conception  of  gro^i;h,  in 
connection  with  the  old;  but  these  nevertheless  are  separate  combina- 
tions of  radicals  with  sfightly  different  arrangement  of  constituents  and 
therefore  slightly  different  properties  and  affinities. 

8.  The  same  is  true  regarding  individual  body-cells  of  the  multicel- 
lular organism.    Workers  in  bacteriology,  at  the  present  day  recognize 


42  HEREDITY  AND  PREDISPOSITION 

that  the  conception  of  central  rings  witli  side-chains  capable  of  renewal 
and  rephicement  by  side-chains  of  another  order,  of  satisfaction  of  the 
side-chains  and  casting  loose  of  the  same  into  the  surrounding  medium, 
is  the  only  concept  fitted  to  explain  the  phenomena  of  recovery  from 
infection,  and  immunity.  Under  the  action  of  bacterial  toxins  certain 
cells  gain  new  or  exalted  properties.  Certain  side-chains,  it  is  held, 
combine  with  and  neutralize  these  toxins,  and  when  satisfied  these 
side-chains  are  cast  loose  and  others  are  formed;  nay  more,  arc  formed 
in  excess  and  cast  loose  in  an  unsatisfied  condition  to  form  the  antitoxic 
substances  present  in  the  blood-serum.  In  cases  of  long-continued  im- 
munity it  is  obvious  that  the  bio{)lasm  of  the  cells  once  incited  to  form 
side-chains  having  a  specific  reaction  with  specific  toxins, — or  with  vege- 
table poisons  such  as  abrin  and  ricin,  is  henceforth  altered.  The  new 
biophoric  molecules  developed  in  the  course  of  growth  retain  for  a  shorter 
or  longer  period  the  properties  impressed  on  the  earlier  molecules,  and 
this  in  the  absence  of  the  specific  toxin  or  poison.  Heredity,  as  dis* 
tinct  from  variation,  must  be  regarded  as  the  expression  of  this  tendency 
on  the  part  of  biophoric  molecules  to  attract  to  themselves  and  build 
up  into  new  biophoric  molecules  identical  ions  of  atoms  and  radicals. 

9.  Before  discussing  sexual  conjugation  and  its  effects  upon  inheri- 
tance and  variations,  it  is  necessary  to  say  a  word  regarding  cell  structure. 
The  argument  that  in  the  nuclear  matter  is  contained  the  heritable  sub- 
stance seems  to  us  impregnable.  We  must  regard  the  biophoric  molecules 
as  contained  in  the  nucleus,  and  our  conception  of  the  cell  and  its  peculiar 
structure  in  all  higher  forms  of  life  must  be  that  the  division  into  nucleus 
and  cytoplasm  is  an  arrangement  whereby  the  highly  differentiated  bio- 
phoric molecules,  unable  to  act  directly  on  the  surrounding  outer  medium, 
become  surrounded  by  an  intermediate  preparatory  medium,  the  cyto- 
plasm, the  component  molecules  of  which  are  not  biophores.  The 
nucleus  alone  cannot  maintain  life;  neither  can  the  cytoplasm  alone  exhibit 
growth.  At  most  this  latter  can  assimilate  and  form  paraplasmic  sub- 
stances which  in  the  absence  of  the  nucleus  do  not  become  part  and  parcel 
of  the  bioplasm;   the  nucleus  is  essential  for  grototh} 

10.  If  we  accept  this  view  of  the  nature  of  the  biophores  it  is  not  neces- 
sary to  demand,  as  does  Weismann,  that  there  is  conveyed  to  the  off- 
spring in  the  germ  two  forms  of  matter — that  constituting  the  germ-plasm 
and  that  forming  the  somatic-plasm,  the  latter  controlling  the  develop- 
ment of  the  individual  tissues  and  cells  of  the  organisms,  the  former 
alone  able  to  react  at  the  proper  time  and  initiate  the  development  of  the 
offspring.  Such  a  conception  introduces  unending  confusion.  Taking 
the  simplest  case,  that  of  a  multicellular  organism  developed  asexually  by 
parthenogenesis,  our  conception  must  be  that  as  the  ovum  segments  and 
the  cells  assume  different  relationships  the  one  to  the  other,  and  to  the 
surrounding  medium,  the  influences  acting  on  the  various  orders  of  cells 
vary,  and  with  this  variation  the  constitution  of  the  biophores  present 
and  "growing"  in  the  nuclei  of  the  difFerent  cell-groups,  undergoes  a  co- 
incident alteration;  so  that,  for  example,  the  biophores  in  the  eventual 
muscle-cell  possesses  a  different  constitution  from  those  in  a  nerve-cell. 

^I  have  discussed  more  fully  this  dominance  of  the  nucleus  and  its  relation  tc 
the  cytoplasm  in  an  address  at  the  Toronto  meeting  of  the  British  Medical  Asso- 
ciation.    British  Medical  Journal,  1906,  II. 


INHERITANCE  AND  DISEASE  43 

Whether  such  a  speciahzed  cell  under  any  conditions  multiplies  and  gives 
rise  to  the  complete  individual — as  happens,  to  quote  trite  examples,  in 
the  case  of  certain  cells  of  the  hydra  and  v^^ith  the  cells  of  the  begonia-leaf 
— depends  upon  the  extent  of  the  departure  of  the  biophores  from  their 
primordial  constitution  in  the  germ-cell;  or,  perhaps  more  correctly, 
upon  the  tenacity  with  vi^hich  they  retain  that  original  constitution.  We 
may  imagine  that  in  such  cases  the  central  ring  remains  unaltered,  the 
cell  differentiation  being  the  result  purely  of  modification  in  the  side- 
chains;  the  newly  formed  biophores,  responsive  to  the  change  in  envi- 
ronment, develop  side-chains  of  the  primordial  type,  and  so  are  capable 
of  developing  the  whole  individual.  The  relationship  of  what  are  to  be 
the  germ-cells  in  a  multicellular  organism  are  such  that  in  the  process  of 
their  development  the  contained  biophores  depart  least  in  constitution 
from  the  biophores  of  the  ovum  from  which  they  have  developed.  Thus 
the  properties  of  any  individual  cell  are  to  be  regarded  as  the  outcome  of 
(a)  the  constitution  of  the  biophoric  molecules  passing  into  the  cell  at  its 
formation  as  a  separate  unit;  and  (6)  the  alteration  in  those  molecules 
and  their  derivatives  induced  by  the  forces  acting  upon  the  cell. 

11,  The  biophores  contained  in  the  germ-cells  of  an  individual  are  not 
those  contained  in  the  germ-cells  of  the  parents ;  they  are  the  6utcome  of 
the  ovum  by  growth,  and  as  in  general  they  have  been  subjected  to  a  like 
environment,  so  in  general  they  have  (with  certain  reservations  to  be 
discussed  later)  the  same  constitution.  But  just  as  with  growth  the  bi- 
ophores of  the  body-cells  are  capable  of  alteration  in  constitution,  so  in 
their  growth  the  biophores  of  the  germ-cells  may  be  modified,  and  that  by 
like  causes;  namely,  by  diffusible  substances  circulating  in  the  nutritive 
fluids,  as  also  by  purely  physical  influences  telling  upon  the  organism  as  a 
whole. 

The  difficulty  in  determining  that  influences  of  this  nature,  telling  upon 
the  body  generally,  affect  also  the  germ-cells,  lies  in  this,  that  in  man  and 
mammals  the  growing  embryo  is  nourished  by  the  maternal  tissues,  and 
so  where  the  mother  is  subjected  to  deleterious  conditions  it  is  difficult, 
not  to  say  impossible,  to  distinguish  surely  between  conditions  due  to  pre- 
conceptional  disturbance  of  the  ovum  and  those  due  to  placental  absorp- 
tions after  fertilization;  and  considering  man  more  particularly,  it  is 
difficult  to  collect  a  sufficient  number  of  cases  in  which  the  evidence  is 
positive  that  the  mother  has  been  normal,  the  father  alone  the  subject  of 
one  or  other  form  of  intoxication — alcoholic,  tuberculous,  etc. 

It  is,  for  example,  a  matter  of  common  belief  that  paternal  alcoholism 
is  frequently  associated  with  the  development  of  offspring  of  a  lower  vi- 
tality, and  more  particularly  exhibiting  mental  instability.  I  am  inclined 
to  hold  that  this  belief  is  well  founded.  At  the  same  time  I  must  admit 
that  sound  statistical  evidence  in  its  favor  is  lamentably  lacking.  Simi- 
larly the  influence  of  paternal  tuberculosis  alone,  not  as  inducing  active 
tuberculosis  in  the  offspring,  but  in  producing  what  may  be  termed  para- 
tuberculous  lesions,  has  not  been  adequately  worked  out.  Too  many  other 
factors  have  to  be  taken  into  consideration:  possible  tuberculous  diathe- 
sis already  inherited  by  the  parent,  the  environment  of  the  young  child, 
etc.  Nevertheless  we  have  a  certain  amount  of  evidence  showing  that 
this  is  actually  the  case — that  paternal  intoxication  does  influence  the 
semen  and  leads  to  the  production  of  vitiated  progeny.    More  than  one 


44  HEREDITY  AND  PREDISPOSITION 

recent  observer  has  directed  attention  to  the  fact  that  in  the  case  of  mon- 
strous births  it  is  noticeable  how  frequently  the  history  is  obtainable  that 
one  or  other  parent  had  suffered  from  some  acute  infection  shortly  before 
conception.  Mairet  and  Combcmale'  subjected  male  dogs  to  acute  and 
chronic  alcoholic  intoxication  and  found  that  the  young  exhibited  various 
arrests  of  development  and  were  subject  to  cpileptoid  seizures.  And  as 
regards  man,  1  have  never  seen  any  refutation  of  Constantine  Paul's 
striking  observations  made  in  the  "sixties"  upon  the  effects  of  paternal 
lead-poisoning — cases  in  which  in  the  course  of  his  work  the  father  was 
subjected  to  plumbism,  the  mother  being  unaffected.  He  obtained  the 
history  of  32  pregnancies  of  this  order;  of  thena  12  resulted  in  the  death 
of  the  fcetus  before  term;  20  children  were  born  alive  but  8  of  them  died 
during  the  first  year,  4  during  the  second,  5  during  the  third;  only  2  were 
living,  1  of  whom  had  reached  the  age  of  twenty.  Children  so  born  were 
found  particularly  liable  to  various  nervous  affections. 

More  recent  work  along  the  same  lines  is  contained  in  the  interesting* 
studies  by  Lustig,"  of  Florence.  Lustig  was  retesting  the  observations  of 
Ehrhch  and  others  upon  the  transmission  of  acquired  immunity.  To 
do  away  with  the  confusion  introduced  by  intra-uterine  existence  he 
employed  fowls,  and  rather  than  employ  bacterial  infections  or  toxins,  he 
chose  a  vegetable  poison  abrin.  By  repeated  inoculations  of  increasing 
amounts  he  gained  an  extremely  high  grade  of  immunity,  so  that  for  as 
much  as  two  years  the  birds  were  unaffected  by  minimum  fatal  doses  of 
the  poison.  While  he  was  unable  to  demonstrate  that  the  young  had 
acquired  any  immunity — on  the  contrary  they  appeared  to  be  more  sus- 
ceptible— he  notes,  without  comment,  one  very  remarkable  fact,  viz., 
that  mating  together  immunized  animals  even  a  year  after  the  injections 
had  ceased,  the  majority  of  the  eggs  did  not  come  to  maturity,  but  con- 
tained monsters,  and  even  of  the  few  chickens  that  were  hatched  several 
were  very  feeble  and  some  showed  distinct  anomalies.  The  animals  had 
apparently  quite  recovered  from  the  injections,  and  the  only  explanation 
for  this  remarkable  series  of  monsters  must  be  that  the  germ-cells,  both 
paternal  and  maternal,  had  been  acted  upon  and  permanently  modified 
by  the  abrin.  Unfortunately  not  realizing,  apparently,  the  bearing  of  these 
results,  Lustig  does  not  seem  to  have  studied  the  effects  of  mating 
an  immunized  domestic  cock  with  a  non-immunized  hen.  We  have  our- 
selves attempted  work  along  these  directions  with  rabbits,  giving  the 
bucks  minute  doses  of  lead-salts  over  long  periods,  and  our  results,  so  far 
as  they  go,  would  indicate  that  the  germ-cells  have  been  seriously  affected. 
But  unfortunately  an  epizootic  of  rabbit  septicaemia  so  affected  our  ex- 
perimental animals  that  we  are  unable  to  state  more  at  the  present 
moment  than  that  our  experiments  certainly  favored  and  did  not  contra- 
dict the  view  here  indicated. 

It  may  be  objected  that  in  all  these  cases  we  are  dealing  with  degenera- 
tive and  not  progressive  changes  in  the  germ-cells.  We  would  only  reply, 
if  our  view  regarding  the  constitution  of  the  molecules  of  living  matter  at 
all  approximates  to  the  truth,  then,  if  it  can  be  shown  that  the  biophores 
may  be  deleteriously  affected  by  diffusible  poisons,  it  is  obvious  that 

^Ctes.  rend.  Acad.  d.  Med.,  Paris,  March  15,  1888. 
^Lustig:   Centralbl.  f.  ally  Pathologic,  15,  1904,  210. 


INHERITANCE  AND  DISEASE  45 

other  combinations  are  possible,  leading  to  what  wc  would  term  favorable 
or  progressive  modifications  in  their  side-chains. 

If^  therefore,  we  accept  this  variation  of  the  biophores  of  the  germ-cells 
by  influences  which  affect  the  other  tissues  of  the  paternal  organism,  we 
gain  a  comprehension  of  why  it  is  that  not  merely  is  the  offspring  not 
identical  with  either  parent,  but  why  it  is  not  even  the  mean  of  the  two 
parents. 

12.  We  see  also  why  it  is  that  there  is  not  an  identical  composition  of 
the  nuclear  material  from  the  two  parents,  which,  uniting,  originates  the 
new  individual;  and  that  in  the  amphimixis  or  fusion  of  the  dissimilar 
biophores  we  have  another  cause  of  individual  variation. 

What  is  the  nature  of  this  amphimixis  ?  We  cannot,  with  the  data  at 
our  disposal,  regard  it  as  an  immediate  chemical  combination  of  maternal 
and  paternal  biophores.  In  not  a  few  forms  in  which  the  stages  of  seg- 
mentation of  the  ovum  has  been  carefully  followed  it  has  been  established 
that  for  a  considerable  period,  at  least,  the  paternal  and  maternal  chro- 
mosomes, while  lying  side  by  side,  remain  nevertheless  distinct;  and  upon 
chemical  and  physical  grounds  it  is  difficult  to  conceive  a  true  conjunc- 
tion or  chemical  combination  between  elaborate  molecules  of  closely 
allied  constitution. 

This  does  not,  however,  mean  that  we  are  compelled  to  accept  Weis- 
mann's  theory  that  ids,  or  groups  of  biophores,  derived  from  long  gen- 
erations back,  each  of  which  has  preserved  its  individual  characters, 
are  contained  in  the  germ-cell.  No  such  deduction  is  necessary.  The 
studies  stimulated  by  Ehrlich's  remarkable  work  indicate  another  and  a 
more  rational  conception.  We  need  but  to  refer  what  has  been  observed 
in  connection  with  the  phenomenon  of  cytolysis.  To  give  an  example: 
histologically,  and  in  their  functions,  the  red  corpuscles  of  a  horse  and  a 
rabbit  or  a  guinea-pig  are  curiously  similar.  Yet  clearly  they  are  of  differ- 
ent molecular  constitution ;  the  one  cannot  replace  the  other.  Introduce 
the  red  corpuscles  of  the  horse  into  the  rabbit  and  they  are  destroyed; 
and,  what  is  more,  the  injection  of  these  corpuscles  leads  to  such  a  reaction 
on  the  part  of  the  rabbit's  organism  that  its  blood-serum  for  some  con- 
siderable period  possesses  the  power  of  breaking  up  the  horse's  red 
blood-corpuscles.  That  in  nature  the  equine  erythrocytes  should  gain 
admission  into  the  blood  of  the  rabbit  is  a  sheer  impossibility;  never- 
theless, the  rabbit's  tissues  produce  substances  which  destroy  the  foreign 
red  corpuscles;  they  adapt  themselves  to  dealing  with  a  novel  compound; 
and  they  do  more — they  continue  to  discharge  into  the  blood-serum  a  sub- 
stance which  is  capable  of  breaking  up  the  red  corpuscles  so  that  the  rab- 
bit's serum  now  causes  a  rapid  disintegration  of  the  corpuscles  of  the 
horse,  although  the  same  serum  may  be  without  effect  on  the  red  cor- 
puscles of  other  species.  We  explain  this  according  to  Ehrlich's  theory  by 
the  development  of  side-chains  on  the  parts  of  the  cells  {i.  e.,  of  the  cell 
molecules)  of  the  one  animal,  which,  uniting  with  the  side-chains  of  the 
molecules  of  the  foreign  red  corpuscles,  set  up  such  constitutional  disturb- 
ance that  the  corpuscles  become  disintegrated.  Here  I  shall  not  discuss 
the  process  at  length.  What  I  wish  to  call  attention  to  is  that  now-a-days 
we  accept  this  view  that  molecules  of  organic  matter  which  are  apparently 
closely  allied  in  function  and  structure  act  the  one  upon  the  other  not 


46  HEREDITY  AND  PHEDISPOSITIOX 

directly,  but  through  their  side-chains,  whether  these  chains  remain  at- 
tached to  the  central  ring  or  whether  these  have  become  liberated  and  are 
free  in  the  surrounding  medium. 

Let  us  apply  this  idea  to  the  fertilized  germ-cell.  Our  conception  so 
far  has  been  that  the  paternal  and  maternal  biophores  are  of  closely  allied 
constitution  We  may  indeed  regard  the  central  rings  in  individuals  of 
the  same  race  as  identical,  the  side-chains,  or  some  of  them  only,  as  dif- 
ferent. It  is  conceivable  that  when  these  allied  biophores  exist  side  by 
side  within  the  germ-cell  a  process  takes  place  similar  to  that  above  indi- 
cated. If  we  acce})t  Ehrlich's  theory  in  its  broad  outline  we  are  justified 
in  supposing  that  such  allied  though  diverse  bioi)h()]'es  existing  side  by 
side  are  not  inert;  that  as  they  grow — i.  c,  as  they  assimilate  other  groups 
of  atoms  to  form  side-chains — through  these  side-chains  they  are  capable 
of  acting  one  on  the  other  in  the  same  way  as  molecules  of  difl'erent 
species — and  even  of  different  individuals  of  the  same  species — have  been 
found  to  act  one  on  the  other,  i'.  e.,  through  their  side-chains.  If,  for 
example,  the  biophores  of  paternal  origin  form  one  particular  order  of 
side-chains,  these,  becoming  liberated  into  the  cytoplasm,  may  become 
attracted  to  and  may  satisfy  the  molecules  of  the  maternal  biophore; 
and  just  as  certain  cells  in  the  rabbit  in  the  presence  of  the  horse's  red 
blood-corpuscles  gain  the  property  to  form  new  affinities  when  side-chains 
of  the  equine  erythrocyte  molecules  are  present  in  their  neighborhood, 
so  gradually  with  "growth"  in  association  Vv'ith  the  paternal  biophores 
the  maternal  biophores  may  be  modified  to  this  extent  that  in  them 
certain  side-chains  become  replaced  by  side-chains  of  paternal  type. 
This  we  regard  as  the  true  amphimixis— ^a  gradual  progressive  inter- 
change of  properties  and  mutual  rearrangement  of  constituent  mole- 
cules tending  in  the  main  to  the  biophores  of  the  two  orders  becoming 
identical,  but  varying  in  the  results  according  to  the  nature  and  prop- 
erties of  particular  side-chains,  and  this  even  though  we  accept  Weis- 
mann's  contention  and  regard  the  biophores  and  chromosomes  of  paternal 
and  maternal  origin  respectively  as  continuing  to  occupy  for  some  con- 
siderable period  a  definite  position  in  the  nucleus  in  regard  one  to  the 
other. 

Along  these  lines  we  can  postulate  cases  in  which  the  side-chains  of  a 
particular  order  from  the  one  source  completely  replace  those  from  the 
other — exclusive  inheritance.  We  can  further  suppose  cases  in  which 
they  antagonize  or  neutralize  each  other,  leading  to  the  practical  loss  of 
the  side-chains  of  one  order,  whereby  the  biophore  assumes  a  simpler  type 
of  constitution;  or,  more  exactly,  the  individual  developed  from  the  con- 
junction of  the  biophores  of  two  orders  is  deficient  in  a  particular  property 
or  group  of  associated  properties.  We  can  thus  understand  the  phenome- 
non of  reversion  and  of  sports  of  defect.  It  is  further  possible  to  compre- 
hend along  these  lines  cases  in  which  side-chains  of  a  particular  order 
augment  each  other — in  which,  that  is,  a  biophore  gains  a  combination  of 
the  side-chains  of  a  particular  order  of  both  paternal  and  maternal  origin. 
Or  otherwise  we  can  understand  progressive  inheritance  and  production 
of  mutations  and  sports  of  excess. 

In  such  a  process  of  amphimixis  as  here  indicated  the  tendency  must 
clearly  be  that  of  replacement  or  augmentation  of  weaker  chemical  affinities 
by  stronger  ones;  and  so  we  should  not  expect  to  find  that  all  the  various 


INHERITANCE  AND  DISEASE  47 

side-chains  with  their  peculiar  properties  belonging  to  one  set  of  biophores 
should  replace  those  of  the  other  set;  or,  in  other  words,  that  the  biophores 
of  the  maternal  type,  for  example,  should  wholly  replace  those  of  the 
paternal  type.  There  would  tend  rather  to  be  a  certain  amount  of  give  and 
take  and  interchange  depending  on  the  affinities  of  the  particular  biophores. 
Further,  it  is  essential  to  regard  the  side-chain  molecules  as  attracted 
in  series  to  form  chains.  And,  also,  judging  from  what  we  know  regard- 
ing immunity,  we  must  infer  the  existence  of  the  law  that  the  i)roperties  of 
the  oldest  acquirement  are  most  tenaciously  retained,  and  those  of  most 
recent  acquirement  most  easily  lost.  Or,  otherwise,  granting  that  a  bio- 
phore  or  biophoric  molecule  acquires  new  side-chains  in  this  interaction 
with  biophores  of  different  origin,  if  that  biophore  and  its  products  be  re- 
moved from  the  influence  of  this  interaction  it  may,  with  relative  ease, 
lose  the  power  of  forming  these  newer  combinations,  and  in  a  new  en- 
vironment revert  to  the  earlier  affinities  and  properties. 

But  to  enter  at  length  into  these  different  possibilities  regarding  the 
interaction  of  maternal  and  paternal  biophores  in  the  germ-cells  is  beyond 
the  scope  of  this  article.  It  may  indeed  be  urged  that  we  have  already 
entered  into  this  matter  at  too  great  a  length,  even  though  we  have  sought 
to  compress  our  presentation  of  the  theory  into  the  smallest  possible  space 
compatible  with  clearness.  But  having  mentioned  and  accepted  Mendel's 
law  for  cases  of  exclusive  inheritance,  it  is  necessary  that  we  should  indi- 
cate how  the  theory  applies  to  this  particular  order  of  phenomena. 

Suppose  we  take  four  marbles,  two  black  and  two  white,  and  shaking 
them  together  let  them  fall  out  of  the  box  two  and  two,  and  in  doing  this 
test  how  often  we  obtain  in  successive  casts,  (a)  a  pair  of  blacks;  (6)  a 

f)air  of  whites ;  and,  (c)  a  combination  of  one  black  with  one  white.  A 
ittle  consideration  will  show  that  the  chances  are  equal  that  the  first 
marble  to  emerge  will  be  either  black  or  white,  and  that  they  are  equal 
whether  the  first  combination  to  be  cast  will  be  a  pair  of  the  one  color  or 
a  combination  of  the  two.  If  the  first  pair  to  emerge  be  a  black  pair  the 
next  must  be  a  white  pair;  if  the  first  two  out  of  the  four  marbles  be  a 
white  and  a  black,  the  next  two  must  also  be  white  and  black.  The 
same  will  be  true  whether  we  deal  with  only  two  pairs  or  200  pairs.  Or, 
otherwise,  for  every  B  B  and  W  W  combination  recorded  once  the  B  W 
combination  will  be  recorded  twice,  and  the  sum  of  repeated  casts  will  be 
some  multiple  of  the  formula  BB  +  2BW  +  WW. 

It  would  seem  obvious  that  to  explain  Mendel's  law  we  must  accept  the 
view  that  in  the  germ-cells  the  paternal  and  maternal  chromosomes  (with 
their  contained  biophoric  molecules)  do  not  fuse,  but  remain  independent 
if  associated  series,  undergoing  coequal  growth  and  multiplication  as  the 
germ-cells  proliferate  (as  indeed  would  seem  to  be  indicated  by  the 
studies  of  Conklin  and  Hacker).  What  is  the  simplest — we  do  not  say 
that  it  is  the  correct — method  of  grasping  what  happens  is  to  suppose 
that  the  nucleus  of  the  sperm  mother  cell  at  one  stage,  of  what  Moore 
terms  the  maiotic  process,  presents  a  complete  separation  of  the  chro- 
matin of  paternal  and  maternal  origin  respectively,  so  that  of  the  four 
spermatozoa  which  eventually  result,  two  carry  on  the  biophores  of 
paternal  origin,  two  those  of  maternal.  And  similarly  that  in  the  devel- 
opment of  the  ovum,  with  the  discharge  of  the  first  polar  body  all  of  one 
group  of  biophores  either  paternal  or  maternal  become  removed,  and 


48 


HEREDITY  AXD  PREDISPOSITION 


with  the  discharge  of  the  second  polar  body  there  is  reduction  with  loss 
of  one-half  of  the  chromatin,  whereby  the  ovum  comes  to  contain  an 
amount  of  chromatin  —  or  number  of  biophores — of  either  paternal  or 
maternal  descent,  equivalent  to  the  amount  of  chromatin  and  number  of 
biophores  in  the  ripe  spermatozoon.  If  now  these  ova  and  spermatozoa 
fuse,  as  indicated  by  the  diagram,  the  proportion  of  progeny  afforded  by 
the  hybrids  will  be  in  the  proportion  demanded  by  Mendel's  law.  In 
the  diagram  the  black  dots  indicate  dominant,  white  circles  recessive, 
biophores,  as  well  as  paternal  and  maternal  origin. 


Fig.  3. 


SfiiT/f/V  MOTHER  CELL  (HYBRID), 

giving  rise  to  four 
spermatozoa. 


OOCYTES  (HYBRID), 
giving  rise  each  to  one  Oi/am,  by  reduction. 


hybrid. 
DR 


Recessive. 
RR 


To  afford  Mendel's  formula  for  cases  in  which  there  is  more  than  one 
pair  of  mutually  exclusive  properties  it  is  necessary  to  invoke  in  addition 
the  principle  already  dwelt  upon;  i.  e.,  that  of  interchange  of  side-chains 
between  the  bioi)hores  of  the  two  series.  We  must  suppose  that  Avhile  the 
series  of  developing  biophores  of  maternal  or  paternal  origin  remain 
distinct,  those  of  the  one  set  have  the  greater  affinity  for  particular  orders 
of  side-chain  radicals.  We  must  conceive  them  as  attracting  those 
orders  and  leaving  the  others  to  be  taken  up  by  the  other  set.  By  this 
means,  although  the  biophores  of  the  one  set  would  still  remain  in  series, 
the  side-chains  would  become  crossed,  and  by  successive  acts  of  fertili- 
zation, there  would  be  developed  the  series  of  forms  represented  by  Men- 
del's formula. 

Complicated  as  the  theory  must  seem  when  first  read,  the  more  it  is 
studied  the  more  fully  we  beUeve  it  will  be  found  to  fit  in  and  accord  with 
the  facts  at  present  known  and  established  with  regard  to  heredity.    We 


INHERITANCE  AND  DISEASE  49 

owe  it  perhaps  to  ourselves  to  explain  that  it  has  not  blossomed  suddenly, 
but  is  the  outcome  of  more  than  fourteen  years  of  study,  the  basal  concep- 
tion— that  primarily  variation  is  due  to  altered  environment — having 
been  borne  in  upon  us  by  an  investigation  into  the  variability  of  bacteria, 
in  1891.^  Its  development,  we  may  add,  has  essentially  been  brought 
about  by  a  consideration  of  the  problems  of  the  inheritance  of  morbid 
conditions.  We  may  add  that  it  gains  strong  support  from  recent  botanical 
studies  which  show  that  by  the  action  of  external  agents  upon  the  ovules 
of  seed  plants,  certain  parental  qualities  may  be  suppressed  and  new 
qualities  gained,  and  this  it  would  seem  not  temporarily,  so  that  actual 
departures  from  the  course  of  the  hereditary  strain  may  be  induced.^ 

To  sum  up  briefly  our  views  with  regard  to  the  inheritance  of  disease, 
they  may  be  expressed  as  follows: 

1.  There  cannot  be  homologous  inheritance  of  gross  structural  dis- 
turbances. 

2.  There  is  no  true  inheritance  of  infectious  disorders. 

3.  The  only  possible  inheritance  of  conditions  acquired  by  the  parents 
is  that  of  conditions  which  act  upon  and  affect  the  bodily  tissues  of  the 
parent  and  affect  also  the  germ-cells. 

These  conditions  may  be  of  two  orders: 

(a)  Extrinsic  and  Direct.  —  Chemical  and  physical  conditions  intro- 
duced from  or  acting  from  without  may  simultaneously  bring  about 
modifications  in  the  constitution  both  of  the  somatic-  and  the  germ-cells. 
As  the  germ-cells  are  part  and  parcel  of  the  parent  at  a  period  when  such 
a  modification  could  or  does  occur,  it  is  futile  to  urge  that  such  modifica- 
tions are  not  strictly  instances  of  transmission  of  parental  acquirements. 
If  this  be  accepted  we  must  admit  that  parental  intoxications,  whether 
from  absorbed  chemical  substances  or  resulting  from  the  growth  of 
pathogenic  organisms,  may  influence  the  organism,  and  that,  in  all  proba- 
bility the  different  toxins  or  poisons,  acting  differently  upon  the  molecules 
of  the  germ-cells,  may  lead  to  the  offspring  becoming  modified  in  its 
development  in  one  or  other  particular  direction. 

(b)  Intrinsic  and  Indirect. — It  is  conceivable  that  specific  influences 
acting  upon  one  or  other  organ  of  the  parent,  or  again  the  destruction  or 
arrest  of  action  of  an  organ  or  part,  may  so  disturb  general  metabolism 
that  the  absence  of  normal  metabolites  or  presence  of  abnormal  metab- 
olites in  the  circulating  blood  may  influence  the  nutrition  of  the  germ- 
cells,  bringing  about  alterations  in  the  constitution  of  the  germinal 
biophores  and  resulting  alteration  in  the  constitution  of  the  offspring. 

Metabolic  disturbances  in  the  parent — gout  and  the  rheumatoid  states, 
for  example;  defect  or  excess  of  internal  secretions — may  tell  upon  the 
germ-cells.  It  is  conceivable  that  the  organism  as  a  whole  which  origi- 
nates from  the  modified  or  Aveakened  germ-cells  may  exhibit  a  special  sus- 
ceptibility toward  the  effects  of  that  particular  order  of  compounds 
which  primarily  caused  alterations  in  the  constitution  of  the  molecules 

^On  the  Variability  of  Bacteria  and  the  Development  of  'Races,  Manches- 
ter Medical  Chronicle,  September,  1892.  Other  articles  upon  'Growth'  (Jacobi, 
Festschrift,  1900,  and  on  Inheritance,  New  York  Medical  Journal,  1901,  and  BiLck's 
Reference  Hand-book,  Heredity  and  Disease,  2d  edition),  show  the  development  of 
the  views  here  brought  forward. 

2 See  D.  T.  Macdougall:  Popular  Science  Monthly,  September,  1906. 
4 


50  HEREDITY  AND  PREDISPOSITION 

of  the  germ-ccU.  Alono;  these  hues  we  best  comprehend  the  development 
and  inheritance  of  diatheses. 

While  admitting  these  possibilities,  two  counteracting  influences  have 
nevertheless  to  be  kept  in  mind:  (a)  The  fact  that  the  individual  is  the 
product  of  the  interaction  of  the  germinal  matter  derived  from  two 
sources  whereby  the  constitution  of  the  germinal  matter  from  the  one 
parent  may  be  neutralized  in  its  effects  to  a  greater  or  less  extent  by  the 
constitution  of  the  germ-plasm  from  the  other  parent  (the  many  different 
ways  in  which  this  interaction  may  show  itself  need  not  here  be  recalled; 
they  have  been  discussed  and  classified  in  the  preceding  pages) ;  and  {h) 
the  action  of  the  law  already  noted  that  properties  of  recent  acquirement 
are  those  which  are  most  easily  lost;  so  that  biophores  modified  by  sub- 
jection to  temporary  influences  may  upon  reversion  to  a  more  normal 
environment  give  rise  to  new  biophores  approximating  to  or  gaining  the 
original  constitution. 

There  may  further  be  a  true  inheritance  of  morbid  conditions  due  not  to 
the  transmission  of  a  property  or  defect  through  the  germ-cells  of  either 
parent  (and  observable,  if  not  in  the  parent,  at  least  in  the  parental 
stock),  but  to  the  interaction  of  the  two  germ-plasms  in  fertilization;  or, 
more  exactly,  due  to  the  modification  in  the  biophoric  molecules  by  the 
interaction  of  their  side-chains. 


PART   II. 

DISEASES  CAUSED  BY  PHYSICAL  AGENTS. 


CHAPTER  11. 

LIGHT.    X-RAYS.    ELECTRICITY. 
By  ALFRED  GORDON,  M.  D 

PHYSIOLOGICAL  EFFECTS  OF  LIGHT. 

The  modern  conception  of  organic  and  inorganic  life  embraces  vari- 
ous conditions.  They  are  not  all  equally  necessary  for  living  organisms: 
while  some  are  absolutely  indispensable,  others  play  only  a  secondary 
role.  Light  belongs  to  the  category  of  objects  without  which  both  plant 
and  animal  life  are  impossible.  Light  makes  available  chemical  energy 
in  the  plant-cell,  and  out  of  this  energy  are  derived  all  the  activities  of  the 
plant  in  a  complex  series.  It  is  an  established  fact  that  out  of  carbonic 
acid  and  water-  which  leave  the  animal  body,  the  plant-cell,  under  the 
influence  of  light-rays,  creates  an  endless  chemical  energy.  The  favor- 
able effect  of  light  and  chemical  rays  of  the  sun  upon  animal  life 
had  been  known  from  most  ancient  times.  The  sun  was  considered 
as  the  source  of  life,  and  therefore  worshipped  (Helios,  Apollo).  The 
ancient  Egyptians  and  Assyrians  devised  various  appliances  which  they 
placed  on  the  roofs,  and  there  they  exposed  their  bodies  to  the  rays  of  the 
sun,  as  they  believed  in  the  invigorating  influence  and  great  curative 
power  of  light.  Hippocrates,  the  father  of  medicine,  was  convinced  of 
the  curative  properties  of  sunlight;  also  of  its  influence  on  the  skin,  and 
of  its  value  in  the  sick-room.  The  Italian  proverb,  "All  diseases  come  in 
the  dark  and  get  cured  in  the  sun,"  is  very  significant.  It  is  sufficient  to 
recall  Moleschott's  experiments  on  frogs:  placed  in  the  same  conditions 
of  temperature,  they  exhaled  more  COj  in  the  light  than  in  obscurity.  Ex- 
perimental physiology  and  clinical  observation  show  that  the  respiratory 

51 


52  DISEASES  CAUSED  BY  PHYSICAL  AGENTS 

chemistry,  formation  of  hirmoglobin  in  the  blood,  growth  of  the  organism, 
and  pigmentation  of  the  skin,  are  directly  dependent  in  a  large  measure 
upon  light.  Finally,  functions  of  various  glands  and  metabolism  in  gen- 
eral are  undoubtedly  in  some  relationship  to  light.  Forbes  Winslow  has 
shown  the  efl'ect  of  light  on  the  growth  of  man.  Growth  of  children  dur- 
ing the  months  poor  in  sunlight  is  slow;  this  is  particularly  noticeable 
in  children  of  the  poor  who  live  in  basements.  Cretinism  is  known  to  ex- 
ist in  dark  mountainous  valleys  where  the  sunlight  penetrates  exception- 
ally. That  the  very  existence  of  certain  organs  depends  upon  light-rays 
can  be  seen  from  the  well-known  observation  that  the  eyes  of  animals 
kept  in  darkness  generally  become  rudimentary. 

Besides  the  direct  physiological  effect  on  the  functions  of  the  organism, 
light  has  also  a  beneficial  effect  upon  the  nervous  system  and  psychic 
sphere.  Disposition,  humor,  general  sensations,  Avill  certainly  be  more 
agreeable  in  a  clear,  sunny  day  than  in  cloudy  and  gloomy  weather. 

Nature  has  provided  us  with  light  also  as  a  means  of  defense  against 
pathogenic  microbes.  That  the  tubercle  bacillus  may  be  destroyed  by 
light  has  been  proved  by  Koch  and  others.  The  favorable  results  ob- 
tained in  the  treatment  of  pathological  conditions  of  the  skin  according 
to  Finsen's  method  are  perhaps  due  to  its  effect  upon  microorganisms. 
The  action  of  light  as  described  above  is,  according  to  the  state  of  our 
present  knowledge,  due  to  the  permeability  of  the  skin  and  other  tis- 
sues. Bouchard  has  shown  that  it  is  principally  the  ultra-violet  rays  that 
penetrate  the  tissues;  the  reflex  stimulation  is  then  transmitted  through 
the  skin  and  from  the  latter  to  the  central  nervous  system,  which  in  its 
turn  influences  various  organs.  The  result  is  that  life-processes  and  meta- 
bolism are  increased. 


PATHOLOGICAL  EFFECT  OF  LIGHT. 

If  moderate  light,  as  we  have  seen,  has  a  favorable  influence  on  the  en- 
tire organism,  intense  light,  on  the  contrary,  acts  unfavorably.  The  de- 
gree of  injury  naturally  depends  upon  the  intensity  of  and  length  of 
exposure  to  sunlight.  Locally  one  may  observe  sunburn,  which  in  mild 
cases  is  manifested  in  a  simple  erythema,  and  in  severe  cases  in  an  inflam- 
mation with  swelling  and  even  destruction  of  skin.  Freund,  among 
others,  has  shown  that  in  such  cases  a  large  number  of  ultra-violet  rays 
traverse  the  epidermis  and  reach  the  deep  layers  of  the  skin,  in  which 
they  affect  the  cellular  elements.  When  oedema  and  exudation,  with  sub- 
sequent.destruction,  take  place,  a  general  reaction,  with  elevation  of  tem- 
perature, will  follow.  In  extremely  severe  cases,  when  destruction  is 
extensive,  internal  complications  may  ensue.  In  ordinary  cases  of  sun- 
burn, pigmentation  may  occur; the  latter  is,  according  to  Finsen,  a  natural 
protection  against  further  effect  of  light-rays. 

Exposure  to  sun-rays  may  be  an  exciting  cause  for  various  affections  of 
the  skin  in  predisposed  individuals.  Lentigo,  for  example,  is  the  well- 
known  freckles,  w^hich  appear  usually  on  the  face,  neck,  and  hands;  they 
disappear  almost  entirely  during  winter  and  reappear  in  summer.  Chlo- 
asma, xeroderma  pigmentosum,  hydroa,  and  even  pellagra,  are  all  cutane- 
ous affections  in  which  sunlight  plays  a  certain  role  as  a  causative  agent. 


LIGHT.     X-RAYS.     ELECTRICITY  53 

The  skin  is  not  the  only  organ  which  may  suffer  from  the  immediate 
effect  of  intense  sunhght.  The  eye  may  become  affected.  Oj)hthalmia 
and  conjunctivitis  are  not  infrequent  occurrences  in  the  polar  regions  and 
in  the  mountains.  A  few  cases  were  reported  in  which  cataract  was  ap- 
parently produced  in  workmen  whose  eyes  were  exposed  to  prolonged 
action  of  intense  light.  ^ 

All  these  changes,  and  particularly  those  of  the  skin,  are  the  result  of  the 
effect  of  light-rays  in  a  comparatively  mild  degree.  The  produced  lesions 
are  usually  limited  to  the  tissue  exposed  to  the  light.  When  the  effect  of 
intense  sunlight  is  manifested  in  general  disturbances,  the  condition  may 
become  alarming,  as  it  may  terminate  by  death.  We  speak  then  of  sun- 
stroke. 

The  term  "sunstroke"  has  been  considerably  abused.  Heat-exhaus- 
tion, heatstroke,  sunstroke,  insolation,  coup  de  soleil,  heat-asphyxia,  and 
thermic-fever,  have  been  described  as  one  condition.  Manson,  in  his  book 
on  tropical  diseases,  brings  some  order  in  the  terminology,  and  his  classifi- 
cation is,  in  my  judgment,  the  most  satisfactory.  He  considers  separately 
a  condition  produced  by  the  elevated  temperature,  to  which  he  gives 
the  name  "heat-exhaustion;"  another  condition  produced  apparently 
and  only  by  the  direct  rays  of  the  sun,  to  which  he  gives  the  name  "sun- 
traumatism;"  and,  finally,  a  third  morbid  state,  to  which  Sambon  gave 
the  name  "siriasis."  The  latter  is  in  all  probability  due  to  a  microorgan- 
ism which  develops  only  in  a  high  atmospheric  temperature. 

1.  Heat-exhaustion. — This  condition  is  characterized  by  a  sudden 
tendency  to  syncope  in  an  atmosphere  with  a  high  temperature.  It  can  be 
brought  on  indoors  or  outdoors.  The  main  etiological  factor  is  heat  from 
any  source.  It  is  observed  in  industrial  plants  where  work  is  carried  on 
at  temperatures  above  120°F.  Individuals  suffering  from  various  diseases, 
those  whose  physiological  activities  are  lowered  by  alcoholic  or  other  ex- 
cesses, or  by  exhaustion,  present  very  little  resistance  to  the  effect  of 
heat.  With  the  syncope  occurring  from  heat-exhaustion  are  also  ob- 
served the  following  symptoms :  shallow  respiration,  small  and  soft  pulse, 
dilated  pupils,  cold  skin,  and  subnormal  temperature.  Recovery  usually 
follows,  but  very  occasionally  death  may  ensue. 

Heat-exhaustion  brought  on  by  exposure  to  the  sun  is  called  sunstroke, 
insolation,  or  coup  de  soleil.  This  condition  is  of  great  interest,  especially 
to  military  surgeons;  insolation  in  the  army  during  summer  months  is  of 
frequent  occurrence.  In  warm  climates  those  who  are  compelled  to  work 
outside  of  dwellings  are  apt  to  be  stricken.  Those  who  use  alcohol  are 
particularly  predisposed  to  the  effect  of  intense  heat,  and  they  constitute 
the  majority  of  the  victims  of  sunstroke.  Some  individuals  are  peculiarly 
predisposed  to  repeated  attacks.  Four  cases  came  under  the  writer's 
personal  observation,  when  the  patients,  free  from  alcoholism,  had  three 
attacks  during  three  successive  summers.  Among  other  predisposing 
causes  we  may  mention  excesses  of  all  kinds,  constitutional  diseases,  or 
low  vitality  following  protracted  diseases.  Finally,  any  cause  which  pre- 
vents the  evaporation  of  the  perspiration,  as,  for  example,  clothing  fit 
only  for  cold  weather  and  worn  on  hot  days,  predisposes  to  sunstroke.  It 
is  interesting  to  note  that  the  black  race  is  remarkably  resistant  to  the 

^Wm.  Eobinson,  British  Medical  Journal,  January  24,  1903 


54  DISEASES  CAUSED  BY  PHYSICAL  AGENTS 

effect  of  intense  sunlight.  Cases  of  insolation  in  children  are  also  rare. 
As  we  see,  the  subject  is  of  sufficient  importance  to  warrant  a  more  de- 
tailed description. 

Sunstroke  (Insolation)  —  Symptoms. —  In  the  majority  of  cases  a  sun- 
stroke is  preceded  by  a  few  premonitory  symptoms  before  complete 
prostration  sets  in.  They  are  headache,  dizziness  with  generalized  tingling 
sensations,  and  nausea.  Pain  in  the  epigastrium,  vomiting,  and  excessive 
thirst  soon  make  their  appearance.  Consciousness  is  retained  in  mild 
cases.  The  patient  enters  into  a  state  of  exhaustion,  which  may  go  to 
complete  prostration  and  end  in  death  quite  rapidly.  If  he  survives,  a 
slight  fever  may  be  present,  which  gradually  goes  down  to  normal.  The 
above-mentioned  symptoms  then  gradually  subside  and  complete  recov- 
ery takes  place.  I3cfore  recovery  occurs  the  patient  will  complain  for  a 
long  time  of  headache;  this  is  practically  the  only  symptom  which  per- 
sists after  others  have  disappeared.  In  severe  cases  of  insolation  there  is 
always  a  loss  of  consciousness,  which  may  be  followed  by  death;  the 
latter  is  rather  exceptional.  In  a  great  majority  of  cases  the  patient  re- 
gains consciousness;  but  there  is  extreme  pallor,  rapid  respiration,  rapid 
pulse,  which  is  soon  succeeded  by  a  slow  pulse;  temperature  is  raised  to 
104°  or  105°  and  in  very  severe  cases  to  108°.  In  some  cases  the  tem- 
perature reached  112°-1 13°,  which,  according  to  certain  observers,  is  not 
uncommon  in  severe  forms  of  insolation.  The  skin  is  usually  dry  or 
covered  with  a  clammy  perspiration.  Convulsions,  epileptiform  in  char- 
acter, may  occur,  while  general  muscular  twitching  is  exceedingly  com- 
mon. Delirium  is  not  an  infrequent  occurrence.  The  entire  body  is  either 
in  a  state  of  rigidity  or  absolute  flaccidity.  Ecch}'mosis,  or  a  petechial 
rash,  was  observed  in  a  certain  number  of  cases. 

The  severity  of  certain  cases  is  not  dependent  upon  the  degree  of  the 
temperature  or  upon  the  state  of  the  pulse,  and  it  is  therefore  difficult  to 
foretell  exactly  the  issue  of  a  given  severe  case.  Despite  the  unusually 
pronounced  symptoms,  recovery  may  follow,  although  not  without  a  per- 
sistent headache  and  various  parjesthetic  disturbances,  as  tingling,  numb- 
ness, pins  and  needles,  etc.,  or  some  physical  and  intellectual  weakness. 
Generally  speaking,  patients  who  remain  unconscious  for  twenty-four  or 
forty-eight  hours  usually  die. 

Sunstroke  is  one  of  the  causes  of  chronic  meningitis,  and  the  cephalea 
which  so  frequently  follows  recovery  from  insolation  finds  its  explanation 
in  the  meningeal  involvement.  Far  more  important  and  frequent  sequelae 
of  sunstroke  consist  of  distinct  mental  disturbances,  as  impairment  of 
memory  or  of  sustained  attention.  Some  writers  pretend  that  delusional 
insanity,  paresis  and  mania  may  be  caused  by  insolation.  The  writer's 
view  is  that  if  insolation  is  sometimes  followed  by  these  mental  derange- 
ments, it  is  only  as  an  exciting  cause  similar  to  trauma;  patients  of  this 
character  undoubtedly  were  predisposed  to  insanity  or  were  already  in- 
sane, and  exposure  to  intense  sun  radiation  only  intensified  the  condi- 
tion. Among  other  possible  consequences  of  sunstroke  we  may  mention 
polyuria  and  glycosuria. 

Pathology  and  Pathogenesis. — The  gross  pathological  changes  found 
in  cases  of  sunstroke  may  be  expressed  in  one  phrase:  general  congestion 
of  the  organs.  The  lungs,  liver,  spleen,  and  particularly  the  meninges  of 
the  brain  and  cord,  are  in  a  state  of  congestion.    The  blood  is  very  fluid. 


LIGHT.     X-RAYS.     ELECTRICITY  55 

The  microscopical  studies  of  various  tissues  and  organs  have  shown 
that  the  cells  of  the  liver  and  kidneys  and  of  the  nervous  system  all  undergo 
parenchymatous  degeneration.  The  nervous  system  suffers  particularly, 
and  there  the  changes  are  similar  to  those  found  in  cases  of  intoxica- 
tion with  poisons,  as  lead  or  alcohol;  namely,  marked  chromatolysis  of  the 
cells.  The  condition  of  the  blood  deserves  special  attention.  Leukocy- 
tosis and  in  some  cases  destruction  of  erythrocytes  with  diminution  of 
the  alkalinity  of  the  blood  are  the  changes  which  occur. 

As  to  the  pathogenesis  of  the  disease,  there  is  a  great  divergence  in  the 
theories  which  have  been  advanced  to  explain  the  symptoms  and  death 
in  insolation.  Vallin  at  first  believed  that  death  is  due  to  heat  coagula- 
tion of  the  cardiac  muscle.  Hirsh  believes  that  the  cause  of  death  lies  in 
alteration  of  the  blood — diminution  of  oxygen  and  retention  of  a  toxic 
principle.  Vincent^  arrived  at  the  conclusion  that  there  is  a  poisoning  of 
the  organism  by  toxic  products  accumulated  in  the  blood.  According  to 
Laveran  and  Regnard,^  who  made  an  extensive  experimental  study  of 
the  question,  death  in  insolation  is  due  to  a  direct  effect  of  sun-rays,  prin- 
cipally upon  the  nervous  system ;  this  effect  is  first  excitant  and  then  par- 
alyzing. The  investigations  of  more  recent  writers  tend  to  the  conception 
of  a  paralyzing  action  on  the  nervous  system  of  some  toxic  elements,  with 
the  probable  result  of  metabolic  changes  in  the  neurons;  and  according 
to  the  degree  of  auto-intoxication  the  effect  of  the  sunstroke  will  be  either 
an  attack  of  ordinary  heat-prostration  or  syncope  with  unconsciousness 
or  death. 

Diagnosis. — It  is  only  in  exceptional  cases  that  the  diagnosis  will  be 
difficult.  Usually  the  history  of  exposure,  with  the  high  temperature  and 
the  condition  of  the  skin,  render  the  diagnosis  easy.  In  some  cases, 
however,  especially  when  there  is  a  history  of  alcoholism  or  cardiac  lesion, 
the  diagnosis  will  be  difficult;  apoplexy  should  then  be  thought  of.  In 
the  latter  case  the  temperature  is  usually  normal,  the  breathing  is  stertor- 
ous, the  pulse  is  slow;  but  the  most  important  symptom  is  the  local  paraly- 
sis, hemiplegia,  or  monoplegia.  In  malarial  districts,  a  pernicious  malarial 
paroxysm  may  give  difficulty  but  a  blood  examination  will  make  the 
diagnosis  clear. 

Prognosis. — ^The  outlook  in  cases  of  sunstroke  will  naturally  depend 
upon  the  degree  of  prostration,  and,  according  to  some  authors,  upon  the 
temperature.  The  latter  condition  is  not  absolute,  as  the  writer  has  ob- 
served a  patient  with  110°  who  recovered.  However,  on  general  principles 
a  very  high  temperature  renders  the  prognosis  unfavorable.  The  previous 
general  health,  and  especially  whether  the  patient  uses  or  does  not  use 
alcohol,  is  of  utmost  importance  in  forecasting  the  outcome  of  his  sun- 
stroke. The  promptness  of  rendered  assistance  and  the  character  of  the 
treatment  are  also  factors  which  play  an  important  role  in  determining 
the  prognosis  of  a  given  case-  In  mild  cases  of  heat-prostration  the 
prognosis  is  favorable.  As  to  the  complications  following  sunstroke, 
they  are  all  as  a  rule  temporary,  except  the  grave  forms  of  insanities. 
As  in  the  latter,  sunstroke  similar  to  trauma  plays  only  the  role  of  exciting 
factor,  the  prognosis  will  be  not  dependent  upon  the  insolation.  In  some 
cases  the  sequelse  of  sunstroke  are  very  rebellious  to  treatment,  and  may 

^  Rech.  exper.  sur  Vhyperthermie ,  1887. 
^Bull  d.  I' Acad  de  MH.,  1894. 


56  DISEASES  CAUSED   BY   PHYSICAL  AGEXTS 

persist  for  a  long  time.    Finally,  as  we  said  above,  some  patients  become 
predisposed  to  repeated  attacks  after  they  have  once  had  a  sunstroke. 

2.  Sun-trauinatism. — Untler  this  name  Manson  describes  a  morbid 
state  characterized  as  a  rule  by  sudden  death  occurring  without  warning 
after  exposure  to"  the  sun.  Paralysis  of  the  heart  or  respiration  seems  to  be 
the  immediate  cause  of  death.  In  a  certain  group  death  may  not  ensue, 
but  the  patient  exhibits  symptoms  of  meningitis;  namely,  fever,  head- 
ache, dry  skin,  rapid  pulse,  photophobia,  and  vomiting.  The  condition 
is  not  invariably  fatal.  If  recovery  follows,  there  are  always  sequehe 
more  or  less  persistent  in  character,  as  tremor,  amaurosis,  amnesia,  deaf- 
ness, epilepsy,  and  paralysis  or  ])aresis  of  the  extremities. 

As  to  the  pathogenesis  of  sun-traumatism,  it  is  highly  probable  that 
caloric  is  not  at  fault,  as  similar  eft'ects  have  not  been  observed  from  ex- 
posure to  heat  from  other  sources — as  a  furnace,  for  example.  Manson 
is  therefore  justified  in  presuming  that  there  is  a  special  element  in  the 
solar  spectrum  capable  of  injuriously  affecting  the  tissues,  particularly 
if  they  have  not  become  gradually  habituated  to  sun  exposure.  To  cor- 
roborate this  view  Manson  calls  attention  to  the  phenomena  of  sun- 
erythema,  of  skin  pigmentation  known  as  sun-burn,  and  possibly  of 
leukodermia;  also  to  the  sensation  of  distress  brought  on  by  exposure  to 
a  hot  sun,  which  is  quite  different  from  that  produced  by  the  heat  of  a  fire. 

3.  Siriasis. — ^This  is  a  specific  disease  developing  in  high  atmospheric 
temperature,  and,  similarly  to  yellow  fever  or  dengue,  is  not  caused  by 
the  elevated  temperature,  but  probably  by  some  microorganism  which 
demands  for  its  development  a  high  atmospheric  temperature  and  certain 
local  conditions.  It  is  known  on  the  east  coast  of  the  United  States  and 
the  South  Atlantic  coast;  in  Africa,  Asia,  and  Australia.  The  mortality 
from  this  disease  is  very  great.  According  to  Manson  (Tropical  Diseases) 
the  case  mortality  among  English  troops  is  about  one  in  four.  The 
symptoms  observed  are  almost  identical  with  those  of  sunstroke,  and  are 
characterized  mainly  by  hyperpyrexia,  coma,  and  extreme  pulmonary 
congestion.  If  a  post-mortem  examination  is  made  shortly  after  death 
and  before  decomposition  changes  have  set  in,  the  heart  is  found  to  be 
remarkably  rigid.  Rigor  mortis  is  an  early  appearance.  The  blood  is 
remarkably  fluid  and  yields  an  acid  reaction.  Venous  engorgement  of 
the  viscera  is  a  notable  feature. 

Treatment  of  Heat-exhaustion,  Sun-traumatism,  and  Siriasis  .^The 
first  indication  in  cases  of  heat-prostration,  be  it  mild  or  severe,  is  rest. 
The  patient  must  be  undressed  and  put  to  bed;  if  stricken  on  the  street, 
his  clothing  must  be  loosened  and  he  should  be  laid  on  his  back  in  a  cool, 
airy,  and  shaded  place.  The  next  indication  is  application  of  cold  to  the 
head,  and  some  stimulant  (brandy  or  others)  administered.  In  mild 
cases  this  treatment  will  be  sufficient.  In  more  severe  cases,  in  addition 
to  these  means,  some  drug  may  be  given  to  alleviate  the  headache  and  re- 
duce the  high  temperature.  The  coal-tar  products,  salicylates,  etc.,  will 
answer  both  indications,  but  should  always  be  used  with  caution.  When,  on 
the  contrary,  the  prostration  is  very  pronounced  and  the  temperature  is 
below  normal,  heat  instead  of  cold  will  have  to  be  applied, — in  con- 
junction with  some  internal  stimulant,  if  there  is  no  coma;  if  coma, 
stimulants  must  be  given  hypodcrmically.  Strychnia,  camphor,  and 
nitroglycerine,  are  the  usual  drugs  for  the  latter  purpose.    Convulsions 


LIGHT.    X-RAYS.     ELECTRICITY  57 

can  be  controlled  by  placing  the  patient  in  a  lukewarm  bath  and  by  admin- 
istration of  morphine  aided  by  atropine.  Restlessness  and  insomnia  are  best 
treated  by  the  bromides.  High  temperature  can  be  controlled  particularly 
by  cold  spongings  frequently  repeated,  or  by  cold  baths,  the  tempera- 
ture of  which  is  gradually  reduced  while  the  patient  is  in  the  tub.  The 
patient  should  be  vigorously  rubbed.  The  same  procedure  can  be  em- 
ployed in  cases  of  unconsciousness.  These  hydrotherapeutic  measures 
can  be  modified  according  to  the  conditions  in  each  individual  case.  If 
baths  are  not  convenient,  cold  packs  may  take  their  place.  Sometimes  a 
shower-bath,  or  a  douche  over  the  spine,  of  short  duration  and  followed 
by  a  dry  rubbing,  reduces  the  temperature  admirably  besides  having  a 
stimulating  effect.  It  should  be  borne  in  mind  that  while  the  patient  is 
treated  with  cold  water,  stimulation  with  the  above-mentioned  means 
be  kept  up.  Among  the  stimulants  the  writer  lays  special  emphasis  on 
saline  infusions,  which  in  many  cases  prove  to  be  an  excellent  adjuvant. 
If  the  patient  is  a  full-blooded  individual,  venesection  followed  by  saline 
infusions  will  be  of  better  service  than  infusion  alone.  When  death 
is  imminent,  repeated  stimulation  with  the  usual  remedies  and  artificial 
respiration  must  be  used. 

After  the  pronounced  symptoms  have  disappeared,  the  treatment  will 
be  symptomatic.  Headache,  insomnia,  nervousness,  parsesthetic  disturb- 
ances, should  be  treated  accordingly. 

When  the  hyperpyrexia  is  great,  as,  for  example,  in  siriasis  or  in  ex- 
treme cases  of  insolation,  all  the  efforts  must  be  directed  toward  reducing 
the  temperature  by  rapidly  acting  measures.  Chandler's^  directions  are 
of  great  value  in  such  cases.  He  advises  to  put  the  patient,  undressed, 
on  a  stretcher  the  head  of  which  is  raised  slightly  so  as  to  facilitate  the 
escape  of  involuntary  evacuations  and  to  provide  for  drainage.  A  ther- 
mometer is  kept  in  the  rectum.  The  body  is  covered  with  a  sheet  upon 
which  is  laid  numerous  small  pieces  of  ice,  larger  pieces  being  closely 
packed  about  the  head.  Ice-water  is  then  allowed  to  drip  for  thirty  or 
forty  minutes  on  the  patient,  from  drippers  hung  at  an  elevation  of  from 
five  to  ten  feet.  A  fine  stream  of  iced  water  poured  on  the  forehead  from 
an  elevation  will  act  as  a  stimulant ;  this  powerful  measure  must  not  be  kept 
up  for  longer  than  one  or  two  minutes.  A  hypodermic  injection  of  forty 
minims  of  tincture  digitalis  is  given  as  soon  as  possible,  its  administration 
being  preceded  in  the  case  of  plethoric  patients  by  a  small  bleeding.  As 
soon  as  the  rectal  temperature  has  sunk  to  104°  the  application  of  cold 
should  be  at  once  discontinued.  On  discontinuing  the  iced  sheet,  the 
patient  should  be  wrapped  in  a  blanket  and  hot  bottles  applied  to  limbs 
and  trunk.  In  this  stage  strychnia  as  a  stimulant  should  be  avoided.  In 
case  of  failure  of  respiration,  artificial  respiration  should  be  resorted  to; 
Chandler  urges  to  keep  it  up  for  half  an  hour.  There  is  a  very  important 
warning  given  by  Manson.  Antipyretics  (antifebrine,  antipyrine,  etc.) 
should  by  all  means  be  avoided,  as  they  are  dangerous  in  view  of  their 
depressing  action  on  the  heart. 

If  the  treatment  of  sunstroke  as  outlined  here  will  save  some  patients, 
the  prophylactic  measures  are  of  greater  importance.  The  above-men- 
tioned investigations  of  Laveran  and  Regnard,  also  those  of  Hiller,  show 

^Medical  Record,  New  York,  1897. 


58  DISEASES  CAUSED  BY  PHYSICAL  AGENTS 

that  prolonged  physical  exercises  facilitate  the  onset  of  sunstroke.  It  is 
therefore  advisable  in  hot  days  to  avoid  as  much  as  possible  all  causes  of 
fatigue.  As  alcoholic  intoxication  predisposes  to  sunstroke,  beverages 
containing  alcohol  must  be  avoided.  Excesses  in  the  use  of  animal  foods 
and  others,  violent  exercises,  want  of  sleep,  constipation,  etc.,  should  be 
avoided.  Indixiduals  suffering  from  malarial  or  other  fevers,  or  from 
chronic  liver  or  kidney  diseases,  run  great  risk  in  exposing  themselves 
carelessly  to  the  sun.  Unnecessary  exposure  to  the  sun  in  summer  is  con- 
traindicated.  A  hat  should  be  always  worn  in  hot  days  in  order  to  avoid  a 
direct  effect  of  the  sun  on  tlie  head.  We  should  not  expose  ourselves  to 
sun-rays  more  than  an  hour,  as  very  long  exposure  brings  on  high  excite- 
ment or  complete  relaxation.  Much  sweating  weakens  and  provokes 
chills ;  a  skin  which  perspires  is  a  better  conductor  for  chemical  rays  than 
a  dry  skin. 

Before  the  discovery  by  Rontgen  of  rays  to  which  the  scientific  world 
attached  his  name,  our  knowledge  of  sources  of  light  was  limited  with  the 
spectrum,  and  all  we  know  about  physiological  effect  of  the  latter  is  that 
only  the  blue,  violet  and  ultraviolet  have  a  vital  function  in  animal  life. 

THE  X-RAYS. 

The  discovery  of  ar-rays  revolutionized  our  knowledge  of  the  composi- 
tion of  light.  Since  1896,  physicists  have  applied  themselves  arduously  to 
the  further  study  of  various  sources  of  light,  and  we  are  now  in  possession 
of  Becquerel's  rays,  of  radium,  of  polonium,  actinium,  Blondlot's  and 
Charpentier's  N  and  N'  rays  respectively.  Some  of  these  rays  have 
proven  to  be  of  certain  therapeutic  value;  others  are  only  in  an  experi- 
mental stage.  Rontgen's  rays  have  almost  accomplished  their  history. 
Their  application  in  medicine  is  of  inestimable  use,  both  for  diagnostic 
and  therapeutic  purposes. 

The  therapeutic  effects  of  rr-rays  became  particularly  known  since 
Freund  applied  them  with  success  for  the  first  time  on  a  nsevus,  and  Kum- 
mel  with  Gocht  on  lupus.  Since  then  various  dermatoses  were  treated, 
namely,  favus,  sycosis,  hypertrichosis,  acne,  eczema,  psoriasis,  prurigo, 
alopecia,  and  ulcerations.  Soon  neoplasms,  both  malignant  and  benign, 
w^ere  submitted  to  the  action  of  .r-rays.  The  results  were  so  encouraging 
in  a  great  many  instances  that  their  beneficial  effects  became  universally 
recognized.  At  the  present  day  many  operable  and  inoperable  cases  of 
tumors,  both  external  and  internal,  receive  the  a--ray  treatment,  before 
or  after  surgical  interference.  The  beneficial  results  obtained  so 
far  led  a  number  of  men  to  extend  the  application  of  the  new 
treatment,  so  that  there  are  on  record  cases  of  neuroses,  and  even  organic 
diseases,  some  symptoms  of  which — pain,  for  example — derived  benefit 
from  a'-ray  treatment.  Some  observers  treated  with  favorable  results 
cases  of  progressive  pernicious  anaemia,  leukaemia,  Hodgkin's  disease,  and 
exophthalmic  disease. 

Inasmuch  as  good  results  are  obtained  from  a;-ray  treatment,  we  meet 
now  and  then  with  accidents,  in  which  tlie  deleterious  effect  of  rc-rays  may 
go  so  far  as  to  produce  permanent  lesions,  with  complete  destruction  of 
tissues. 


LIGHT.    X-RAYS.     ELECTRICITY  59 

PATHOLOGICAL  EFFECT  OF  X-RAYS. 

The  disturbances  produced  by  a;-rays  are  (1)  local  and  (2)  general. 

1.  Local — Dermatitis. — The  first  case  of  rc-ray  burn  we  find  men- 
tioned by  O.  Leppia;^  and  the  first  case  of  alopecia  caused  by  a;-rays  was 
reported  by  Daniel.^  Since  then  a  large  number  of  observations  were 
made  and  recorded,  all  showing  that  while  we  have  in  the  ar-rays  a  pow- 
erful physical  remedy,  nevertheless  it  must  be  handled  with  greatest 
caution  and  with  full  knowledge  of  its  physical  properties. 

It  is  generally  accepted  that  the  specific  effect  of  .T-rays  consists  of 
eventual  destruction  of  tissue,  (analogous  to  the  ultra-violet  rays  of  the 
spectrum  when  they  are  in  superabundance).  Ulcerations,  necrosis,  and 
sloughing  of  skin,  are  frequent  occurrences  in  exposures  to  a;-rays.  The 
consensus  of  opinion  concerning  rr-ray  burns  is  that  the  latter  undergo 
three  stages,  namely:  (1)  Hypersemia,  leading  to  exfoliation  in  scales,  degen- 
erative changes  with  subsequent  atrophy  in  the  tissues  depending  upon 
the  skin,  as  hair,  nails,  glands,  etc.;  (2)  vesiculation ;  and  (3)  escharotic 
destruction;  the  intima  of  the  blood-vessels  becomes  thickened  and  the 
whole  process  presents  a  chronic  inflammation  with  all  its  usual  conse- 
quences. Freund  described  increase  of  pigment  in  the  cells  of  the  Mal- 
pighian  layer  of  the  epidermis.  The  histological  changes  affect  chiefly  or 
exclusively  the  cellular  elements  of  the  skin,  which  undergo  a  slow  degen- 
eration with  destruction,  while  the  connective,  the  elastic,  the  muscular, 
and  the  cartilagenous  tissues  are  not  at  all  or  only  in  a  slight  degree  altered; 
or,  if  they  do  suffer,  it  is  only  secondarily  to  the  inflammatory  reactions. 
As  to  cells  themselves,  the  epithelial  cells  are  affected  first;  in  a  slighter 
degree  are  affected  the  cells  of  glandular  organs  and  of  vessels.  The  nu- 
cleus suffers  conjointly  with  the  cell-body.  If  the  a:-rays  are  intense,  the 
leukocytes  of  the  dilated  vessels  penetrate  into  the  degenerated  cells,  and 
as  phagocytes  bring  on  their  complete  destruction  and  resorption.  The 
cicatrization  is  of  especial  character;  it  is  irregular,  without  a  tendency  to 
retraction,  and  perfectly  white. 

The  a:-ray  burn  has  its  symptomatology.  At  first  there  is  a  tingling  sen- 
sation, which  is  followed  by  redness  and  swelling  similar  to  the  effect  of 
solar  rays.  Later  vesicles  appear,  which  finally  break  down,  leaving  a 
raw  surface.  In  severe  cases  ulcerations  will  follow  the  vesiculation.  As 
the  process  is  inflammatory,  a  few  general  symptoms  may  be  present; 
namely,  chills,  fever,  pain,  general  malaise,  etc.  The  characteristic  fea- 
ture of  the  lesions  is  their  late  appearance.  The  initial  paraesthetic  dis- 
turbances may  exist  from  a  few  days  to  two  or  three  weeks  before  the 
erythema  with  the  subsequent  symptoms  wdh  be  manifested.  Bar-Boulle 
reports  a  case  of  severe  burn  with  ulceration  appearing  tAvo  months  after 
exposure.  This  is  perhaps  due  to  the  cumulative  property  of  a:-rays,  a 
fact  which  is  accepted  by  all  workers  in  that  line.  The  healing  process  is 
also  slow. 

Other  Local  Effects  of  X-rays— (a)  Atrophy  of  the  SMn.— H.  E. 
Schmidt,  Kienbock,  Gocht,  Albers-Schonberg,  Hahn,  and  Scholz,  re- 
ported cases  of  marked  atrophy  of  the  skin,  with  dystrophy  or  shedding 

^Deut.  Med.  Wochenschr.,  1896,  No.  28. 
^Medical  Record,  New  York,  April  25,  1896. 


60  DISEASES  CAUSED  BY  PHYSICAL  AGENTS 

of  the  nails,  following  .r-ray  exposure.    They  were  probably  due  to  angio- 
neurotic and  trophoneurotic  processes. 

(h)  Alopecia. — In  connection  with  this  disturbance  it  is  well  to  men- 
tion Gerwood's  observation:  in  one  case  of  his,  curly  hair  grew  in  place  of 
smooth;    and  in  another  black  hair  took  the  place  of  white. 

(c)  Scleroderma-like  changes  have  been  reported  by  Hallopeau,  Four- 
nier,  Bartheleniy,  Gadaud. 

(d)  Gangrene  has  been  observed  by  some  writers. 

(<?)  Cancer  was  first  reported  by  Allen  and  then  by  a  few  others. 

(/)  Swelling  of  muscles  was  observed  by  some  French  workers  in 
a;-rays. 

(g)  Lesions  of  the  eye  leading  almost  to  complete  blindness.  W. 
Rollins^  made  animals  blind  by  .r-rays.  Cases  of  optic  neuritis,  ulcera- 
tion of  the  cornea,  conjunctivitis,  myopia,  amblyopia,  and  amaurosis,  are 
on  record.    Periostitis  and  ostitis  have  been  observed  by  a  few  writers. 

2.  General  Sjrmptoms.— Oudin,  Barthelemy,  and  Darier,  who  made 
extensive  experimental  studies  and  clinical  observations,  observed  gastro- 
intestinal disorders  from  a'-ray  exposure,  as,  for  example,  symptoms  of 
gastritis  from  exposure  of  the  abdomen.  Vertigo,  nausea,  headache, 
insomnia,  rise  of  temperature,  general  nervousness,  tremor,  palpitation  of 
the  heart  with  oppression,  and  in  some  rare  cases  slight  cerebral  disturb- 
ances constituting  the  symptom-group  of  meningitis,  were  observed 
following  a:-ray  treatment.  An  established  dermatitis  may  be  accom- 
panied in  exceptional  cases  by  a  general  illness.  Holzknecht  observed  an 
intermittent  vesperal  fever  (103°  F.  and  above),  chills,  and  concentrated 
urine.  Fever  usually  lasts  only  a  few  days  and  ends  with  the  beginning 
of  a  new  skin.  In  four  cases  he  observed  skin  lesions  with  a  high  tempera- 
ture, which  were  taken  for  the  eruption  of  scarlet  fever.  It  is  noteworthy 
to  mention  occasional  occurrence  of  general  toxaemia  following  a;-ray, 
treatment  of  cancer  and  sarcoma;  this  is  probably  due  to  auto-intoxica- 
tion produced  by  the  cancerous  and  sarcomatous  material.  In  excep- 
tional cases,  paralysis  (mono-  and  paraplegia)  and  convulsions  were 
observed.  Finally,  death  followed  in  a  few  cases  of  x-Taj  exposure.  In 
these  cases  this  was  secondary  to  a  general  septic  condition  brought  on  by 
deep  ulcerations  with  suppuration,  but  not  by  direct  action  of  the  rays;^ 
at  least  the  histories  of  the  cases  are  not  convincing. 

Effect  of  X-rays  on  Internal  Organs,  with  Special  Reference  to 
the  Generative  Organs. — The  effect  of  .-r-rays  on  internal  organs  has  been 
the  subject  of  investigation  since  1903.  Senn,  B.  Ahrens,  Krone,  Fried,  and 
Hahn,  were  the  first  workers  in  this  field.  Leukaemia  and  diseases  of  the 
spleen  were  reported  as  being  very  favorably  influenced  by  a;-ray  expos- 
ures. Heineke  examined  microscopically  spleens  of  mice  and  guinea- 
pigs  which  were  submitted  to  a;-rays  for  seven  to  fourteen  days.  He 
found  excessive  increase  of  pigment  and  disappearance  of  follicles.  The 
changes  in  the  latter  occurred  long  before  other  degenerative  processes 
made  their  appearances  in  the  spleen  and  the  epidermis;  the  so-called 
latent  period  and  cumulative  action  which  are  observed  in  epidermis  are 
totally  absent  in  adenoid  tissue.  This  was  observed  not  only  in  the  spleen 
but  also  in  the  lymphoid  glands.    The  investigations  of  Boermann  and 

*  Boston  Medical  and  Surgical  Journal,   1903. 

^See  H.  E.  Resmer's  case,  in  New  York  Slate  Medical  Journal,  1903,  p.  296. 


LIGHT.     X-RAYS.    ELECTRICITY  61 

Linser  have  shown  that  x-r&ys  attack  first  the  bloodvessels  and  especially 
their  intima;  all  other  phenomena  are  secondary  to  this  effect.  Milchner 
and  Mosse  described  changes  in  the  bone-marrow;  Birch-Hirschfeld 
observed  optic  atrophy  after  exposure  to  a;- rays.  Symptoms  of  paralysis 
in  small  animals  have  also  been  noticed  by  some  investigators,  showing 
involvement  of  the  nervous  system.  Whether  in  the  latter  case  there  were 
real  pathological  changes  or  only  a  dynamic  disturbance,  it  is  difficult  as 
yet  to  tell.  At  all  events  the  effect  of  a;-rays  on  internal  organs  became  an 
acquisition  of  science,  and  facts  began  to  accumulate.  Among  these  the 
most  interesting  and  important  are  those  concerning  the  effect  of  Ront- 
gen's  rays  on  the  generative  organs. 

Albers-Schonberg"^  was  the  first  to  observe  that  a;-rays  produced  steril- 
ity in  rabbits  and  guinea-pigs  without  any  change  in  the  sexual  potency. 
Death  of  spermatozoa  was  the  immediate  cause.  Azoospermia  and 
atrophy  of  the  testicles  followed.  The  experiments  consisted  of  daily 
exposures  for  15  to  30  minutes,  and  about  195  to  377  minutes  were  necessary 
to  produce  the  desired  results.  According  to  Frieben,^  the  reason  of  the 
azoospermia  lies  in  the  disappearance  of  the  epithelium  of  the  seminal 
canals,  which  leads  to  atrophy  of  the  testicles.  Seldin  verified  and  corrob- 
orated in  all  its  details  the  discovery  of  Albers-Schonberg  and  Frieben's 
explanation  of  the  azoospermia.  A  year  later  Buschke  presented  at  the 
International  Congress  of  Dermatology  macroscopical  and  microscopical 
specimens  of  testicles  atrophied  from  a;- ray  exposure.  Philipp  reports 
similar  observations  made  in  man.  His  first  patient  was  a  man  of  twenty- 
five  with  personal  and  family  histories  of  advanced  tuberculosis.  In  order 
to  avoid  an  increase  in  his  family,  he  accepted  willingly  the  proposition  to 
undergo  an  exposure  of  his  testicles  to  rc-rays  with  the  distinct  purpose  of 
bringing  on  sterility.  For  thirty  days  he  had  a  daily  sitting  of  ten  to  fifteen 
minutes'  duration.  During  the  treatment  the  sperm  was  examined  every 
eight  days.  Five  examinations  were  made,  and  all  gave  the  same  result: 
normal  spermatozoa  without  the  slightest  change  in  size,  number,  or  form. 
No  trace  of  nuclear  degeneration  or  pigmentation  was  noticed.  A  sixth 
specimen  was  obtained  from  the  patient  and  exposed  directly  to  the  effect 
of  the  a;-rays,  but  without  the  slightest  result.  After  the  failure  of  this 
method  the  patient  had  a  bilateral  resection  of  the  spermatic  ducts  done. 
As  according  to  Albers-Schonberg  at  the  end  of  six  months  an  atrophy 
develops  gradually  in  the  testicles,  Philipp  extracted  directly  from  the 
testicle  with  a  hypodermic  needle  a  few  drops  of  semen.  The  micro- 
scopical examination  confirmed  entirely  Albers-Schonberg's  and  Seldin's 
views :  no  trace  of  spermatozoa  could  be  found.  The  testicles  diminished 
in  size,  but  the  sexual  power  remained  normal.  In  another  case  a  man 
of  thirty-one  suffered  from  intertrigo  with  pruritus  ani.  X-ray  exposure 
over  the  perineum  was  proposed.  A  daily  exposure  for  ten  minutes,  and 
altogether  195  minutes,  cured  the  patient  from  the  intertrigo  and  pruritus 
ani.  Seven  months  later  a  small  quantity  of  sperm  was  examined  and  no 
trace  of  spermatozoa  was  found. 

Very  recently  F.  Tilden  Brown  reported  his  observations  concerning 
the  sexual  condition  of  physicians  and  patients  who  have  been  exposed  to 
the  x-rays.    He  announced  at  the  January  meeting  of  the  New  York 

^  Munch.  Med.  Wochenschr.,  1903,  No.  43. 
^  Munch.  Med.  Wochenschr.,  1903. 


02  DISEASES  CAUSED  BY  PHYSICAL  AGENTS 

Academy  of  ISIcclicine  that  "men  by  their  mere  presence  in  an  .r-ray 
atmosphere  incidental  to  radiography  or  the  therapeutic  uses  of  the  rays, 
after  a  period  of  time  as  yet  undetermined,  will  be  rendered  sterile. 
In  the  last  few  days  ten  individuals  who  have  devoted  more  or  less  time 
to  the  work  during  the  past  three  years — none  of  whom  have  had  any 
venereal  disease  or  traumatism  involving  the  genital  tract — have  been 
found  to  be  the  subjects  of  absolute  azoospermia.  None  of  the  number 
are  conscious,  however,  of  any  change  or  deterioration  in  regard  to  their 
potency."  In  the  re{)ort  of  Drs.  Brown  and  Osgood^  we  find  similar 
observations.  Within  the  last  three  months  they  observe  eighteen  cases  of 
azoospermia  or  oligonecrospermia  in  men  who  have  operated  Rontgen-ray 
tubes  for  a  half  to  four  hours  three  times  a  week  for  the  past  two  to  six 
years. 

It  is  remarkable  that  similar  observations  were  made  upon  insects  and 
plants.  Seeds,  for  example,  exposed  for  even  a  few  hours  to  the  action  of 
a'-rays,  lose  their  ability  to  grow. 

The  action  of  Rontgen  rays  upon  the  female  generative  organs  has 
also  been  the  subject  of  special  study  very  recently.  Ludwig  Halber- 
staedter^  reports  the  results  of  his  experiments  on  mammalia.  Series  of 
dogs  were  selected,  and  exposure  to  the  rays  was  carried  out  in  the  usual 
manner.  Ten  or  more  days  later  extirpation  of  the  ovaries  was  per- 
formed. Marked  microscopical  changes  were  noticed  as  to  size  of  the 
organs  and  to  the  number  of  Graafian  follicles.  As  to  the  latter,  the  later 
the  examination  is  made  the  fewer  follicles  are  found.  This  was  also 
verified  by  histological  changes.  In  exposure  to  mild  rays  the  disappear- 
ance of  follicles  is  not  as  complete  as  in  the  experiments  with  stronger 
rays.  Besides  degeneration  of  the  follicles,  the  microscope  also  shows  a 
more  or  less  large  number  of  vacuolated  spaces  which  according  to  the 
author  are  perhaps  traces  of  degenerated  follicles.  The  same  experi- 
ments have  also  shown  that  ovaries  present  a  far  greater  susceptibility  to 
a;-rays  than  the  skin,  a  fact  which  becomes  evident  a  very  short  time  after 
the  exposure. 

The  practical  importance  of  all  these  investigations,  both  from  a  per- 
sonal standpoint  and  in  regard  to  assistants  and  patients,  is  certainly  too 
evident  to  dwell  upon.  Prophylaxis  in  an  a:-ray  atmosphere  is  of  para- 
mount importance;  adequate  protection  to  all  parts  of  the  body  not 
directly  exposed  for  examination  or  treatment  should  be  provided.  On  the 
other  hand,  the  facts  herein  set  forth  give  us  a  convenient,  painless  and 
harmless  method  for  rendering  a  male  or  female  sterile  in  cases  in  which 
sterility  must  be  obtained  for  serious  reasons.  Resection  of  seminal  ducts, 
or  removal  of  ovaries,  although  more  or  less  safe  with  the  modern  surgical 
methods,  are  nevertheless  inferior  to  bloodless  methods.  A  patient  is  far 
less  likely  to  object  to  this  measure  than  to  mutilation,  and  it  is  to  be  hoped 
that  investigation  will  continue  along  these  lines. 

Pathogenesis — It  is  yet  debatable  what  particular  element  plays  such 
an  important  role  in  producing  lesions  during  exposure  to  rr-rays.  Some 
believe  that  it  is  the  ozone  which  is  formed  around  the  tube;  others, 
electric  discharges  emanating  from  the  tubes;  and  still  others,  the 
a;-rays  themselves.   The  latter  view  is  accepted  by  the  majority  of  writers. 

^American  Journal  of  Surgery,  April,  1905. 
-  Berl.  Klin.  Wochenschr.,  January  16,  1905. 


LIGHT.    X-RAYS.     ELECTRICITY  63 

It  is  their  direct  action  that  causes  the  lesions  described  above.  Accord- 
ing to  Scholz,  the  a;-rays  have  a  specific  action  on  the  elements  of  the 
skin,  causing  a  slow  degeneration  of  the  cells  of  epidermis,  hair-follicles, 
glands,  and  also  of  the  connective-tissue  cells  of  the  corium;  the  nu- 
cleus is  affected  by  the  degenerative  process  as  well  as  the  protoplasm 
of  the  cell.  As  to  the  question  whether  the  a; -rays  have  only  a  local  or  a 
general  effect  on  all  the  tissues  through  which  they  pass,  the  concensus  of 
opinion  is  that  the  first  effect  is  on  the  skin;  the  deeper  tissues,  as  muscles 
and  bones,  are  influenced  only  slightly.  If  necrosis  follows,  it  is  only 
secondary  to  a  pronounced  inflammation  and  ulceration.  Curiously 
enough,  they  affect  not  only  the  skin  at  the  point  of  their  penetration,  but 
also  at  the  level  of  their  exit.  Revillet  and  Kiimniel  have  shown  that 
illumination  of  the  thorax  produced  an  erythema  on  the  thorax  and  back. 
As  to  the  intermediate  organs  the  effect  is  usually  little  or  none  whatever. 
This  observation  is  also  in  accordance  with  clinical  experience. 

Treatment. — ^There  is  no  special  treatment  fora;-ray  accidents.  As 
the  superficial  lesions  are  similar  to  those  produced  by  the  violet  rays  of 
the  spectrum.  Bar's  suggestion  as  to  the  use  of  red  light,  which  is  proven 
to  be  antagonistic  to  the  violet,  is  certainly  very  interesting.  He  at  least 
obtained  very  encouraging  results.  On  the  other  hand.  Kaiser  reported 
recently  that  blue  light-rays  gave  him  good  results.  Pain  may  be  re- 
lieved by  static  electricity,  according  to  d'Apostoli.  High-frequency  cur- 
rents have  been  also  suggested  for  a;-ray  burns.  As  to  local  applications 
to  the  diseased  tissues,  various  drugs  have  been  recommended,  but  none 
has  any  specific  value.  Nitrate  of  silver  (2  per  cent.),  picric  acid  (J  per 
cent.),  zinc  ointment,  cocaine  (for  pain),  peroxide  (in  cases  of  exudation 
and  suppuration),  pyoktanin  (3  per  cent.),  and  others,  are  all  remedies 
which  are  advised  in  a;-ray  burns;  but  they  have  been  used  in  burns  of 
any  other  origin.  It  is  well,  however,  to  remember  that  the  effect  of  the 
drugs  just  mentioned  is  not  as  prompt  as  in  ordinary  burns. 

A  few  hints  concerning  special  features  of  the  action  of  a;-rays  will  aid 
in  forming  an  idea  of  prophylactic  measures.  Daily  radiation  has  a  cumu- 
lative effect.  Various  parts  of  the  body  are  differently  affected.  Parts 
covered  with  hair  (head  and  chin),  the  nails,  and  bloodvessels,  are  more 
predisposed  to  inflammatory  dermatitis  than  any  other  portion.  A  dis- 
eased skin  is  much  more  easily  penetrated  by  a;-rays  than  a  healthy  skin. 
According  to  Scholz  the  more  rays  emanate  from  the  tube,  the  stronger  is 
the  effect  on  the  skin.  He  also  advises  the  use  of  soft  tubes  for  therapeutic 
purposes  instead  of  hard  ones,  as  from  the  latter  emanate  few  a;-rays, 
but  there  is  much  electrical  discharge.  Large  doses,  prolonged  exposures, 
and  proximity  of  the  tube,  are  capable  of  devitalizing  tissue-elements  and 
causing  their  degeneration.  An  important  point  to  remember  concerning 
the  administration  of  rc-rays  is  the  danger  of  disseminating  the  malignant 
process  in  cases  of  neoplasms,  or  of  causing  a  more  rapid  growth. 

OTHER  RAYS. 

Becquerel's  discovery  of  rays  given  off  by  uranium  (pitchblende) 
or  its  salts  led  to  the  discovery  of  radium  and  polonium,  by  M.  and 
Mme.  Curie;  also  of  actinium  (Debienne),  of  rays  N  and  W  (Blondlot 


6-4  DISEASES  CAUSED  BY  PHYSICAL  AGENTS 

and  Charpenticr).  They  all  possess  a  highly  penetrating  power  which 
is  not  present  in  ordinary  light.  Although  the  therapeutic  value  of  these 
rays  is  at  present  not  definitely  determined  (see  above),  we  know,  never- 
theless, of  damages  which  are  sometimes  produced  by  their  indiscrimi- 
nate use.  Welkhoft'  and  Gicsel  have  first  shown  the  deleterious  effect  of 
Becquerel's  rays  upon  the  skin,  namely,  ulcerations  and  necrosis.  Simi- 
larly to  .r-rays  there  is  a  latent  {)criod  only  after  which  the  lesions  begin 
to  appear;  the  redness  apj^ears  only  a  few  days  after  the  exposure,  the 
ulceration  weeks  later.  In  Curie's  case  of  his  own  person  ulceration  ap- 
p»-ared  fifty-two  days  after  the  onset.  In  Askinass's  case  inflammatory 
cnanges  commenced  to  show  themselves  thirty  days  after  two  hours'  ex- 
posure. According  to  Ilalkin,  Becquerel's  rays  act  simultaneously  on  the 
bloodvessels  and  epithelial  and  connective-tissue  cells.  V.  Henri  and 
A.  INIayer  have  demonstrated  the  effect  of  radium  on  the  blood ;  haemo- 
globin is  transformed  into  methfiemoglobin,  and  its  solubility  is  diminished. 
Askinass  and  Caspari  have  shown  that  Becquerel's  and  Curie's  rays  have 
an  inhibitory  influence  upon  the  metabolism  in  living  tissue.  In  this 
respect  their  effect  is  identical  with  that  of  a;-rays,  but  their  action  is  more 
intense  and  destructive  than  the  latter. 


ELECTRICITY. 

To  Galvani  belongs  the  discovery  of  animal  electricity,  in  1786;  and 
Pfaff,  Humboldt,  Ritter,  Nobili,  Matteucci,  and  others,  labored  in  the 
further  development  of  it.  It  was  reserved  for  the  classic  investigations  of 
DuBois-Reymond  (1848-1884)  to  place  this  part  of  physiology  upon  an 
exact  foundation.  The  electrogenetic  properties  of  animal  tissue  led  to 
series  of  discoveries  which  finally  have  proven  that  electricity  is  an  impor- 
tant therapeutic  agent.  Its  utility  in  various  affections  of  the  nervous  sys- 
tem is  established  beyond  doubt. 

Electricity  may  under  certain  conditions  produce  local  and  general 
disturbances  and  even  death.  The  universal  utilization  of  electrical 
energy  in  industry  exposes  human  beings  to  its  deleterious  effects  to  a 
considerable  degree.  The  numberless  accidents  caused  by  electrical  cur- 
rents, and  the  facility  with  which  they  are  produced,  makes  it  the  duty  of 
physicians  to  become  familiar  with  these  accidents  and  with  the  means  of 
removing  the  consequences.  The  currents  became  dangerous  only  when 
their  energy  reached  the  high  degree  necessary  for  industry.  Before  the 
invention  of  the  dynamo  there  were  rarely  serious  accidents.  The  first 
cases  of  death  occurred  when  electricity  was  applied  industrially.  Every- 
body is  exposed  to  the  danger  of  receiving  accidental  electrical  discharges 
more  or  less  powerful.  A  rupture  of  a  wire  is  not  an  infrequent  occur- 
rence, and  accidental  contact  with  a  wire  which  has  fallen,  and  in  which 
still  circulates  a  current,  is  liable  to  lead  to  very  serious  disturbances 
in  the  organism. 

It  is  considered  that  contact  with  a  wire  in  which  circulates  electricity 
of  500  volts  is  fatal.  Resistance  of  the  human  body  to  the  passage  of  a 
current  of  this  intensity  is  considerable.  It  varies  with  the  degree,  extent 
and  duration  of  contact,  the  state  of  moisture  and  thickness  of  the  skin, 
the  state  of  general  health,  and  whether  alcoholism  is  present  or  not.    In 


LIGHT.    X-RAYS.     ELECTRICITY  65 

one  case  a  man  in  good  physical  health,  whose  flannel  undershirt  was 
thoroughly  wet  from  perspiration,  withstood  without  ill  effects  a  shock  of 
2,000  volts.  Lowenheim  and  Jellinck  report  a  case  of  5,500  volts  which 
did  not  terminate  fatally;  Picon  and  Leblanc  report  a  similar  case.  The 
immediate  effect  of  electrical  current  may  be  death,  shock  with  tempo- 
rary loss  of  consciousness,  painful  sensations,  and,  finally,  burns  of  the 
skin. 

Death. — When  an  individual  is  stricken  by  a  fatal  current  there  is  a 
violent  tetanic  contraction  of  all  the  muscles  of  the  body,  followed  by  loss 
of  consciousness.  Three  or  four  minutes  later  the  respiration  ceases.  The 
mechanism  of  death,  according  to  Provost  and  Battelli,  depends  upon  the 
degree  of  tension  of  the  current.  In  high  tension  (1200  volts  or  above) 
there  is  inhibition  of  the  nervous  centres;  the  respiratory  centre  is  first 
affected,  and  the  heart  ceases  to  beat  only  subsequently  to  asphyxia. 

Low-tension  currents  (not  above  120  volts)  produce  paralysis  of  the 
heart,  but  the  respiration  continues  for  a  certain  time.  The  heart  shows 
a  fibrillary  tremor,  and  as  soon  as  the  latter  appears  the  beating  is  im- 
mediately arrested  and  no  more  blood  is  thrown  into  the  circulation. 
Currents  of  average  tension  (240  to  600  volts)  produce  paralysis  of  the 
heart  in  a  state  of  fibrillary  tremor,  and  an  absolute  cessation  of  respira- 
tion. We  therefore  see  that  the  fibrillary  tremor  of  the  heart  is  the  most 
dreaded  phenomenon,  while  the  shock  of  the  nervous  centres  is  of  no 
special  import.  The  cessation  of  the  heart-beat  is  independent  of  the 
extrinsic  innervation  of  its  muscles.  When  there  is  no  fibrillary  con- 
traction of  the  heart,  there  is  no  danger  to  life. 

The  currents  used  in  industry  are  either  continuous  or  alternating. 
Both  cause  shock  or  death  by  the  same  mechanism.  It  is  interesting  to 
note  that  the  continuous  current  requires  a  higher  voltage  than  the  alter- 
nating current  to  bring  on  a  paralysis  of  the  heart.  On  the  other  hand, 
the  inhibition  of  the  nervous  system  is  more  pronounced  with  continuous 
than  with  alternating  currents. 

Other  Consequences  of  Electrical  Shock. — If  death  does  not  ensue, 
in  ordinary  conditions  the  sudden  contact  with  an  electrical  conductor  will 
produce  syncope,  which  is  usually  of  short  duration.  The  reestablish- 
ment  of  normal  functions  may  be  complete  and  rapid,  but  sometimes  the 
various  nervous  disturbances  may  remain  very  tenaciously.  In  the  latter 
case  there  is  usually  a  state  of  hebetude  for  several  days,  accompanied  by 
weakness,  headache,  and  sometimes  palpitation  of  the  heart.  In  some 
cases  there  was  a  state  of  mental  confusion  or  delirium,  tremor,  and  a 
general  depression  of  the  nervous  system  similar  to  that  following  trauma- 
tism. Psychoses  were  observed  by  Bucknill,Tuke,  Sanze,  Pick,  Cipriano, 
Lahnson,  and  others;  but  the  mental  disturbances  were  all  transient  in 
character.  Amnesia  was  reported  by  Heusner,  Ebertz,  Winiwarter,  and 
others.  Painful  sensations,  more  or  less  pronounced,  in  the  muscles  and 
in  the  thorax  have  been  recorded  in  a  number  of  cases  as  of  frequent 
occurrence. 

Besides  these  immediate  disturbances,  there  are  quite  a  number  resem- 
bling well-defined  nervous  affections.  Functional  nervous  diseases,  as 
hysteria  and  neurasthenia,  are  common  occurrences  after  an  electrical 
shock.  Nothnagel,  Gibier  de  Sarigny,  and  Charcot,  contributed  con- 
siderably to  the  subject.     Abundant  examples  of  either  of  these  two 


66  DISEASES   CAUSED   BY   TllYSlCAL  AGENTS 

neuroses,  or  of  a  combination  of  both,  are  found  in  recent  literature.  One 
of  the  most  typical  cases  of  hysteria  was  observed  by  the  writer  in  a  woman 
who  was  touched  at  the  elbow  by  an  electric  wire  which  broke  while  she 
was  walking  on  the  street.  A  conij)lete  hemiauiiesthesia  to  touch,  pain, 
and  temperature,  covering  also  the  face,  pharynx,  conjiuictiva,  ear,  and 
head,  was  present  in  this  case;  the  visual  field  was  markedly  contracted 
on  the  same  side.  She  was  seen  by  the  writer  shortly  after  the  accident  and 
kept  under  observation  during  two  years.  The  above  sensory  disturbances 
persisted  in  spite  of  complete  recovery  from  the  immediate  effects  of  the 
electric  shock.  Another  young  woman  was  struck  by  lightning  while 
sitting  near  an  open  window.  She  was  seen  by  the  writer  after  she  re- 
gained consciousness,  viz.,  about  an  hour  after  the  shock.  She  developed 
typical  hysterical  paroxysms;  suddenly  she  would  fall,  being  seized  with 
a  slight  tremor  in  the  extremities;  a  minute  later  the  trunk  would  begin 
to  assume  various  positions,  opisthotonos  being  the  most  frequent.  At 
the  same  time  the  patient  would  scream,  or  laugh  loudly,  or  cry.  The 
seizure  would  last  ten  minutes.  At  first  the  attacks  were  very  frequent, 
averaging  five  or  six  a  day.  A  month  later  they  began  to  disappear 
gradually,  and  at  the  end  of  three  months  she  was  entirely  free  from 
them. 

Epileptiform  and  apoplectiform  seizures  were  reported  in  old  and 
recent  literature.  Smurthwaite^  observed  a  case  of  general  convulsions 
in  a  laborer  who  accidentally  came  in  contact  with  a  current  of  2,150 
volts,  and  who  completely  recovered.  Batteli^  made  a  special  study  of 
the  continuous  and  alternating  industrial  currents  with  a  comparatively 
low  voltage  (120  to  240  volts).  He  observed  that  when  one  electrode  is 
placed  in  the  mouth  or  nostrils  and  the  other  on  the  neck,  the  heart  is  not 
affected,  the  nervous  centres  alone  being  excited.  With  this  arrangement 
an  epileptiform  convulsion  makes  its  immediate  appearance  as  soon  as 
the  current  is  closed.  A  contact  of  2^0  of  a  second  is  sufficient  to  bring 
on  an  attack;  the  latter  becomes  very  violent  if  the  duration  of  the  con- 
tact is  prolonged  to  -^q  or  ^  of  a  second.  The  attacks  present  the 
typical  tonic  and  clonic  contractions  of  the  muscles,  with  froth  at  the 
mouth  and  dilated  pupils,  followed  by  the  usual  comatose  state.  Bulbar 
symptoms,  transient  in  character,  were  reported  in  a  few  cases,  but  in  view 
of  their  temporary  nature  they  were  probably  cases  of  functional  neuroses. 
However,  Charles  K.  Mills  reported  two  cases  observed  by  him  personally 
in  which  there  cannot  be  any  doubt  of  the  organic  character  of  the  involve- 
ment of  the  medulla. 

There  are  also  in  the  literature  records  of  apparently  undoubted  cases 
of  hemiplegia,  spastic  paraplegia,  and  of  disseminated  sclerosis,  following 
lightning  or  shocks  from  other  electric  sources,  but  all  these  records  are 
only  clinical.  The  pathological  findings  of  those  few  cases  that  came  to 
autopsy  are  in  general  negative,  except  a  few  capillary  hemorrhages  or 
small  cellular  changes  in  some  cases.  Congestion  of  brain  and  cord  was 
found  in  some  cases  (Kratter).  Our  knowledge,  therefore,  of  the  sup- 
posed organic  cases  is  extremely  unsatisfactory. 

Eye  disturbances  have  been  observed  by  various  authors.  Dimness 
of  vision,  ptosis,  contraction  of  pupils,  sluggish  reflex  reactions,  subcon- 

'  British  Medical  Journal,  1901. 
2  Soci^te  de  Biologie,  1903. 


LIGHT.     X-RAYS.     ELECT  RICITY  67 

junctival  ecchymoses,  cloudiness  of  cornea — these  are  the  external 
ocular  changes  reported.  In  a  certain  number  of  cases  profound  altera- 
tions of  the  eye  were  noticed,  viz.,  apoplectic  hemorrhages  in  the  retina, 
with  pigmentation,  tearing,  bleeding,  and  rupture  of  the  choroid,  irido- 
cyclitis, luxation  of  the  retina;  anaemia  of  the  optic  nerve,  optic  atro- 
phy, and  blindness.  Fuchs,  Knies,  Meyerhofer,  Priendisberger,  and 
Vossius,  report  the  formation  of  cataract.  Hess  observed,  experimentally, 
cataract  formation  in  animals.  Disturbances  of  the  auditory  apparatus 
occurred  in  many  cases.  Pain  in  the  ear,  with  difficulty  of  hearing,  are  fre- 
quent symptoms  following  electric  shock.  The  writer  recalls  a  case  of  ab- 
solute deafness  in  a  man  of  tweny-five  occurring  after  having  been  shocked 
by  lightning.  In  this  case  there  was  loss  of  consciousness  and  a  partial 
hemiplegia  on  the  left  side;  but  the  deafness  was  complete  in  both  ears. 
Only  one  month  later  improvement  in  hearing  appeared.  The  patient 
recovered  entirely.  Clark,  Ludewig  and  others  report  tears  of  the  drum. 
Kayser  and  Freund  report  permanent  deafness  from  paralysis  of  the 
eighth  nerve,  with  or  without  simultaneous  perforation  of  the  drum. 
Gognel  observed  hemorrhages  from  the  ear. 

Burns. — ^A  conductor  charged  with  electricity  will  produce  burns  in 
living  tissue  when  it  is  brought  in  contact  with  the  latter.  Radiation  of 
electric  light  may  produce  some  superficial  burns,  but  the  appearance  of 
the  burns  and  the  accompanying  general  symptoms  are  different  when 
electricity  has  a  direct  effect  on  tissue  from  immediate  contact.  The  effect 
of  a  current  is  not  always  in  direct  relation  with  its  strength,  as  sometimes 
currents  of  5,000  volts  produce  only  superficial  burns,  and  of  500  volts 
deep  burns.  Individual  circumstances  accompanying  the  accident — dura- 
tion and  degree  of  contact,  dampness  of  skin,  the  degree  of  cleanliness  of 
the  latter — all  are  of  ^'eat  importance  as  to  the  effect  of  the  contact. 

In  electrical  burns  all  the  tissues,  from  the  epidermis  to  the  bones,  may 
be  affected.  They  may  be  superficial  or  deep.  They  are  usually  not 
limited  to  the  dermis;  the  muscle  and  bones  are  also  affected.  The  loss 
of  substance  may  be  small,  or  may  invade  a  portion  of  the  limb.  Imme- 
diately after  the  contact  the  skin  becomes  black,  and  the  affected  portion 
is  soon  covered  vvdth  a  hard  layer  resembling  parchment.  During  the 
process  of  reparation  the  wound  acquires  a  red  and  smooth  surface.  There 
is  never  present  at  the  periphery  that  whitish  ring  which  is  found  in  ordi- 
nary burns.  Electrical  wounds  never  suppurate  and  are  never  moist;  the 
parchment-like  layer  is  preserved  until  a  new  epidermis  is  formed.  The 
characteristic  feature  of  electrical  burns  consists  in  their  absolute  pain- 
lessness during  the  entire  process  of  healing.  The  duration  depends 
upon  the  degree  of  the  burns;  so  that,  when  the  bone  is  involved,  the 
course  will  be  prolonged  and  complications  will  set  in.  Superficial  burns 
heal  up  entirely  and  rapidly.  In  deep  burns  gangrene  may  occur  and 
necessitate  amputation  of  the  limb. 

Burns  may  be  accompanied  by  a  nervous  shock  more  or  less  serious, 
frequently  by  syncope.  The  latter  may  be  fatal  and  the  patient  dies  in  a 
few  minutes  despite  all  possible  care.  We  said  above  that  from  a  tension 
of  500  to  600  volts  upwards,  electrical  accidents  may  be  fatal.  It  is  to  be 
noted  that  the  voltage  alone  does  not  determine  the  question  of  death. 
Perhaps  the  danger  lies  in  the  fact  that  an  electrical  burn  forms  a  bad 
contact  by  interposition  of  gaseous  products  between  the  tissue  and  the 


68  DISEASES  CAUSED  BY  PHYSICAL  AGENTS 

metallic  conductor.  The  histological  changes  of  electrical  burns  are 
identical  with  those  of  .r-ray  burns.     (See  section  on  A'-Rays.) 

Treatment  of  Accidents  Produced  by  Electricity.— When  the  per- 
sonisstill  in  contact  with  the  conductor,  an  effort  should  be  made  toforma 
short  circuit,  by  means  of  a  body  which  is  considered  a  good  insulator,  as  a 
piece  of  wood.  If  there  is  no  object  at  hand,  we  should  free  the  victim  by 
giving  him  a  push  with  the  foot;  the  person  that  touches  the  victim  will 
feel  but  a  slight  shock,  because  the  resistance  of  the  shoes  is  great.  After 
the  contact  is  interrupted,  recovery  usually  follows  if  there  is  no  loss  of 
consciousness.  If  consciousness  is  lost  respiration  may  continue  or  else 
be  arrested.  In  the  first  case  the  ordinary  means  usually  employed  in 
syncope  should  be  ap])lied,  as  traction  of  the  tongue,  flagellation,  friction, 
cold  water,  etc.  In  the  second  case  it  is  advisable  to  institute  artificial 
respiration  at  once,  if  the  heart  continues  to  beat.  In  case  the  heart  is  in  a 
state  of  fibrillary  tremor,  artificial  respiration  is  useless. 

Burns  should  be  treated  on  general  principles.  The  affected  limb 
should  be  immobilized ;  protection  of  the  wound  with  sterilized  gauze  is 
usually  sufficient.     In  cases  of  extensive  burns,  skin-grafting  is  indicated. 


CHAPTER  111. 
AIR. 

By  ALFRED  GORDON,  M.D. 

PHYSIOLOGICAL  EFFECT  OF  AIR. 

Air  is  a  mechanical  mixture  of  oxygen  (21  per  cent.),  nitrogen  (79  per 
cent.),  water-vapor,  small  quantities  of  carbon  dioxide,  and  traces  of 
ammoniaandperoxideof  hydrogen;  also  organic  matter.  The  most  vital 
element,  without  which  life  is  impossible,  is  oxygen.  Priestly,  its  dis- 
coverer, recognized  the  enormous  importance  of  this  gas  for  life;  it  is  a 
life-sustaining  element,  of  which  an  adult  consumes  one-half  of  a  cubic 
inch  at  each  inspiration.  Its  activity  in  life  is  regulated  by  nitrogen.  In 
respiration  free  oxygen  is  taken  up  by  the  living  substance  and  in  return 
carbonic  acid  is  given  off;  hence  combustion  (Mayo)  {viz.,  oxidation) 
takes  place.  Without  the  process  of  oxidation,  metabolism  (viz.,  life) 
cannot  exist.  This  is  true  in  regard  to  individual  cells,  tissues,  organs, 
and  the  entire  organism. 

In  normal  condition  there  is  a  certain  output  ofC02  and  intake  of  O. 
As  soon  as  the  equilibrium  is  interrupted,  as  for  example  an  excess  of 
CO2  and  deficiency  of  O,  the  organism  will  be  disturbed;  and  if  this  is 
carried  to  a  higher  degree  of  difference,  a  diseased  condition  will  develop 
with  more  or  less  persistent  symptoms;  and  even  death  may  ensue. 

PATHOLOGICAL  EFFECT  OF  AIR. 

CO2,  or  the  gas  which  we  exhale,  is  an  obnoxious  element,  and  may  be- 
come even  dangerous  if  it  is  present  in  excess.  It  is  a  familiar  fact  that 
in  assemblies  behind  closed  doors  after  a  certain  time  one  feels  uncom- 
fortable, and  may  develop  a  sense  of  weight,  uneasiness,  oi  pain  in  the 
head,  dizziness,  or  singing  in  the  ears;  sometimes  vomiting,  disposition 
to  sleep,  difScult  respiration,  rapid  loss  of  sensibility;  and  at  times  syncope. 
This  symptom-group  is  mainly  due  to  excess  of  carbonic  dioxide  (CO 2). 
In  this  condition  exhalation  of  vapor  should  also  be  taken  into  considera- 
tion. 

Atmospheric  humidity  is  as  essential  to  the  life  of  organized  beings  as 
oxygen  itself.  Tyndall  says  that  the  vapors  of  water  interfere  with  the 
rapid  ascent  of  warm  air,  which  without  this  protection  would  have  been 
lost  for  us.  The  vapors  become  warm,  envelop  the  earth,  and  protect  its 
surface  from  becoming  cold. 

69 


70  DISEASES  CAUSED  BY   PHYSICAL  AGENTS 

The  action  of  humidity  on  the  organism  is  very  important  from  the 
standpoint  of  respiration  and  tiie  function  of  the  skin.  In  dry  and  warm 
air  tlie  cutaneous  evaporation  is  very  active;  in  dry  and  cold  air  the  pul- 
monary evaporation  is  stimulated.  The  humid  and  cold  air  presents  this 
inconvenience,  that  by  diminishing  cutaneous  evaporation  and  increasing 
the  loss  of  heat  from  the  surface  of  the  body,  it  predisposes  to  catarrhal 
affections,  to  renal  diseases,  and  to  rheumatism.  The  humid  and  cold 
air  diminishes  the  cutaneous  evaporation,  and  when  perspiration  is  not 
evaporated  the  variations  in  the  temperature  are  apt  to  cause  diseases 
which  are  usually  attril)ute{l  to  cold.  Besides,  the  appetite  and  metab- 
olism in  general  suffer  and  disable  the  affected  individuals  for  any  work; 
intestinal  diseases  develop  easily,  and  pulmonary  tuberculosis  finds  a 
favorable  condition  for  its  rapid  development.  Moist  and  warm  air  has 
a  special  affinity  for  organic  matter,  and  therefore  predisposes  to  develop- 
ment of  pathogenic  organisms,  which  makes  the  surrounding  atmosphere 
insalubrious. 

If  the  inhalation  of  impure  air  is  prolonged  or  constant,  as,  forexample, 
in  unclean  dwellings,  etc.,  malnutrition  and  anaemia,  with  gastro-intestinal 
disorders,  will  be  the  consequence.  These  factors  play  a  predisposing 
role  in  pulmonary  diseases,  especially  in  tuberculosis.  Sewer  air  is  charac- 
terized by  diminution  of  oxygen  and  increase  of  carbon  dioxide  (more  so 
in  summer),  and  association  of  ammonia  compounds  with  hydrogen  sul- 
phide. All  these  elements  are  undoubtedly  obnoxious,  but  what  par- 
ticularly makes  the  sewer  air  unwholesome  is  the  association  of  organic 
matter,  which  is  an  excellent  carrier  of  pathogenic  microbes.  It  is  readily 
understood  that  some  infectious  diseases  may  be  directly  traced  to  this 
origin,  especially  during  epidemics. 

The  disturbance  in  the  proportion  of  the  normal  constituent  elements 
of  air  is  observed  not  only  in  association  with  organic  material  subject  to 
putrefaction,  but  also  in  changes  of  atmospheric  pressure.  In  normal  con- 
ditions there  is  an  antagonism  between  the  internal  pressure  and  the  pres- 
sure produced  by  the  surrounding  atmosphere.  Equilibrium  is  maintained 
when  one  counteracts  the  other;  but  should  local  atmospheric  disturb- 
ances make  their  appearances,  air  pressure  is  felt. 

We  have  seen  above  that  oxygen  is  indispensable  for  life,  and  the  purity 
of  air  is  judged  by  the  presence  of  a  sufficient  amount  of  this  gas.  If 
oxygen  is  conducive  to  health,  it  may  under  certain  conditions  become 
obnoxious  and  cause  a  pathological  state.  The  latter  is  precisely  ob- 
served in  changes  of  atmospheric  pressure.  Paul  Bert  says  pure  oxygen 
may  act  as  a  poison,  and  animals  die  in  ordinary  air  when  pressure  of  O 
falls  to  3.4  per  cent,  of  atmosphere,  while  in  superoxygenated  air  they  die 
when  pressure  of  CO 2  rises  to  25  per  cent,  of  atmosphere.  In  order  to 
collect  facts  regarding  the  effect  of  various  degrees  of  air  pressure  on 
human  life,  investigators  employed  the  method  of  balloon-travel.  The 
first  trip  was  made  in  Paris  in  1875,  by  Spinelli,  Sivel,  and  Tissandier. 
They  rose  to  a  height  of  7,000  meters.  At  that  level  they  felt  a  constantly 
incrf  asing  weakness  and  apathy  until  they  reached  a  complete  absence  of 
power  of  motion,  although  their  mentality  remained  unchanged.  Soon 
they  could  not  use  their  tongue  for  speaking.  At  the  height  of  8,000 
meters  they  all  lost  consciousness.  Tissandier  regained  consciousness  and 
survived,  while  the  other  two  perished.     The    principal  facts  noted  in 


AIR  71 

both  fatal  cases  were  bleeding  from  the  mucous  membranes  of  the  mouth 
and  lungs,  accompanied  by  extreme  lassitude  and  temporary  paralysis  of 
the  respiratory  muscles,  which  proved  fatal. 

Since  the  famous  ascension,  which  has  been  followed  by  many  others, 
we  have  learned  the  effect  of  rarified  air  on  the  human  organism.  On  the 
other  hand,  we  know  that  travelers  experience  disagreeable  symptoms 
when  they  climb  mountains.  Alterations  of  atmospheric  pressure  have 
been  regarded  by  some  as  coincident  with  pulmonary  congestion  and  with 
neuralgic  and  rheumatic  pains;  but  a  well-defined  symptom-group  due 
exclusively  and  directly  to  altered  air  pressure  we  find  in:  (a)  mal  des 
montagnes;   and  (b)  caisson  disease. 

Mountain  Sickness  (Mal  des  Montagues). — The  physiological  dis- 
turbances experienced  on  altitudes  have  been  known  since  the  fifteenth 
century  when  Da  Costa  described  them  under  the  name  of  mal  des  mon- 
tagnes. His  first  description  has  been  verified  and  corroborated  by  many 
savants  since,  so  that  at  present  the  condition  has  a  clearly  defined  symp- 
tom-group. At  the  height  of  3,000  to  4,500  meters  the  first  noticeable 
symptoms  are  palpitation  of  the  heart  and  rapid  pulse.  Soon  the  respira- 
tion becomes  accelerated ;  the  patient  becomes  restless,  cannot  sleep,  and 
sometimes  has  vomiting-spells.  There  is  more  or  less  pronounced  pain 
in  the  knees  and  legs.  Walking  is  diflScult,  and  the  patient  feels  exhausted. 
At  the  same  time  thirst  increases  the  suffering.  The  tongue  is  dry;  the 
appetite  is  lost;  nausea  and  eructations  torture  the  patient.  In  extreme 
cases  hemorrhages  may  occur  which  are  followed  by  syncopal  attacks. 
The  hemorrhages  are  most  frequently  from  the  mucous  membranes  of 
the  air  passages.  Lazarus  also  observed  cyanosis  of  the  extremities  when 
a  height  of  7,000  meters  is  reached.  The  symptoms  are  therefore  analo- 
gous to  those  of  ascent  in  a  balloon,  but  it  is  remarkable  that  in  the  latter 
case  the  effects  of  diminished  pressure  are  not  felt  until  twice  the  height 
has  been  reached.  The  reason  of  it  lies  in  the  wasting  of  considerable 
muscular  energy  in  climbing.  The  wasting  is  accompanied  by  a  larger 
loss  of  calories  than  the  organism  can  supply,  as  the  respiratory  combus- 
tion cannot  furnish  a  sufficient  amount  of  heat  because  of  low  density  of 
the  air.  The  body  temperature  falls  below  normal  and  the  ascent  becomes 
difficult.  Consequently  in  mal  des  montagnes  we  have  two  factors:  the 
effects  of  rarefication  of  air  and  those  of  fatigue. 

The  effects  of  mal  des  montagnes  are  not  uniform  in  various  individuals 
and  at  various  heights.  They  depend  upon  the  age,  habits,  antecedent 
health,  etc.  At  3,000  meters  the  symptom-group  is  present  in  every  case. 
Passive  movements  can  be  produced  in  healthy  individuals  without 
marked  effect  in  their  health  even  at  the  level  of  4,000  meters.  Active  move- 
ments even  at  a  lower  height  will  produce  the  symptoms  enumerated 
above.  This  observation  is  a  sufficient  hint  for  preventive  measures.  In 
addition  to  the  latter,  care  should  also  be  taken  not  to  remain  in  the 
rarefied  air  longer  than  two  to  three  hours. 

When  a  more  or  less  prolonged  sojourn  in  mountainous  regions  is  taken 
up  by  persons  who  come  from  lower  altitudes,  they  become  subject  to  the 
following  symptoms,  which  are  particularly  marked  when  the  barometer 
stands  low:  hemorrhages  and  bronchial  and  nasal  catarrhs.  Attacks  of 
haemoptysis  are  often  seen  in  tuberculous  patients  who  come  to  high  alti- 
tudes in  search  of  health.      Epistaxis  is  observed  in  perfectly  healthy 


72  DISEASES  CAUSED  BY  PHYSICAL  AGENTS 

individuals.  The  catarrhal  trouble  is  quite  frequent  and  rebellious  to  treat- 
ment. W.  H.  Gardner^  describes  a  curious  symptom-group  observed  on 
himself.  Besides  the  usual  symptoms  described  above,  he  developed  a 
confusion  af  ideas  and  a  paretic  condition  on  the  entire  left  side  of  the 
body,  including  the  tongue,  so  tiiat  he  could  not  articulate;  he  also  felt  a 
throbbing  in  the  carotids,  and  his  pupils  were  dilated.  He  describes 
several  cases,  in  one  of  which  he  also  observed  hemianesthesia  followed 
by  epileptiform  convulsions  on  the  same  side;  in  other  cases  he  observed 
apoplectiform  attacks  with  or  without  aphasia.  The  same  author  speaks 
also  of  "rheumatism,"  which  is  exceedingly  common  not  only  among  per- 
sons who  have  recently  come  to,  but  also  among  the  inhabitants  of, 
mountainous  regions. 

Pathology. — As  to  the  pathogenesis  of  the  affection,  several  theories 
have  been  advanced.  Some  believe  that,  in  view  of  the  fact  that  the 
symptoms  are  analogous  to  the  physiological  and  pathological  effects  of 
ozone,  and  that  ozone  is  more  abundant  the  higher  the  level  of  atmos- 
pheric air  is  considered,  for  these  reasons  it  is  probably  the  direct  cause 
of  mal  des  montagnes.  Others  believe  that  the  lowering  of  air  pressure 
produces  a  congestion  of  inner  organs,  or  circulatory  disturbances.  Paul 
JBert  has  shown  that  the  cause  of  the  disturbances  lies  in  the  diminution 
of  oxygen  in  the  inhaled  air,  and  "that  the  symptoms  can  be  entirely  re- 
moved by  inhalations  of  oxygen.  The  latter  view  is  the  most  accepted, 
as  the  majority  of  the  symptoms  can  be  readily  explained.  In  fact,  the 
accelerated  respiratory  and  circulatory  movements  have  for  their  purpose 
not  only  a  larger  absorption  of  oxygen,  but  also  the  removal  of  carbon 
dioxide.  But  the  exhalation,  although  very  active,  is  not  longer  sufficient 
for  maintaining  the  normal  composition  of  the  blood,  which  is  saturated 
with  CO 2.  In  this  fact  lies  the  reason  of  the  headache,  the  nausea,  the 
irresistible  insomnia,  the  low  bodily  temperature,  and  other  symptoms 
observed  in  travellers  on  mountains.  The  treatment,  therefore,  consists 
of  supplying  the  gas  which  is  wanting.  Gardner  suggests,  that  in  view  of 
the  difficulty  of  furnishing  the  inaccessible  mountainous  localities  with 
oxygen,  its  administration  through  the  stomach  is  beneficial.  In  his 
hands  chlorate  of  potash  was  very  useful. 

Caisson  Disease,  or  Diver's  Paralysis. — Above,  w^e  considered  the 
effect  of  rarefied  air  on  human  economy.  If  the  condition  is  reversed — 
viz.,  if  the  organism  is  subjected  to  a  high  atmospheric  pressure — the  mor- 
bid manifestations  will  be  almost  exclusively  confined  to  the  nervous 
system.  The  symptoms  observed  in  divers  or  workers  in  caissons  will 
appear  only  after  they  return  to  the  surface.  It  is  therefore  the  lessened 
atmospheric  pressure  which  is  the  immediate  cause  of  the  disorder  of 
the  nervous  system.  Nevertheless,  as  this  lessening  follows  the  in- 
creased pressure  beneath  the  surface,  it  is  the  latter  that  is  primarily  at 
fault. 

The  effect  of  rapid  changes  of  barometric  pressure  was  observed  for 
the  first  time  by  Trizus,  in  1839,  on  men  working  in  cylinders  with  com- 
pressed air;  and  in  1854,  by  Pal  and  Watelle,  on  miners.  Later  other  con- 
tributions were  put  on  record;  but  they  all  have  reference  to  the  clinical 
side  of  the  subject.    The  first  complete  description  of  pathological  find- 

^  American  Journal  of  the  Medical  Sciences,  1876. 


AIR  73 

ings  which  threw  some  light  on  the  pathogenesis  of  the  affection  and 
could  explain  the  clinical  manifestations  was  given  in  1879,  by  Leyden.^ 

Symptoms. — Shortly  after  the  return  to  the  surface  and  after  a  pro- 
dromal stage  consisting  of  pain,  more  or  less  severe,  in  the  large  joints,  and 
also  in  the  epigastrium  and  sometimes  over  the  entire  body,  a  paralysis 
occurs.  The  most  frequent  form  of  this  is  paraplegia,  but  sometimes 
hemiplegia  is  observed.  The  onset  and  the  character  of  the  paralysis  is 
very  similar  to  that  of  transverse  myelitis.  If  we  take  into  consideration 
the  frequent  involvement  of  the  sphincters  (retention  and  constipation), 
and  the  sensory  disturbances,  the  resemblance  to  myelitis  will  be  com- 
plete. All  these  symptoms  may  present  variations  in  degree;  in  some 
cases  the  loss  of  power  is  only  partial,  in  others  more  or  less  pronounced, 
and  in  still  others  absolute.  Also  both  extremities  may  not  equally  be 
involved  in  regard  to  motor  power  as  well  as  to  sensations.  In  some 
cases,  in  addition  to  the  myelitic  symptoms  there  are  also  vertigo,  head- 
ache, vomiting,  slight  confusion,  convulsions,  and  double  vision.  Pros- 
tration is  present  in  more  severe  cases.  In  fatal  cases,  deep  coma,  irregular 
respiration,  and  symptoms  of  cardiac  paralysis,  announce  approaching 
death.  As  an  occasional  occurrence  we  may  mention  small  perforations  of 
the  ear-drums,  which  are  due  to  the  pressure  either  externally  or  from 
within  outward. 

Prognosis. — Generally  speaking,  recovery  occurs  frequently.  In  com- 
plete paralysis  the  loss  of  power  may  last  only  a  few  days.  In  severe 
cases  the  power  may  never  return  and  the  victim  will  remain  permanently 
crippled.  Death  in  protracted  cases  results  from  the  same  causes  as  in 
chronic  myelitis;  namely,  from  suppurating  bed-sores,  cystitis,  pyelitis, 
etc.,  or  from  an  intercurrent  disease.  On  the  other  hand,  death  may 
occur  shortly  after  the  onset  as  in  acute  myelitis.  The  hemiplegic  form 
of  paralysis  bears  usually  a  favorable  prognosis.  Deep  coma  with  irreg- 
ular respiration  is  usually  a  bad  omen. 

The  degree  of  damage  and  consequently  the  probabilities  of  recovery 
depend  in  a  general  way  largely  upon  personal  predisposition,  previous 
health  (condition  of  heart,  bloodvessels,  kidneys,  etc.),  habits  (alco- 
holism), age  (fifty  years  is  considered  the  maximum),  upon  the  length  of 
time  spent  in  the  caisson  under  high  pressure,  and  iSnally  and  mainly 
upon  the  manner  in  which  the  diver  is  brought  to  the  surface.  That  is  to 
say,  the  less  rapid  and  abrupt  the  decompression  of  air  is  done,  the  less 
damage  the  nervous  system  undergoes  and  the  more  chances  for  recovery 
there  are.    In  the  remarks  on  treatment  this  question  will  be  discussed. 

Pathogenesis  and  Pathology. — ^The  authors  are  divided  in  regard  to 
the  explanation  of  the  symptoms.  There  are  only  two  theories  in  vogue 
at  the  present  time.  According  to  one  of  them,  the  so-called  gaseous 
theory,  the  blood  while  under  high  pressure  becomes  overcharged  with  gas 
(oxygen  and  carbonic  acid),  and  the  longer  the  exposure  the  greater  the 
amount  of  gas.  When  the  surface  is  reached,  the  gas  attempts  to  escape 
through  the  lungs,  but  this  can  be  done  only  gradually  and  progressively. 
In  the  meantime  the  superfluous  gas  circulates  in  the  blood  in  bubbles, 
and  may  either  form  emboli  or  escape  through  the  vessel-walls  into  the 
surrounding  tissues  and   consequently  produce   considerable  pressure. 

^Arch.f.  Psych.  IX.  S.  316. 


74  DISEASES  CAUSED  BY  PHYSICAL  AGENTS 

If  during  this  time  the  lungs  \vill  continue  to  remove  gradually  some  super- 
fluous gas,  the  air  of  the  tissues  may  become  gradually  reabsorbed  and 
thus  relieve  the  pressure.  This  is  precisely  what  is  observed  in  the  ma- 
jority of  cases;  at  first  paralysis  with  the  associated  symptoms,  and  then 
their  gradual  disappearance.  The  reason  of  the  special  effect  of  this 
mechanism  on  the  nervous  system  lies  in  the  fact  that  the  latter  (brain 
and  cord)  are  situated  in  cavities  which  to  a  large  degree  are  hermetically 
closed.  The  spinal  cord  suffers  the  most,  as,  besides  the  cause  just  men- 
tioned, its  return  circulation  is  very  slow  because  of  the  large  number  of 
plexuses.  There  are  a  number  of  facts,  particularly  experimental,  which 
are  in  accord  with  this  theory.  It  is  sufficient  to  recall  the  experiments  of 
Hoppe  Seyler,  in  1S55,  and  Paul  Bert,  in  1872  and  1873,  in  which  sudden 
changes  of  atmospheric  pressure  produced  the  presence  of  a  considerable 
amount  of  gas-bubbles  in  the  blood. 

According  to  the  other  view  there  is  a  congestion  followed  by  a  stasis. 
The  high  pressure  drives  the  blood  from  the  periphery  to  the  internal 
organs,  especially  to  the  nervous  system.  The  bloodvessels  of  the  latter, 
unlike  those  of  other  organs,  have  no  support  from  counter-pressure,  and 
therefore  remain  dilated.  A  paralysis  of  the  vessel-walls  follows.  When 
the  atmospheric  pressure  is  diminished,  and  consequently  the  blood-press- 
ure relieved,  the  paralyzed  vessels  cannot  follow,  and  stasis  of  the  brain 
and  cord  wull  be  the  result. 

While  both  theories  are  tenable,  nnd  apparently  do  explain  all  the  symp- 
toms of  the  affection,  it  is  nevertheless  difficult  as  yet  to  tell  which  of  the 
two  has  the  more  solid  basis.  As  to  the  pathological  findings,  there  are 
only  a  few  cases  on  record  with  necropsies,  and  unfortunately  their  de- 
scriptions are  incomplete.  In  those  important  cases  which  could  throw 
much  light  on  the  subject,  the  cord  was  unfortunately  not  examined 
microscopically. 

The  latter  are  the  cases  which  ended  fatally  soon  or  immediately  after 
the  patients  were  brought  to  the  surface;  they  are  the  genuine  divers'- 
paralysis  cases.  The  most  constant  microscopical  changes  found  in 
almost  every  case  are  congestion  of  brain  and  cord  and  internal  organs  in 
acute  cases,  and  softening  in  chronic  cases.  In  the  incurable  cases  of 
long  standing  in  which  the  condition  remained  permanent  until  death, 
lesions  of  typical  chronic  myelitis  were  the  usual  findings.  A  typical 
example  of  such  a  condition  can  be  seen  in  Fr.  Schultze's  case.^  There 
was  a  complete  paraplegia  twenty  minutes  after  the  diver  left  the  caisson. 
Pain,  decubitus,  and  cystitis,  complicated  by  pyelitis,  completed  the 
myelitic  picture.  The  patient  lived  two  and  one-half  months.  On  au- 
topsy yellow  spots  were  found  in  the  posterior  and  lateral  columns  of  the 
thoracic  cord.  Ascending  and  descending  degenerations  were  traced. 
The  bloodvessels  showed  cell-infiltration  in  the  perivascular  lymph 
spaces.  There  were  also  degenerated  portions  in  the  gray  substance  on 
one  side  of  the  cord. 

Treatment. — The  management  of  well-developed  symptoms  of  myeli- 
tis indicating  a  permanent  and  definite  lesion  of  the  cord,  must  be  con- 
ducted on  the  same  principles  as  in  myelitis.  When  the  symptoms  are 
only  commencing  to  appear,  it  has  been  found  that  with  an  immediate 

>  Virchow's  ArcMv.,  79  Bd.  S.  124,  1880. 


AIR  ,    75 

return  to  the  surface,  or  by  subjecting  the  individual  to  increased 
atmospheric  pressure  in  any  manner  at  all  (pneumatic  cabinet,  etc.),  the 
symptoms  may  disappear.  It  would  be  a  matter  of  importance,  if  not  of 
absolute  necessity,  to  have  on  hand  an  apparatus  in  which  the  patient 
could  undergo  high-pressure  stances. 

Preventive  measures  constitute  the  most  important  part  of  the  treat- 
ment. Bad  physical  health,  diseases  of  the  kidneys  or  heart,  alcoholism, 
obesity,  and,  finally,  hunger,  are  all  contra-indications  for  subjecting  one's 
self  to  the  high  atmospheric  pressure.  As  to  the  limit  of  time  which  is 
permissible  to  spend  in  the  caisson,  CoUingswood's  rule  is  particularly 
to  be  recommended.  For  the  first  exposure  only  one  hour;  for  those  who 
are  accustomed  to  the  work  the  number  of  hours  should  decrease  as  the 
number  of  atmospheres  increase,  as,  for  example,  three  hours  in  four 
atmospheres,  four  hours  in  three  atmospheres,  etc.  The  locks  with  which 
the  caissons  are  supplied,  and  in  which  the  pressure  is  gradually  reduced, 
should  be  used  very  frequently,  according  to  Smith, 


CHAPTER  IV. 

HEAT  AND    COLD. 
By  ALFRED  GORDON,  M.D. 

EFFECT  OF  TEMPERATURE,  TROPICAL  AND  COLD  CLIMATES. 

In  the  preceding  sections  we  have  seen  that  light  and  a  certain  chemical 
or  physical  condition  of  air  are  indispensable  to  life.  Besides  these  con- 
ditions, upon  which  metabolism  directly  depends,  certain  dynamic  re- 
quirements must  be  fulfilled  if  life  is  to  be  maintained.  Among  them  is 
the  temperature  of  the  air  within  certain  limits. 

The  activity  of  chemical  phenomena  of  living  tissue  undergoes  consider- 
able modifications  as  soon  as  the  temperature  of  the  tissues  is  subjected 
to  variations.  The  temperature  limits  in  which  life  can  exist  are  of  course 
very  different  for  dift'erent  organisms.  It  is  well  known  that  a  man  can 
resist  great  variations  of  temperature.  This  is  probably  due  to  the 
fact  that  his  internal  temperature  remains  unchanged.  However,  this 
natural  tendency  in  maintaining  the  central  temperature  unchanged  does 
not  go  on  Avithout  certain  disturbances  in  the  functions  of  certain  organs. 
If,  for  example,  the  external  temperature  increases,  there  is  a  diminution 
in  the  production  of  COj,  the  respiration  becomes  accelerated,  and  the 
skin  perspires  profusely;  all  the  secretory  organs  eliminate  excessively; 
the  nervous  system  is  irritated.  If  the  elevation  of  temperature  is  only 
temporary,  the  related  functional  disturbances  will  be  transitory.  When 
the  action  of  heat  is  prolonged,  local  as  well  as  general  symptoms  will 
make  their  appearance. 

Heat. — ^The  eft'ect  of  heat  must  be  considered  from  three  standpoints: 
(1)  Immediate  contact  of  living  tissue  with  a  hot  object;  (2)  effect  of 
solar  heat  (see  sunstroke  and  sun-traumatism) ;  (3)  effect  of  hot  climates. 

Solid  or  liquid  objects,  and  gas  and  vapors,  when  their  temperatures  are 
elevated,  will  produce  burns  on  coming  in  contact  with  living  tissue; 
local  destructions  of  skin  and  mucous  membranes  will  be  the  consequence. 

Fluids,  when  they  do  not  reach  a  temperature  of  100°,  produce  only  a 
slight  erythema.  Water  boils  at  the  temperature  of  100°  C.;  salty  water 
and  oil  must  have  a  larger  quantity  of  calories  and  are  therefore  to  be 
feared.  Burns  of  mucous  membranes  of  the  rectum  and  vagina  occur 
when  very  hot  enemas  or  injections  are  administered,  ffidema  of  the 
glottis  may  be  the  consequence  of  burns  of  buccal,  pharyngeal  and 
oesophageal  mucous  membranes.  Caustic  fluids  taken  by  mistake  or  in 
attempting  suicide  lead  to  very  grave  injuries  of  the  mucous  membranes. 

76 


HEAT  AND  COLD  77 

Solid  objects,  especially  metals  at  a  red  heat,  produce  deep  lesions;  but 
the  burn  is  confined  to  the  point  of  application  if  the  substance  is  not 
adherent.  Gas  causes  accidents  through  its  flame.  Those  whose  work 
exposes  them  to  explosions  (chemists,  miners,  etc.),  are  frequently  victims 
of  burns;  their  clothing  takes  fire  and  cannot  be  separated  from  the 
body;  the  skin  becomes  carbonized  and  the  subcutaneous  fat  burns; 
the  consequences  may  be  very  serious.  Hot  vapors  are  particularly  ob- 
noxious. Droplets  of  hot  water  accumulated  on  the  skin  will  burn  it,  but 
they  may  be  also  inhaled  and  penetrate  the  mucous  membranes  of  the 
larynx  and  lungs. 

In  burns  we  meet  with  all  degrees  of  active  hyperfemias  and  formation 
of  oedema,  hemorrhages,  and  necrosis  in  the  skin.  Since  Dupuytren,  it 
has  been  generally  accepted  to  consider  six  degrees  of  burns.  The  first 
degree  is  characterized  by  redness,  pain,  and  tumefaction.  The  pain  is 
pronounced  at  the  beginning.  The  swelling  is  of  short  duration.  The 
symptoms  are  transient,  and  desquamation  of  the  epithelium  takes  place. 
In  the  second  degree  the  Malpighian  layer  is  affected.  The  epidermis  is  ele- 
vated by  vesicles.  When  the  latter  are  ruptured  and  the  epidermis  is 
removed,  granulation  and  suppuration  are  found  on  the  underlying  layer, 
which  is  extremely  painful.  Deformed  scars  will  always  form,  if  the 
epidermis  is  removed.  It  is  therefore  advisable  to  leave  the  epidermis  in 
place.  The  third  degree  is  characterized  by  destruction  of  all  the  super- 
ficial layers  of  the  dermis.  The  vesicles,  which  are  large,  do  not  contain 
a  serous  fluid  as  in  the  preceding  degree,  but  a  dark  bloody  fluid.  Some- 
times dry,  dark  or  yellow  scabs  are  formed.  The  pain  is  exquisite, 
especially  on  the  sixth  or  seventh  day,  when  the  scab  falls  off.  The  latter 
leaves  a  granulated  and  suppurating  surface  which  is  replaced  later  by  a 
deformed  cicatrix.  In  the  fourth  degree  the  destruction  of  the  skin  is  com- 
plete; even  the  subcutaneous  cellular  tissue  is  affected.  The  scabs  are 
here  more  or  less  large,  dark,  and  dry.  Pain  is  not  pronounced,  because 
the  nerve-ends  are  destroyed.  The  gangrenous  layers  fall  off  and  cause 
sometimes  an  inflammatory  condition.  The  cicatrices  are  formed  very 
slowly  and  are  very  irregular.  In  the  fifth  degree  we  often  find  destruction 
of  skin,  muscles,  bloodvessels,  and  nerve-trunks.  When  the  scabs  fall  off, 
sometimes  articular  cavities  are  laid  open.  When  the  gangrenous  tissue 
falls  off,  purulent  arthritis,  visceral  inflammation  and  abundant  hemor- 
rhages may  occur.  In  the  sixth  degree  all  the  tissues  are  carbonized, 
the  periosteum  is  destroyed,  the  bone  is  necrosed,  and  an  entire  limb 
may  be  lost. 

In  addition  to  local  symptoms  there  are  frequently  general  phenomena 
more  or  less  pronounced.  They  depend  upon  the  extent  of  the  lesion. 
When  the  burn  is  grave,  the  pain  may  be  so  intolerable  that  the  patient 
falls  in  a  stuporous  state.  He  is  somnolent,  does  not  speak  or  move;  the 
face  is  pale;  the  skin  is  covered  with  a  cold  perspiration;  the  tempera- 
ture goes  down  below  normal;  the  pulse  is  imperceptible;  and  the  respir- 
ation becomes  irregular;  anuria  may  occur.  In  another  series  of  cases 
with  the  same  lesions  the  general  condition  is  of  a  diametrically  opposite 
character;  extreme  excitement  with  delirium  and  convulsions  T\dll  be  ob- 
served. In  a  certain  number  of  cases  there  is  a  marked  elevation  of  tem- 
perature, which  is  due  to  visceral  inflammation.  Here  we  observe  loss  of 
appetite;  constipation,  or  else  a  diarrhoea;  generalized  bronchitis,  bron- 


78  DISEASES  CAUSED  BY  PHYSICAL  AGENTS 

chopncumonia,  or  pleurisy.  The  kidneys  may  become  involved,  and  albu- 
men is  found  in  the  urine.  Finally,  cerebral  congestion,  with  exudation 
in  the  ventricles,  has  also  been  observed. 

During  the  period  of  disapjiearance  of  the  scabs  the  suppuration  de- 
scribed above  is  always  accompanied  by  general  symptoms.  In  pro- 
nounced cases  amyloid  degeneration  of  the  viscera  may  occur  and  lead  to 
cachexia  and  death.  In  other  cases  new  infections  may  occur  in  the  sup- 
purating wound:  erysipelas,  septica?mia,  secondary  hemorrhages,  and 
tetanus  may  develop. 

Pathology  and  Pathogenesis. — The  common  findings  are  congestion 
of  the  digestive  and  respiratory  tracts  and  of  the  nervous  system.  But 
the  complications  cited  above  will  add  other  lesions  independently  of 
burns.  As  to  the  ])athogenesis  of  burns  various  views  have  been  advanced, 
and  among  them  the  ideas  of  Metchnikoff's  and  Ehrlich's  schools  are 
the  most  acceptable.  In  burns  there  is  complete  or  partial  destruction  of 
the  cell-elements  of  the  blood;  this  has  for  consequence  formation  and 
absorption  of  cell  poison  (hfemotoxin).  In  extensive  burns  we  have  to  deal 
with  destruction  of  a  greater  number  of  cells,  and  therefore  with  a  larger 
surface  for  absorption  of  the  products  of  this  destruction.  Capillary  em- 
boli, thrombi,  and  infarcts,  especially  in  the  kidneys,  are  of  frequent 
occurrence;  they  explain  the  cases  of  sudden  death  so  frequent  after 
extensive  burns. 

Prognosis. — It  depends  largely  upon  the  extent  and  depth  of  the  burn 
and  upon  the  importance  of  the  affected  organs.  A  lesion  which  would  be 
insignificant  on  the  skin  will  be  of  paramount  gravity  if  it  occurs  in  the 
throat,  as  oedema  of  the  glottis  may  ensue  and  be  followed  by  death.  On 
the  other  hand,  a  burn  of  second  degree,  if  it  is  extensive,  may  be  more 
serious  than  one  of  the  third  or  fourth  degree  which  is  less  extensive. 
The  complications  play  a  great  role  in  the  course  and  termination  of  a 
burn. 

Treatment. — In  burns  of  the  first  degree,  sedatives  for  the  pain  and 
external  applications  of  liniments  containing  cocaine  or  morphine  are 
sometimes  sufficient.  Prolonged  baths  at  a  temperature  slightly  lower 
than  the  body  temperature  are  particularly  recommended.  In  bums  of 
the  second  degree  one  must  not  remove  the  epidermis  raised  by  the  ves- 
icles. The  latter  should  be  punctured  at  its  lowest  point.  If,  however, 
the  epidermis  is  accidentally  removed,  the  burn  should  be  covered  with  a 
thick  layer  of  antiseptic  cotton.  Cotton  is  a  good  filter  for  air,  protects 
the  nerve-ends,  and  lessens  the  inflammatory  condition  by  pressure.  In 
case  the  cotton  is  moist  with  exudation  from  the  wound,  it  must  be  changed. 
It  should  remain  in  place  until  a  new  epidermis  is  formed.  When 
the  burns  are  deep  and  scabs  are  formed,  care  should  be  taken  to  avoid 
formation  of  irregular  cicatrices.  Antiseptic  dressings,  and  particularly 
carbolized  vaseline,  or  iodoform  incorporated  in  vaseline,  and  also  gauze 
saturated  with  a  weak  solution  of  sublimate  and  protected  with  oiled  silk, 
are  all  of  value;  they  prevent  extensive  suppuration  with  its  usual  com- 
plications. In  some  cases  it  is  extremely  difficult  if  not  impossible  to  avoid 
deformed  cicatrices ;  deformities  about  the  mouth,  eyelids,  nostrils,  have 
been  reported.  Syndactylism  was  also  observed  in  cases  in  which  the 
nude  surface  of  one  finger  was  in  contact  with  the  next  finger.  Similar 
adhesions  have  been  observed  between  the  arm  and  thorax.    In  such  cases 


HEAT  AND  COLD  79 

grafting  of  skin  will  be  of  great  service.  In  extreme  cases,  when  the  de- 
struction of  the  skin  or  of  a  portion  of  a  limb  is  so  great  that  the  function 
will  be  hopelessly  disturbed,  amputation  becomes  necessary. 

As  to  the  general  symptoms  accompanying  burns,  they  must  be 
treated  on  general  principles.  For  depression  use  stimulants;  for  excite- 
ment and  pain,  sedatives.    Good  nutritious  food  should  always  be  given. 

Hot  Climates  and  Health. — A  question  of  great  practical  im- 
portance is  the  morbid  effect  of  hot  climates  on  health.  If  an  individual 
from  a  moderate  climate  is  thrown  accidentally  or  otherwise  into  an 
atmosphere  with  an  elevated  temperature,  what  will  be  the  effect  on  his 
health?  The  first  symptom  noticeable  will  be  increase  of  perspiration. 
This  is  followed  by  a  low  arterial  tension.  The  urine  is  reduced.  While 
the  lungs  expand,  the  number  of  inspirations  is  reduced,  and  as  hot  air 
contains  less  oxygen  than  cold,  the  general  metabolism  is  diminished.  The 
tolerability  or  intolerability  of  hot  air  is  always  associated  with  humidity. 
Atmospheric  humidity  interferes  with  free  evaporation  of  sweat,  and  this 
necessarily  interferes  with  the  mechanism  concerned  in  heat  generation. 
A  diminution  of  capacity  for  intellectual  work — with  a  condition  of 
languor  and  general  weakness,  loss  of  appetite,  disturbance  of  digestion, 
of  respiration,  and  of  circulation,  are  the  usual  symptoms  observed  in 
individuals  who  come  from  a  moderate  climate  to  reside  a  more  or  less 
prolonged  period  of  time  in  tropical  countries. 

There  are  certain  diseases  that  are  most  common  in  the  tropics,  such 
as  malaria,  yellow  fever,  beri-beri,  dengue,  cholera,  dysentery,  leprosy, 
hepatic  abscess,  and  others.  This  is  probably  due  to  the  fertile  ground 
which  certain  bacteria  find  in  heat  associated  with  humidity.  On  the 
other  hand,  hot  air  with  moisture  predisposes  to  various  affections,  as 
intestinal  diseases,  bronchitis,  and  meningitis.  The  latest  reports  on 
mortality  in  tropical  climates  show  that  there  is  a  special  group  of  diseases 
which  predominate  and  are  highly  fatal.  They  are  nervous  diseases,  and 
convulsions  in  children.  According  to  V.  Harvard^  the  mortality  from 
nervous  disorders  is  nineteen  per  thousand.  Sleeping  sickness,  (pro- 
duced by  trypanosoma),  cachexia  (caused  by  ankylostomum),  leprosy, 
and  hepatic  abscess,  are,  according  to  the  same  author,  causes  of  high 
death-rates  in  hot  climates. 

Cold. — Similarly  to  heat,  the  effect  of  cold  varies  with  the  age,  with  the 
state  of  general  health,  with  constitutional  diseases,  fatigue,  alcoholism, 
and,  finally,  upon  the  degree  of  cold.  We  will  consider  here,  first,  the  local 
effect  of  cold,  and  then  its  general  effect. 

The  effect  of  extreme  cold  upon  the  portions  of  the  body  which  are 
exposed  (feet,  hands,  ear,  nose)  presents  three  degrees.  In  the  first  degree 
there  is  a  dark  redness  of  the  skin.  The  circulation  is  poor,  the  stagnation 
of  the  blood  in  the  peripheral  capillaries  leads  to  infiltration  of  the  subcu- 
taneous tissue,  and  the  skin  is  thickened.  When  the  skin  is  exposed  to 
heat,  tingling  and  itching  will  be  present.  Generally  the  condition  does 
not  last  long.  In  some  cases  it  may  become  chronic.  The  second  degree 
is  characterized  by  ulcerations.  In  acute  forms  they  appear  at  once.  The 
epidermis  is  raised  by  a  serous  or  bloody  fluid;  the  thin  membrane  be- 
comes detached,  and  an  ulcerated  surface  is  seen.    In  the  chronic  form 

^American  Medicine,  1905. 


80  DISEASES  CAUSED  BY  PHYSICAL  AGENTS 

the  skin,  which  is  infihr.itcd,  bursts,  and  the  yellow-brownish  fluid  turns 
into  crusts  under  which  pus  is  accumulated.  The  third  degree  is  charac- 
terized by  death  of  the  dermis  and  sometimes  of  the  other  underlying 
tissues.  Elimination  of  necrosed  tissue  begins  very  soon.  If  it  is  moder- 
ate, the  sloughing  Avill  leave  a  bleeding,  ulcerated  surface,  under  which 
is  sometimes  found  diseased  bone. 

Pathology  and  Pathogenesis. — Laveran  and  Cohnheim  have  studied 
the  effect  of  cold,  and  found  the  bloodvessels  to  be  the  main  tissue  in- 
volved. The  action  of  cold  consists  in  narrowing  the  lumen  of  the  blood- 
vessels, which  may  go  even  to  its  complete  obliteration;  the  blood  does 
not  circulate  and  the  involved  area  becomes  white.  Soon  the  cajjillaries 
dilate  so  that  the  circulation  is  slow  and  sometimes  arrested.  Thrombosis 
is  the  usual  consequence,  and  small  emboli  may  be  detached  and  thrown 
into  the  general  circulation.  Changes  in  nerves  are  sometimes  very  pro- 
nounced; ruptures  of  the  vasa  nervorum  and  interstitial  hemorrhages 
have  been  observed.  Laveran  and  Tillaux  sj)eak  of  fatty  degeneration  of 
the  myelin  sheath,  a  fact  which  will  explain  muscular  atrophy,  pain,  and 
trophic  ulcers,  with  anaesthesia  of  the  skin.  The  inflammation  of  the 
neuritis  may  sometimes  ascend  to  the  cord.  Other  lesions  were  observed. 
Mathieu  and  Gubler  speak  of  visceral  congestion  caused  by  capillary 
emboli;   Laveran,  of  loss  of  mobility  of  leukocytes. 

Prognosis. — The  first  and  second  degrees  may  run  their  course  without 
general  disturbances.  However,  in  soldiers  who  suffer  hardships,  in  aged 
people  and  cachectic  individuals,  cedema  of  the  face  and  of  eyelids,  and 
albuminuria,  were  observed.  Weak  individuals,  old  people,  children, 
those  who  overfatigue  themselves,  those  who  do  not  eat  enough,  those 
who  use  alcohol  to  excess,  are  all  very  readily  predisposed  to  the  eft'ects  of 
cold,  and  in  such  cases  the  prognosis  is  therefore  always  serious.  During 
the  stage  of  suppuration  general  septicaemia  may  occur.  Recovery  is 
usually  slow;  the  cicatrization  is  very  sluggish,  and  may  be  arrested  from 
the  slightest  cause.  This  is  particularly  true  in  regard  to  individuals  of 
lymphatic  nature. 

Treatment. — Prophylactic  measures  are  of  utmost  importance.  The 
extremities  (hands  and  feet)  should  be  well  protected.  Sudden  changes 
of  temperature  should  be  avoided.  Dry  astringent  friction  and  massage 
are  recommended. 

When  the  first  degree  is  present,  the  congestion  of  the  skin  will  be  re- 
lieved by  washing  it  with  a  stimulating  fluid  (alcohol  and  others).  When 
ulcei'ations  make  their  appearance,  they  should  be  protected  from  infec- 
tion. The  third  degree  requires  special  attention.  The  greatest  pre- 
caution is  necessary  to  avoid  extension  of  the  inflammation.  The  old 
Avell-known  friction  of  frozen  limbs  Avith  snow  or  with  very  cold  water  is 
not  to  be  neglected.  In  case  of  apparent  death  artificial  respiration  is 
indicated.  There  are  cases  on  record  showing  that  individuals  after  having 
remained  under  snow  for  several  days  could  be  brought  to  life  with 
artificial  respiration.  It  is  therefore  important  to  have  recourse  to  it  in 
every  case. 

Under  normal  conditions  a  temperature  which  is  not  very  low  will  pro- 
duce rather  an  agreeable  sensation;  one  feels  more  active,  and  the  respira- 
tion becomes  better.  There  is  more  oxygen  taken  in  and  more  carbon 
dioxide  exhaled.    When  the  temperature  is  very  low,  and  the  organism 


HEAT  AND  COLD  81 

is  exposed  to  it  for  a  long  time,  functional  disturbances  make  their  appear- 
ance. At  first  the  circulation  becomes  more  active,  and  the  temperature 
rises;  but  soon  this  excitation  disappears,  the  limbs  become  numb,  and 
the  sight  impaired.  A  general  lassitude  and  an  imperative  desire  to 
sleep  make  their  appearance;  general  sensations  become  obtunded,  respi- 
ration is  difficult,  the  heart  rate  is  slow,  and  syncope,  followed  by  death, 
may  ensue.  There  are,  however,  cases  on  record  showing  that  individ- 
uals remained  four,  six  and  even  eight  days  under  snow  and  neverthe- 
less continued  to  live. 

Before  death  occurs,  the  muscular  fibers  cease  to  contract  voluntarily; 
the  muscles  of  the  neck  and  of  the  extremities  become  rigid,  and  thus  im- 
mobilize the  body  in  a  position  which  it  had  assumed  at  the  time  it  was 
overtaken  by  cold.  This  explains  the  bizarre  attitudes  in  which  the 
bodies  of  individuals  who  died  from  extreme  cold  are  found.  According 
to  Desgenettes,  muscular  contractures  may  spread  over  the  entire  body, 
and  epileptiform  seizures  may  carry  off  the  unfortunate  victims.  It  has 
been  also  observed  that  in  a  certain  number  of  cases  the  cold  air  entering 
the  lungs  produced  excruciating  pain  and  sudden  arrest  of  respiration. 
In  some  cases  there  is  a  state  of  delirium,  with  a  tendency  to  suicide. 

The  degree  of  cold  which  is  apt  to  cause  death  is  difficult  to  determine, 
because  there  is  a  considerable  difference  in  resistance  in  various  individ- 
uals. A  man  in  perfect  health  is  capable  of  tolerating  a  very  low  tempera- 
ture which  an  individual  in  a  state  of  fatigue  or  exhaustion  is  unable  to 
resist.  In  Tagetthoff's  "Le  tour  du  monde,  1896,"  we  see  that  the  crew 
of  the  ship  lived  812  days  in  a  temperature  alternating  between  40°  and 
50°  below  zero.  Other  travelers  reported  similar  facts.  Adults  are  able 
to  stand  cold  provided  they  are  not  under  the  influence  of  alcohol,  because 
alcohol  causes  a  dilatation  of  the  capillaries  and  thus  facilitates  the  deleteri- 
ous effect  of  cold.  Children  are  less  apt  to  resist  low  temperature  than 
adults,  because  they  produce  less  heat.  Excessive  mental  and  physical 
work  and  inanition  are  also  causes  of  death  from  cold.  It  is  interesting  to 
note  that  insane  individuals  possess  remarkable  resistance  power;  they 
never  complain  of  cold. 

At  autopsy  the  muscular  tissue  is  found  red;  the  blood  is  dark;  the 
heart  and  bloodvessels  are  filled  with  blood;  ecchymoses  are  found  on 
the  pleura;  the  lungs  are  either  ansemic  or  congested.  The  brain  is 
either  ansemic  or  congested.  Wichniewski^  was  the  first  to  observe  small 
hemorrhages  in  the  mucous  membrane  of  the  stomach.  Since  then  this 
sign  has  been  considered  pathognomonic.  Schrimpton  observed  an  in- 
flammation of  the  gastro-intestinal  tract  in  soldiers  who  died  from  cold 
during  campaigns. 

The  mechanism  of  death  is  as  yet  not  satisfactorily  explained.  Ac- 
cording to  Magendie,  there  is  a  contraction  of  the  peripheral  capillaries, 
with  this  result,  that  there  is  an  increase  of  intravascular  tension;  con- 
gestion of  lungs  and  brain  follows.  Pouchet  thinks  that  the  blood  becomes 
frozen  and  stagnant  in  the  peripheral  bloodvessels,  and  this  leads  to 
embolism  in  central  bloodvessels.  According  to  Horwatt,  weaknesses 
of  the  muscular  system  and  of  the  heart  are  the  main  factors  in  the 
causation  of  death. 

^Mess.  de  Vhyg.  publ.  et  med.,  leg.  1895. 


PART  III. 


DISEASES  DUE  TO  CHEMICAL  AGENTS. 


By  DAVID  L.  EDSALL,   M.D. 

As  is  indicated  in  the  title,  the  following  discussions  will  be  devoted 
solely  to  the  diseases  produced  by  certain  important  chemical  substances. 
Acute  poisonings,  belonging  exclusively  to  special  works  dealing  with 
toxicology,  will  not  be  touched  upon  except  in  so  far  as  they  produce 
peculiar  disease-pictures  (such  as  that  in  acute  phosphorus  poisoning), 
or  are  of  immediate  importance  in  relation  to  subsequent  symptoms. 
Many  inorganic  chemical  substances  which  have  been  accused  of  causing 
disease,  but  apparently  do  not  produce  any  definite  symptoms,  have 
been  excluded;  while  zinc  and  copper,  for  example,  concerning  which 
there  is  much  difference  of  opinion,  have  been  briefly  mentioned. 

Unfortunately,  in  America  the  study  of  dangerous  industries  must  as  yet 
be  carried  out  almost  solely  through  individual  effort.  The  states  have 
only  general  regulations  governing  their  industries,  except  in  so  far  as 
they  involve  danger  of  accident  or  are  likely  to  become  public  nui- 
sances, specific  regulations  protecting  the  workmen  from  the  dangers 
peculiar  to  special  trades  being  almost  entirely  wanting.  Governmental 
study  of  the  influence  of  trade  upon  health  has  been  extremely  frag- 
mentary, and,  from  a  scientific  standpoint,  usually  extremely  casual,  so 
far  as  the  writer  has  determined  by  somewhat  diligent  inquiry  among 
the  federal  and  State  labor  bureaus  and  the  health  boards,  though 
Massachusetts  is  now  undertaking  an  investigation  of  this  sort  that  bids 
fair  to  be  of  some  breadth.  Extensive  governmental  study  of  the  ques- 
tion, with  a  view  to  exercising  reasonable  control,  is  very  much  to  be 
desired  in  this  country,  because  there  are  special  circumstances  which 
render  some  European  statistics  and  laws  of  doubtful  applicability  here. 
Among  these  circumstances  are  concentration  of  capital  and  ownership, 
the  very  general  use  of  mechanical  apparatus  in  place  of  men,  peculiarities 
of  the  purchasing  public,  and  of  the  American  as  compared  with  the 
European  workman.  All  these  have  an  influence  upon  occupation- 
diseases,  and  in  some  instances  this  is  extremely  marked. 


83 


CHAPTER  V. 
CHRONIC  LEAD  POISONING. 

In  clinical  and  economical  importance,  as  well  as  in  historical  interest, 
chronic  satnrnism  largely  overshadows  all  other  chronic  intoxications 
except  that  dne  to  alcohol. 

Historical. — Evidence  that  lead  poisoning  was  known  appears  even 
in  the  works  of  some  of  the  earlier  Greek,  Roman,  and  Arabian  authors. 
Their  earliest  observations  relate  largely  to  the  medicinal  use  of  lead, 
accidental  and  industrial  chronic  ]:)oisoning  having  been  apparently  but 
indefinitely  recognized  or  studied  at  that  time.  Ramazzani  makes  an 
attempt  to  demonstrate  that  Hippocrates  had  a  fairly  clear  idea  of  the 
occupational  dangers  to  workers  in  metals,  but  the  original  scarcely 
indicates  this.  Ramazzani  seems  somewhat  over-enthusiastic  also  in  his 
suggestion  that  the  early  death  of  Raphael  was  largely  due  to  the  use  of 
metallic  pigments.  Tanquerel  states,  however,  that  Nicander  knew  that 
lead  may  cause  colic  and  paralysis,  and  that  Dioscorides  saw  the  dangers 
to  workers  in  lead  and  some  of  the  clinical  results,  and  even  described 
certain  hygienic  measvires  to  prevent  them.  Galen  and  some  other  lay 
and  medical  writers  of  the  same  general  period  recognized  the  dangers 
from  drinking  water  conducted  through  lead  pipes.  The  additions  to  the 
subject  then  and  later  were  but  fragmentary,  however,  up  to  the  time 
of  Avicenna,  who  gave  a  clear  description  of  lead  colic.  After  this,  little 
that  was  new  was  added  during  the  middle  ages;  but  Citois,  in  1616, 
though  he  failed  to  recognize  the  cause,  aroused  widespread  interest  in 
epidemic  colic  through  his  description  of  the  conditions  resulting  from 
wine  drinking  by  the  people  about  Poitou.  The  name  colica  pidonum 
was  derived  from  this  source,  and  was  soon  applied  to  the  colic  of  paint- 
ers and  of  others  who  worked  in  lead,  since  this  presented  symptoms 
identical  with  those  seen  in  Poitou  colic.  Evidence  that  the  colic  due  to 
wine  was  lead  colic  was  furnished  by  Wepfer,  in  1671;  and  Sir  George 
Baker  demonstrated  the  same  thing  a  century  later  in  regard  to  the  Devon- 
shire epidemics,  which  were  ascribed  to  cider.  That  the  danger  from  this 
source  was  recognized  much  earlier  than  this  is  shown  by  the  fact  that 
imperial  ordinances  were  issued  in  Europe  forbidding  the  use  of  lead  in 
wine  even  as  early  as  the  first  half  of  the  fifteenth  century.  After 
Stockhausen  showed  the  frequency  of  lead  colic  in  the  lead  miners  at  Goslar, 
in  1656,  and  its  dependence  upon  their  occupation,  lead  poisoning  was 
frequently  discussed  by  medical  writers  of  the  seventeenth  and  eighteenth 
centuries,  one  point  of  some  interest  being  that  de  Haen  appears  to 
have  described  saturnine  gout,  though  our  clinical  knowledge  of  this 
condition  is,  of  course,  essentially  due  to  the  initiative  of  Garrod.  Among 
later  writers,  two  stand  out  with  especial  prominence,  one  of  them  being 
supreme.     Tanquereldes  Planches,  in  1838,  published  the  result  of  a  ten 

84 


CHRONIC  LEAD  POISONING  85 

years'  study,  including  1,217  cases,  which  is  by  far  th(!  most  profound  and 
important  work  ever  devoted  to  the  subject.  His  countryman,  Duchenne, 
first  studied  thoroughly  by  modern  methods  the  nervous  disorders  pro- 
produced  by  lead. 

From  the  economist's  standpoint  it  is  noteworthy  that  no  chemical  so 
readily  capable,  in  its  ordinary  uses,  of  causing  chronic  poisoning,  is 
handled  by  such  large  numbers  of  persons,  and  none  is  employed  for 
such  manifold  and  important  purposes.  Layet^  made  a  list  of  111  occu- 
pations in  which  industrial  lead  poisoning  may  more  or  less  readily 
occur,  and  my  reading  and  clinical  experience  have  added  a  consider- 
able number  of  others  in  which  poisoning  has  actually  been  observed. 
The  influence  that  may  be  exerted  upon  the  productiveness  of  persons 
engaged  in  some  of  these  occupations  is  illustrated  by  the  statement  of 
Kaup,^  that  the  statistics  of  the  sick  benefit  societies  of  Vienna  show 
that  among  the  printers  and  type  founders  the  cases  of  definite  lead 
poisoning  throughout  a  period  of  ten  years  numbered  more  than  the 
cases  of  tuberculosis;  and,  besides  many  disturbances  of  health  that 
were  essentially  due  to  lead  were  probably  grouped  under  other  headings. 
Yet  these  persons  exhibit  tuberculosis  more  frequently  than  the  general 
populace.  The  printers,  painters,  potters,  and  earthenware  makers,  in 
and  about  Vienna,  numbering  in  all  about  44,380,  furnish  yearly  at 
least  1,563  cases  of  lead  poisoning,  with  43,045  sick  days  from  this  cause 
alone;  and  in  the  whole  of  Austria  there  were  in  this  small  group  of 
workers  about  double  this  number  of  lead  poisonings  yearly,  with  the 
result  that  these  persons  were  pure  consumers  instead  of  producers  for 
from  85,000  to  90,000  days  yearly.  These  figures  are  worse  than  those 
from  some  other  sources,  and  the  conditions  in  Austria  are  undoubt- 
edly bad  as  compared  with  those  in  a  number  of  other  countries ;  but 
these  statistics  are  given  because  the  manner  in  which  they  were  gathered 
is,  on  the  other  hand,  exceptionally  satisfactory  for  this  purpose,  and, 
while  they  would  be  somewhat  misleading  if  applied  to  the  world  at  large, 
they  indicate  conditions  that  may  actually  exist  in  other  countries  where 
occupations  are  not  specifically  controlled  by  law.  They  serve  to  demon- 
strate the  importance  that  these  and  some  other  occupations  may  have 
for  the  economist,  and  for  the  clinician  as  w^ell. 

The  clinical  interest  in  the  subject  is  even  wider  and  more  complex 
than  the  economic,  for  many  of  these  industries  furnish  products  that 
occasionally  cause  poisoning  in  those  who  use  them,  as  w^ell  as  in  those 
who  make  them;  and  lead  is,  furthermore,  used  in  many  other  ways  that 
involve  little  or  no  risk  to  the  producer  but  occasionally  endanger  the 
consuming  public.  Accidental  lead  poisoning  is  much  less  important 
than  industrial,  and  is  less  common  now  than  it  was  a  decade  or  two  ago; 
but  its  sources  are  almost  innumerable,  some  of  them  being  evident, 
some  most  unexpected,  and  not  a  few  dependent  upon  the  use  of  lead  in 
preparations  which  are  of  secret  nature  and  therefore  more  dangerous 
because  the  risk  from  them  is  often  discovered  only  through  the  occurrence 
of  poisoning.  The  clinical  importance  of  the  subject  and  its  complexity  are 
also  very  largely  increased  by  the  fact  that  saturnism  at  times  appears  in 

^Poisons  Industrielles. 

^  Gesundheitsgefdhrliche  Industrien,  etc.,  1903;  edited  by  Bauer;  pub.  by 
Fischer,  Jena. 


86  DISEASES  DUE  TO  CHEMICAL  AGENTS 

most  peculiar  clinical  guises,  and  the  nature  of  the  condition  is  extremely 
likely  to  be  overlooked,  particularly  if  a  source  of  intoxication  is  not 
readily  suggested  by  the  history. 

Etiology — Race. — Racial  susceptibility  is  not  usually  recognized,  but 
Mr.  J.  T.  Monell,  of  Flat  River,  Missouri,  whose  experience  as  an  engi- 
neer in  lead  mines  is  probably  unexcelled,  and  who  has  observed  lead 
poisoning  accurately,  states  that  he  is  convinced  that  negroes  have  an 
undoubted  tendency  to  lead  convulsions;  a  statement  which  is  very  sug- 
gestive in  regard  to  the  general  question  of  race,  and  which  agrees  with 
the  general  neurotic  history  of  the  negro.  Investigation  of  this  point  in 
the  records  in  some  of  the  Philadelphia  hospitals  shows  extremely  few 
cases  in  negroes,  since  very  few  are  employed  here  in  occupations  that 
cause  exposure  to  lead.  Of  the  6  cases  of  which  records  were  found, 
3  were  ence])halopathies. 

A  point  that  is  not  wholly  pertinent  under  this  heading,  but  that  is  of 
importance,  is  that,  in  this  country,  a  very  abnormal  jiercentage  of  cases 
occurs  in  foreigners,  which  may  be  chiefly  attributed  to  their  exposing 
themselves  unduly,  owing  to  imperfect  understanding  of  the  English 
language  and  to  their  personal  habits. 

It  is  of  interest  to  note  that  some  of  the  lower  forms  of  life  seem  to  be 
more  or  less  immune  to  the  action  of  lead,  and  that  the  higher  types  of 
animals  also  differ  greatly  in  their  susceptibility.  In  the  latter,  it  is  prob- 
ably largely  a  question  of  the  facility  with  which  they  make  soluble,  and 
absorb,  the  more  insoluble  forms  of  lead.  For  example,  Mr.  Monell 
states  that  he  has  observed  that  dogs  and  cats  live  but  a  short  time  about 
the  mine  where  he  is  at  present,  while  the  cows  in  the  neighborhood  come 
regularly  to  drink  the  turbid  water  below  the  place  where  the  ore  is  washed, 
and,  although  the  sediment  from  this  water  contains  as  much  as  3  per 
cent,  of  lead  sulphide,  the  cows  show  no  alterations  of  health.  Similar 
observations  have  been  made  before.  The  explanation  probably  is  that 
herbivora  have  a  relatively  small  amount  of  hydrochloric  acid  in  their 
stomach  contents,  while  carnivora  have  a  relatively  large  amount;  the 
latter,  therefore,  can  get  much  larger  amounts  of  insoluble  lead  salts  into 
solution  as  chloride. 

Heredity. — Fairly  good  support  for  the  reasonable  proposition  that 
there  is  a  family  tendency  to  lead  poisoning  is  given  by  various  observa- 
tions, such  as  that  of  Oliver,  in  which  a  father  and  four  sons  had  fatal 
saturnism.  Though  habits  and  environment  may  often  have  had  an  im- 
portant influence  in  such  instances,  the  latter  factors  are  probably  bet- 
ter excluded  in  the  reports  of  intense  involvement  of  certain  families  in 
some  water  epidemics.  Anker  alone  has  described  a  case  of  direct 
heredity  producing  lead  paralysis;  but  this  case  may  be  excluded,  as  it 
developed  only  when  the  child  was  several  years  old,  and  the  father,  not 
the  mother,  had  plumbism.  The  observations  of  Porak  and  Oliver  that 
foetuses  of  animals  poisoned  with  lead  have  the  metal  in  their  tissues,  and 
particularly  the  careful  study  of  Legrand  and  Winter,  which  showed 
relatively  large  amounts  in  the  organs  of  a  premature  sickly  infant  that 
died  a  few  days  after  birth,  and  that  was  born  of  a  mother  chronically 
intoxicated  with  lead,  indicate  strongly  that  the  frail  infants  of  lead- 
poisoned  mothers,  that  are  so  likely  to  die  soon  and  usually  of  convulsions, 
have  often  acquired  saturnism  directly  from  the  mother. 


CHRONIC  LEAD  POISONING  87 

Age. — The  argument  of  Russell  for  the  greater  predisposition  of  those 
past  middle-life  is  not  wholly  convincing;  but  that  of  Geo.  PI.  Wood/ 
is.  It  is  generally  agreed  that  children,  when  employed  in  trades  that 
expose  to  lead,  are  especially  likely  to  suffer,  though  this  may  be  partly 
due  to  greater  carelessness,  and  partly  a  question  of  relative  dosage;  a 
child  weighing  fifty  pounds  would  be  more  likely  to  suffer,  if  equally 
exposed,  than  an  adult  weighing  three  times  as  much.  Brown,  Putnam, 
Sinkler  and  others  consider,  indeed,  that  children  have  a  relative  immu- 
nity, their  most  eflfective  argument  being  that  in  the  epidemic  in  the  family 
of  Louis  Philippe,  at  Claremont  and  in  Brown's  water  epidemic  at 
Tredegar,  children  were  largely  spared.  Equally  impressive  testimony  for 
the  contrary  view  is  found  in  the  occasional  observation  of  the  poisoning 
of  a  number  of  children  in  a  family  from  causes  that  affected  the  adults  but 
little,  if  at  all,  such  as  Baines'  fatal  cases  due  to  burning  staves  from 
barrels  that  had  contained  white  lead — though  here  again  relative  dosage 
may  play  a  part.  But  most  important  indications  of  a  special  suscepti- 
bility of  children  are  seen  in  the  recent  reports  of  Turner  and  Gibson^  of 
wholesale  poisoning  in  the  Queensland  children.  A  definite  answer  to  the 
question  whether  there  is  a  special  susceptibility  in  childhood  is,  however, 
of  interest,  but  not  of  great  practical  importance;  for  the  essential  facts  are, 
that  children  are  less  frequently  exposed  to  accidental  poisoning,  and  far 
less  commonly  to  industrial  poisoning;  but  when  exposed  they  often  suffer. 

Sex. — Oliver^  particularly  insists  that  women  show  a  strong  suscepti- 
bility to  lead  poisoning,  and  many  authors  agree  with  him.  It  is  unques- 
tionable that,  if  equally  taxed  physically  and  equally  exposed  to  lead, 
women  suffer  more  than  men;  but  there  is  no  satisfactory  evidence  that 
they  exhibit  any  special  susceptibility  that  is  dependent  upon  sex  as 
against  general  physical  resistance.  Lead  poisoning  in  women  is  of  rela- 
tively little  consequence  in  this  country;  in  the  past  five  years  ninety-eight 
industrial  cases  in  men  have  been  admitted  to  the  wards  of  the  Episcopal 
Hospital,  Philadelphia,  while  there  have  been  no  industrial  cases  in 
women.  This  is  sufficient  evidence  of  the  recognized  fact  that  women 
are  but  little  exposed  to  industrial  lead  poisoning  in  this  country,  for 
this  hospital  draws  from  a  large  number  of  such  industries.  In  a  few 
occupations,  such  as  decorating  pottery,  women  are  freely  employed  here, 
and  are  then  much  exposed  unless  carefully  protected. 

Period  of  the  Year. — Both  industrial  and  accidental  poisonings  are  in- 
fluenced by  this  factor.  It  is  generally  recognized  that  workers  in  lead 
suffer  more  frequently  during  hot  months,  possibly  because  they  take  in 
more  fluid  and  thus  wash  down  more  lead  into  their  stomachs,  (increase 
in  the  use  of  alcoholic  beverages  perhaps  also  playing  a  part) ;  probably, 
also,  because  the  more  actively  functionating  skin  absorbs  lead  with  rela- 
tive readiness.  The  especial  frequency  during  the  summer  and  autumn 
of  accidental  cases  due  to  drinking-water  has  been  repeatedly  noted, 
particularly  in  the  more  recent  English  epidemics,  and  has  been  shown 
by  the  extensive  work  of  Power  and  Houghton*  to  be  apparently  due  to 

^  Gesundheitsgefdhrliche  Industrien. 
'  Australasian  Medical  Gazette,  1897,  1899,  1904. 
^  Dangerous  Trades. 

*  Reports  of  the  Medical  Officer  of  the  Local  Government  Board  of  Great  Britain; 
for  1895,  1900-01,  and  1902-03;  Supplements. 


88  DISEASES  DUE  TO  CHEMICAL  AGEXTS 

the  tendency  of  waters  coming  from  peaty  gathering  grouncLs  to  be 
especially  acid  at  these  periods  of  the  year.  The  acidity  seems  to  be  due 
chiefly  to  organic  acids  produced  by  bacterial  decomposition  of  vegetable 
matter  in  the  soil. 

Previous  Diseases  and  Previous  Attacks  of  Saturnism. — Any  preexist- 
ing disease  that  reduces  ihv  resistance,  j)erlia])s  chronic  renal  trouble 
especially,  increases  the  liability  to  attack.  The  tendency  to  further  at- 
tacks, after  once  suffering  from  saturnism,  is  very  striking.  This  is 
usually  due  to  further  exposure,  but  Bernhard  especially  has  dwelt  upon 
the  fact  that  characteristic  sym])toms  may  appear  without  any  renewal 
of  exposure,  one  case  having  shown  a  new  appearance  of  paralysis 
twenty  years  after  exposure  had  ceased.  In  the  last-mentioned  instance 
there  must  be  doubt  whether  the  later  attack  was  due  to  the  renewed  pres- 
ence of  circulating  lead;  but  in  some  less-protracted  cases  this  was  almost 
certainly  the  cause.  Such  instances  are  apparently  due  to  the  esca])e  into 
the  circulation  of  previously  insoluble  deposits  of  lead.  Kaufi'man  con- 
siders that  deprivation  of  food  is  often  responsible  for  this,  through  break- 
ing down  of  tissue  in  the  process  of  emaciation  and  the  consequent  setting 
free  of  tissue  combinations  of  lead;  but  it  is  quite  as  likely  that  this  is  due 
to  reduction  of  general  resistance. 

Habits. — Alcoholism  is  unquestionably  very  important  in  increasing 
the  liability  to  saturnism,  and  alcoholic  excess  frequently  determines  the 
actual  onset  of  an  attack,  particularly  of  encephalopathy.  Maximilian 
Sternberg's  theoretical  views  to  the  contrary  are  opposed  to  an  almost 
unanimous  clinical  opinion,  and  to  the  experiments  of  Combemale,  Fran- 
cois, and  Oliver.  Sexual  excesses  are  especially  insisted  upon  by  Oliver 
as  a  predisposing  factor,  women  of  loose  life  suffering  particularly. 
All  other  depressing  excesses,  lack  of  exercise,  and  unhygienic  habits, 
strongly  favor  poisoning;  but  the  most  important  factor  of  all  in  a  vast 
proportion  of  industrial  cases  is  carelessness  as  to  cleanliness.  In  most 
industrial  poisonings,  and  therefore  in  the  majority  of  all  instances,  the  lead 
is  actually  ingested  as  a  direct  result  of  eating,  drinking,  using  tobacco, 
and  the  like,  without  properly  cleansing  the  hands,  and  often  in  k'ad-laden 
rooms;  or  lead  is  taken  in  through  skin  absorption,  largely  as  a  result  of 
lack  of  cleanliness  of  the  clothes  or  person.  There  is  a  tradition  among 
some  workmen  that  tobacco  chewing  is  a  prophylactic,  a  mistaken  idea 
in  general,  though  it  might  possibly  act  occasionally  as  a  crude  but  un- 
hygienic preventive  if  accompanied  by  industrious  spitting. 

Occupation. — This  is  overwhelmingly  more  important  than  any  other 
factor  and  the  occupations  in  which  lead  poisoning  may  occur  are  mani- 
fold. Some  are  naturally  much  more  dangerous  than  others,  the  worst 
being  those  in  which  lead  is  freely  handled  and  in  which  the  exposure  is 
most  continuous,  and  particularly  those  in  which  there  is  much  lead  dust. 
Bauer  mentions  the  following  as  the  most  dangerous:  lead  mining  and 
smelting;  zinc  smelting;  working  in  white  lead  and  lead  colors;  making 
lead  pipes  and  various  other  lead  objects;  making  pottery  and  earthen- 
ware; t}'pe  setting  and  t\^e  making;  working  in  electric-storage-battery 
factories;  file  making;  diamond  cutting,  and  polishing  gems  and  semi- 
precious stones ;  weaving,  especially  Jacquard  weaving;  making  tinware; 
and  installing  gas  and  water  pipes.  Of  these,  file  making  and  Jacquard 
weaving  may  be  practically  excluded  in  this  country,  because  of  improved 


CHRONIC  LEAD  POmONING  89 

methods;  type  setting  seems  certainly  to  ])ro(luce  saturnism  only  rarely 
here,  because  of  improvements  in  the  type  and  mechanical  methods  liave 
largely  supplanted  handwork;  and  apparently  tinsmithing  is  not  particu- 
larly dangerous  at  present,  owing  to  improvements  in  solder  and  in  general 
hygienic  conditions.  Installing  gas  and  water  pipes  is  certainly  not  a  com- 
mon cause,  but  it  may  evidently  be  more  dangerous  if  in  large  operations 
men  are  exposed  more  or  less  continuously  to  the  dangerous  parts  of  the 
work,  for  an  epidemic  occurred  recently  in  Vienna  in  the  men  who 
installed  the  pipes  for  the  new  water  works  (Kaup).  Diamond  cutters, 
who  have  their  diamond  chips  set  in  lead  staffs,  are  said  by  Norden,  of 
Amsterdam,  to  show  saturnism  in  nearly  every  instance,  if  they  have  been 
long  at  this  work;  but  Pel,  who  also  is  in  the  centre  of  this  industry,  says 
that  plumbism  is  uncommon  among  them.  In  this  country,  diamond  cut- 
ting, which  is  confined  almost  entirely  to  New  York  City,  Brooklyn,  Cin- 
cinnati, and  Boston,  has  aroused  no  interest  in  relation  to  lead  poisoning; 
and  lapidaries  here,  as  well  as  others  who  once  used  lead  wheels  in  grinding 
(cutlers,  razor-grinders,  etc.),  appear  to  be  now  very  little  exposed  to  lead, 
chiefly  because  of  the  increasing  substitution  of  carborundum  wheels.  In 
the  whole  country,  diamond  cutters  and  lapidaries  together  number,  at 
any  rate,  only  a  few  hundreds.  Razor  grinders  and  cutlers  are  said  to 
have  still  a  somewdiat  dangerous  custom  of  rubbing  lead  on  the  surfaces 
of  their  wheels.  The  other  occupations  mentioned  by  Bauer  are  all 
dangerous  here.  Poisoning  in  miners  occurs  principally  in  carbonate 
mines,  and  not  in  those  in  which  chiefly  the  sulphide  is  present,  a  fact  that 
is  usually  considered  to  be  due  to  the  insolubility  of  the  sulphide.  Mr. 
Monell,  however,  considers  this  to  be  at  least  partly  due  to  the  fact  that 
carbonate  mines  are  likely  to  be  dry,  and  therefore  more  dust  is  produced 
in  them,  while  sulphide  mines  are  often  wet;  and  the  water  in  the  latter 
usually  contains  sulphuric  acid,  which  prevents  formation  of  the  carbon- 
ate from  the  sulphide.  A  process  recently  introduced  into  several  places 
in  this  country,  of  separating  the  lead  in  the  comminuted  ore  by  means  of 
a  blast  of  air,  in  order  to  overcome  difficulties  previously  met  in  washing 
some  ores,  seems  likely  to  be  very  productive  of  plumbism  through  the 
dust  created.  Smelting  ores  containing  lead  is  dangerous,  particularly 
when  the  ventilating  apparatus  is  not  excellent.  There  is  doubt  whether 
this  is  due  purely  to  inhaling  or  swallowing  solid  particles,  or  partly  to 
inhaling  lead  vapor;  but  it  is  extremely  probable  that  the  latter  is  of  little 
or  no  consequence,  for  (Leclerc  de  Pulligny)  at  the  volatilizing  temper- 
ature of  lead,  gases  are  irrespirable;  and  Lodin  also  found  that  at  temper- 
atures between  250°  and  300°  C,  no  lead  was  volatiUzed,  although  this  is 
far  above  its  melting  point.  Nevertheless,  the  heat  produced  in  smelting 
undoubtedly  adds  to  the  danger  by  increasing  the  motion  of  the  atmos- 
phere and  hence  the  intake  of  lead  dust. 

Of  all  occupations  the  manufacture  of  white  lead  and  of  lead  colors 
furnishes  the  greatest  proportion  of  cases ;  though  electric  storage  battery 
makers,  and,  in  potteries,  those  engaged  in  dipping  the  ware  into  the  glaze 
and  handling  it  immediately  afterward,  in  spraying  decorative  glazes,  and 
in  dusting  on  pigment  in  the  decalcomania  process,  are  in  practically  as 
much  danger  as  lead  workers,  unless  cleanliness  is  insisted  upon  and 
hygienic  improvements  such  as  exhaust  fans,  proper  fritting  of  the  glaze, 
etc.,  are  used.    The  possible  dangers  in  white  lead  works  are  sufficiently 


90  DISEASES  DUE  TO  CHEMICAL  AGENTS 

shown  without  further  discussion,  by  Kaup's  figures  for  the  Blaiberg 
Leatlworkers'  Union  in  Klagenfurt.  In  1894,  the  45  members  showed  61 
attacks  of  lead  poisoning  (135.6  per  100),  and  the  average  per  man  was 
46.7  sick-days  in  the  year.  Since  then  the  conditions  have  fluctuated  and 
in  general  have  im])roved,  but  the  attacks  in  a  year  have  never  fallen 
below  56.4  per  100  men.  In  Herbert's  works,  in  the  same  town,  the 
attacks  each  year,  per  100  workers,  have  ranged  from  13.2  to  24.6.  The 
influence  that  has  a])parently  been  exerted  by  careful  regulation  of  this 
industry  in  France  is  seen  in  the  statement  of  Lcclerc  de  Pulligny  that 
although  Paris  and  Lille  are  the  centres  for  the  production  of  white  lead 
in  France,  the  cases  of  lead  poisoning  in  the  hospitals  of  Paris  among 
those  employed  in  this  occupation  numbered  only  13  in  two  years. 
Electric  storage  battery  factories,  though  not  numerous,  are  very  danger- 
ous, unless  they  are  well  conducted.  At  the  Episcopal  Hospital  in  Phila- 
delphia there  were  23  cases  in  the  wards  in  a  little  over  two  years  from 
one  factory,  and  many  others  in  the  out-patient  department;  since  this 
time  they  have  been  going  chiefly  to  a  new  hospital  nearer  by.  The 
"lead  burning"  in  this  industry  has  an  especially  evil  name  among  the 
workmen;  but,  as  already  noted,  it  is  not  probable  that  lead  vapors  are 
respired,  and  most  of  the  patients  had  done  no  lead  burning  themselves. 
A  large  proportion  of  them,  as  is  so  commonly  the  case  in  any  industrial 
lead  poisoning,  were  unskilled  laborers.  Most  of  the  trouble  could  be 
overcome  by  exhaust  fans,  hoods,  and  scrupulous  cleanliness  of  the  rooms 
and  the  men.  Concerning  potteries,  Prof.  Edward  Orton,  Jr.,  of  Colum- 
bus, Ohio,  who  has  been  the  pioneer  in  America  in  putting  the  teaching 
of  ceramics  on  a  broad  basis  and  who  has  extensive  knowledge  of  the 
conditions  throughout  the  country,  states  that  there  has  been  much 
improvement,  particularly  in  the  use  of  exhaust  fans,  etc. ;  but  proper  frit- 
ting and  some  other  important  measures  are  still  little  used.  The 
dusting  and  spraying  processes  are,  unless  controlled,  exceedingly  dan- 
gerous, and  in  one  pottery  it  is  customary  to  employ  frequently  in  this 
work  persons  with  tuberculosis,  carcinoma,  or  other  diseases,  because 
none  who  hoped  to  live  would  accept  the  risk,  even  at  high  wages.  The 
measures  that  are  frequently  used  now  to  protect  these  persons  are  not 
effectual  with  the  dippers  and  their  helpers,  who  have  their  hands 
almost  constantly  covered  with  lead  glaze.  Proper  fritting  of  the  glaze 
is,  however,  an  almost  complete  preventive. 

Painters  are  common  sufferers,  and  usually  in  inverse  proportion  to  their 
cleanliness,  intelligence,  and  skill.  For  example,  a  large  proportion  of 
those  affected  had  been  merely  acting  as  "  helpers,"  while  out  of  their 
usual  work,  and  were  not  painters  by  trade.  A  considerable  number  of 
the  skilled  artisans,  however,  always  suffer;  burning  off  paint,  through 
the  dust  produced,  polishing  painted  surfaces,  particularly  when  this  is 
done  by  hand,  and  to  some  extent  perhaps  inhalation  of  lead  laden  tur- 
pentine vapor  in  interior  painting,  all  make  them  more  or  less  unavoid- 
ably liable  to  intoxication,  though,  as  is  always  the  case,  lack  of  proper 
cleanliness  is  the  chief  factor.  The  difficulties  in  controlling  poisoning  in 
painters  have  led  to  the  passing  of  laws  in  France  and  Belgium  forbidding 
the  use  of  lead  paints  in  public  buildings,  and  the  new  French  law  for- 
bidding the  use  of  lead  paints  in  any  buildings  is,  as  stated  in  a  letter 
from  the  French  Bureau  of  Labor,  likely  to  be  in  force  soon,  as  at  the 


CHRONIC  LEAD  POISONING  91 

time  of  writing  it  was  before  the  Senate,  having  passed  the  Chamber  of 
Deputies. 

Among  others  in  some  danger  are  the  makers  of  rubber  goods,  partic- 
ularly the  heavier  kinds,  and  of  glazed  and  enameled  metal  ware;  gla- 
ziers, ship  builders,  sailors,  laborers  in  structural  iron  works  (handling 
freshly  painted  iron),  Bessemer  steel  workers  (Ormerod),  workers  in 
brass  foundries  and  occasionally  in  other  foundries,  makers  of  the  mod- 
ern "secession"  bric-a-brac,  etc.;  lace  and  passementerie  makers,  and 
workers  in  silk  mills  (when  the  silks  are  weighted  with  lead).^  The  great 
number  of  textile  workers  makes  the  determination  of  the  conditions  ex- 
isting in  their  occupations  of  extreme  importance.  Poisoning  among 
them  from  lead  dyes  was  once  rather  common;  trades  people  and  trade 
journals  tell  me,  however,  that  lead  chromate  is  still  used  a  little,  but  this 
is  now  of  insignificant  importance;  a  statement  that  is  in  consonance 
with  the  known  general  use  of  aniline  dyes  and  also  with  the  experi- 
ence of  the  Episcopal  Hospital,  in  Philadelphia,  where  in  the  midst  of 
vast  textile  industries  we  have  had  no  industrial  cases  in  women  in  the 
past  five  years,  and  where  among  the  ninety-eight  industrial  cases  in  the 
men's  ward  in  this  time  there  was  but  a  single  weaver,  and  this  man 
was  probably  poisoned  from  another  source. 

In  any  obscure  case  the  details  of  the  patient's  occupation  should  be 
investigated  most  minutely,  for  occupational  sources  of  lead  poisoning 
are  multitudinous  and  often  utterly  unexpected. 

Accidental  Poisoning. — Detailed  investigation  of  many  points  is  often 
necessary  in  this  instance,  also,  to  determine  the  source  and  do  away  with 
it.  Water  is,  of  course,  the  most  common  source,  though  its  frequency 
has  been  distinctly  lessened  by  the  considerable  reduction  in  the  use  of 
lead  pipes  for  public  and  particularly  for  private  supplies.  That  lead 
service  pipes  are  still  important  in  towns  is  evident,  however,  for  causal 
conditions  in  most  places  have  not  greatly  changed  since  the  epidemic  in 
Sheffield,  England,  a  decade  and  a  half  ago,  in  which  six  physicians 
alone  saw  in  six  months  one  hundred  and  twenty-nine  cases;  and  town 
epidemics  have,  in  fact,  been  repeatedly  discovered  here  and  in  Europe 
since  then,  as  have  house  epidemics  from  private  water  supplies.  Lead 
tanks  for  domestic  water  supplies  have  gradually  disappeared  in  most 
places,  on  land  as  well  as  on  ship-board,  since  study  of  the  colique  seche 
of  the  French  navy,  and  other  observations,  showed  their  danger;  but 
that  tanks  containing  lead  still  have  opportunity  to  do  extensive  harm  in 
some  regions  is  shown  by  the  reports  concerning  the  Queensland  children. 
Drinking-water  becomes  poisoned  in  a  number  of  ways.  The  carbonic 
acid  in  rain-  or  spring-water  may  be  the  cause  of  poisoning,  especially 
when  new  lead  pipes  are  in  use,  soluble  acid  carbonate  being  formed; 
a  deposit  of  relatively  insoluble  basic  carbonate  is  gradually  formed  on 
old  pipes,  and  acts  as  a  partial  but  not  absolute  protective.  Power  and 
Houghton  emphasize  two  especial  causes,  one  of  them  a  direct  oxidizing 
or  "erosive"  action  due  to  oxygen  in  solution  in  the  water;  the  other 
the  formation  of  soluble  salts  of  nitric,  nitrous,  or  organic  acids ;  and  of 
these,  they  consider  the  latter  to  be  of  much  the  greatest  importance. 
Benjamin  Franklin  referred  to  the  essential  points  of  these  latter  obser- 

^For  recent  conditions  in  Austria  concerning  this  point  see  Kaup,  loc.  cit. 
It  has  not  been  well  studied  recently  elsewhere. 


92  DISEASES  DUE  TO  CHEMICAL  AGENTS 

vations  in  17SG  in  a  letter  to  Benjamin  \'aughan,  in  which  he  speaks 
of  a  family  that  had  for  several  years  drunk  with  impunity  water  col- 
lected from  a.  leaden  roof,  until  young  trees  grew^  up  and  their  falling 
leaves  were  deposited  on  the  roof;  these  then  decomposed  and  "lent  to 
the  water  its  baneful  qualities  and  ])articles"  and  jjroduced  a  series  of 
cases  of  poisoning  in  the  family.  This  occurrence  is  probably  the  same  as 
that  described  by  Tronchin  and  referred  to  by  Oliver. 

Lockhart  Gibson  makes  an  interesting  suggestion  concerning  the  possi- 
ble poisoning  of  the  Queensland  children  by  ingestion  of  lead  from  painted 
wood  work  of  houses;  he  found  a]:)j)reciable  quantities  of  lead  in  the 
dust  collected  in  rooms  and  also  on  the  hands  after  they  had  been  rubbed 
over  painted  surfaces,  especially  if  the  hands  Avere  moist.  Sleeping  in 
freshly  ])ainted  rooms  has  occasionally  been  the  cause,  the  lead  in  this 
instance  being  inhaled  and  apparently  carried  by  the  turpentine  vapors. 
Poisoning  of  women,  practically  epidemic  in  its  extent,  has  been  observed 
from  washing  the  clothes  of  lead  workers,  a  fact  that  suggests  the  possi- 
bility of  occasional  poisoning  in  the  wives  and  children  of  lead  workers, 
from  careless  habits  as  to  clothing,  etc.;  the  opportunities  of  the  last  men- 
tioned kind  are  shown  by  the  fact  that  plumbism  is  said  to  have  arisen  in 
the  dogs  of  lead  workers  from  sleeping  on  their  masters'  coats,  and  human 
cases  due  to  sleeping  on  horsehair  sofas  have  been  reported  (horsehair  as 
well  as  bristles  of  brushes  and  some  other  articles  being  dyed  black  w'ith 
lead  sulphide,  and  the  manufacture  of  these  articles  having  occasionally 
produced  industrial  poisoning).  Glazed  earthenware  and  enameled  me- 
tallic vessels  that  are  used  for  cooking  and  preserving  foods,  have  caused 
poisoning,  though  this  is  uncommon  now,  and  extremely  so  with  the  better 
grades.  The  lead  in  the  solder  or  tin  itself  at  one  time  made  the  eat- 
ing of  canned  goods,  or  the  use  of  tin  vessels  for  acid  foods,  somewhat 
dangerous,  but  the  risk  is  now^  minimal  owing  to  improvements  in  the  tin, 
the  solder,  and  the  methods  of  sealing;  and  the  actual  number  of  cases 
know-n  to  have  been  poisoned  in  this  way,  even  in  earlier  years,  is  small. 
Because  of  its  cheapness,  lead  is,  however,  sometimes  used  in  sophisticat- 
ing tin  and  other  drinking  vessels,  a  point  of  interest  chiefly  in  relation  to 
children.  Variot  has  recently  reported  saturnism  in  a  child  from  this 
cause.  The  now  nearly  obsolete  custom  of  making  drinking  and  other 
vessels  of  lead  caused  many  cases  in  earlier  times,  especially  when  such 
vessels  were  used  for  cider,  wine,  or  other  acid  beverages.  Children's 
toys,  w^hen  made  of  lead,  have  caused  poisoning  in  recent  times  (Variot), 
and  the  same  may  occur  w^hen  they  are  colored  with  lead  pigments,  though 
the  latter  are  now  probably  used  but  little  for  this  purpose.  Candies  w^ere 
at  one  time  colored  with  lead  dyes,  but  this  is  rare  at  present;  and  the  use 
of  lead  chromate  in  baker's  products  has  hardly  been  heard  of  since  INIar- 
shall  showed  how  freely  it  was  being  practised  in  Philadelphia,  and  D.  D. 
Stewart'  very  acutely  demonstrated  here  a  most  dangerous  epidemic  from 
this  cause.  Foods  in  general  are  so  carefully  watched  now  that  there  is 
little  danger  from  them  directly,  though  epidemics  are  still  occasionally 
reported  in  Europe  as  a  result  of  "filling"  mill-stones  with  lead,  the  lead 
being  gradually  ground  off  into  the  flour.  The  opportunities  for  such  an 
occurrence  in  this  country  have  been  greatly  reduced  by  the  fact  that  rol- 

^  Medical  Xews,  December  31,  1887;  and  Third  Annual  Report  State  Board 
of  Health  of  Pennsylvania. 


CHRONIC  LEAD  POISONING  93 

ler  mills  have  practically  done  away  with  the  old  fashioned  mill-stones, 
though  where  the  latter  are  still  used,  possibilities  of  lead  poisoning  exist 
in  this  country,  for  lead  is  still  used  in  these  mill-stones  here.  Soda  water 
or  carbonated  water  in  siphons  may  cause  poisoning,  particularly  if  the 
tanks,  the  siphons,  etc.,  contain  lead;  and  Cao  has  recently  found  lead  in 
carbonated  water  in  siphons  and  reported  a  series  of  poisonings  due  to 
this  cause;  but,  excepting,  perhaps,  for  some  old  apparatus,  there  Is  little 
danger  from  this  source  in  this  country,  as  block  tin  and  zinc  have  almost 
completely  supplanted  lead  for  this  purpose.  The  siphons  tested  here 
were  made  of  tin  or  zinc.  Cosmetics,  hair  dyes,  and  false  teeth  are 
commonly  known  to  have  been  sources  of  poisoning.  Medicinal  lead 
poisoning  was  known  to  the  physicians  of  the  ancients;  it  is  generally 
thought  to  be  very  uncommon  now,  but  Miller^  has  recently  reported 
two  personal  observations  and  discussed  a  series  collected  from  the  litera- 
ture, and  he  thinks  that  slight  or  moderate  symptoms  from  this  cause  are 
probably  not  infrequent.  The  use  of  diachylon  ointment  over  large  ecze- 
matous  surfaces  is  certainly  dangerous,  and  has  caused  fatal  poisoning  in 
infants  (Passler,  Hahn);  and  poisoning  from  internal  use  of  diachylon  as 
an  abortifacient  has  also  been  repeatedly  observed  in  recent  years  in 
England  (Ransom). 

Infants  have  also  been  poisoned  by  dusting  powders  containing  lead,  or 
by  cosmetics  or  ointments  used  on  the  person  of  the  nurse.  As  in- 
stances of  extremely  odd  sources  of  accidental  poisoning.  Dodge's  case  in 
which  the  patient  was  ultimately  discovered  to  have  taken  for  a  month 
a  dozen  No.  7  shot  before  each  meal  "to  cleanse  his  blood,"  and  Klister's 
case  of  a  soldier  who  was  wounded  in  1870,  developed  lead  poisoning 
in  1888,  and  recovered  after  the  partially  dissolved  fragments  of  the  ball 
had  been  removed  by  operation,  may  be  mentioned.  Several  fairly 
authentic  cases  that  appeared  to  be  due  to  the  same  cause,  though  less 
protracted  in  their  course,  are  on  record. 

The  duration  of  exposure  before  the  development  of  plumbism  has 
naturally  varied  greatly.  This  is  usually  tacitly  or  openly  attributed  to 
variations  in  individual  susceptibility.  A  certain  degree  of  immunity 
undoubtedly  exists  in  some  persons,  others  are  certainly  especially  sus- 
ceptible, and  intercurrent  factors  are  known  to  increase  or  decrease  sus- 
ceptibility; but  it  is  difficult  to  establish  the  importance  of  immunity  in 
considering  industrial  cases,  because  individuals  differ  so  largely  in  their 
care  in  avoiding  exposure;  and  the  matter  is  far  from  simple  in  even 
water  epidemics  and  other  accidental  poisonings. 

Accidental  or  medicinal  ingestion  of  single  large  doses  has  repeatedly 
caused  somewhat  prolonged  poisoning,  usually  colic;  though  encephal- 
opathy has  repeatedly,  and  paralysis  has  in  rare  instances,  followed  a 
single  dose  or  a  few  doses.  Quensel  mentions  a  case  reported  by  Sommer, 
in  which  furor  appeared  after  a  few  hours'  intense  industrial  exposure ;  the 
reference  appears  to  be  incorrect,  and  the  report  could  not  be  foimd.  Colic 
and  indefinite  sjTuptoms  of  poisoning  often  occur  soon  after  beginning 
work  in  lead.  Tanquerel  repeatedly  saw  wrist-drop  after  a  week's  ex- 
posure, and  others  have  had  similar  experiences.  As  a  rule  marked  colic 
does  not  occur  for  several  weeks  or  longer,  and  symptoms  of  poisoning 

1  Therapeutic  Gazette,  1904. 


94  DISEASES  DUE  TO  CHEMICAL  AGENTS 

may  first  appear  after  even  many  years  of  exposure.  Paralysis  is  usually 
rather  a  late  development,  eommonly  appearing  only  after  preceding 
cachexia  or  colic  and  therefore  after  prolonged  exposure.  Encephalop- 
athy is  not  infrequently  seen  within  a  few  weeks  or  months,  but  often 
arises   late. 

Pathology. — The  pathology  is  chiefly  not  characteristic  or  obscure;  it 
has  not  been  extensively  studied,  especially  by  modern  methods.  There 
is  usually  general  emaciation;  the  teeth  and  particularly  the  gums  are  fre- 
quently in  bad  condition,  the  latter  usually  loosened  and  often  slightly 
ulcerated.  The  blue  line  is  generally  found,  particularly  in  the  gums  of 
the  central  and  lateral  incisors  and  the  canines,  and  especially  on  the 
lower  jaw.  This  line  is  due  (Fagge,  Stewart,'  Ruge")  to  deposits  of  lead  sul- 
phide in  the  apices  of  the  papilhe,  the  granules  being  found  partly  in  the 
lumen  of  the  capillaries,  but  more  largely  in  their  walls  and  in  the  sur- 
rounding tissues.  The  lead  sulphide  is  formed  from  circulating  lead- 
compounds,  through  the  action  of  the  hydrogen  sulphide  produced  by 
decomposition  of  small  food  particles  lying  between  the  teeth  and  under 
the  edges  of  the  gums.  Arteriosclerosis  is  common  in  the  subjects 
of  saturnism.  It  is  doubtful  whether  lead  produces  this  directly,  ex- 
perimental work  on  the  subject  being  inconclusive  (Jores);  Ruge's 
observation  of  proliferative  changes  of  the  vessels  of  the  gums  in  the  neigh- 
borhood of  the  lead  sulphide  deposits  is,  however,  somewhat  suggestive 
in  this  connection.  Lead  appears  also  occasionally  to  cause  chronic 
sclerotic  endocarditis.  Pulmonary  tuberculosis  is  very  common  in  lead- 
workers,  and  they  may  show  also  the  ordinary  lesions  due  to  working  in  a 
dusty  atmosphere  if  their  occupation  has  exposed  them  much  to  dust. 
Chronic  gastro-enteritis  is  common,  but  no  special  changes  have  been 
described  in  the  digestive  tract  except  pigmentation  of  the  walls  of  the 
intestine  with  lead  sulphide,  and  degeneration  of  the  cells  in  the  ganglia 
of  the  intestine;  the  latter  and  degenerative  changes  in  the  abdominal 
sympathetic  ganglia  supposedly  produce  the  attacks  of  colic.  In  ex- 
perimental cases  (Oliver)  the  intestine  is  often  found  in  extreme  spasm; 
and  this  is  very  probably  the  mechanism  of  producing  the  pain  in  colic. 
In  his  experimental  work  on  animals  and  in  his  postmortems,  Oliver 
found,  as  the  earliest  lesions,  intercellular  cirrhosis  of  the  liver  and  an 
acute  nephritis,  with  degenerative  changes  in  the  epithelium  of  the  con- 
voluted tubules ;  cellular  proliferation  within  the  capsules  and  around  the 
afferent  vessels  of  the  glomeruli,  and  later  within  the  glomeruli  them- 
selves; and,  finally,  progressive  interstitial  nephritis.  A  considerable 
number  of  other  observers  have  noted  nephritis  in  the  early  stages  and 
have  produced  it  experimentally.  Oliver  believes  that  these  hepatic  and 
renal  changes  occur  regularly  in  lead  poisoning  and  are  the  chief  lesions 
due  directly  to  lead;  many  and  perhaps  most  of  the  other  symptoms  he 
considers  the  result  of  secondary  metabolic  disturbances..  In  old  cases 
interstitial  nephritis  is  a  very  common  lesion,  often  the  most  important. 
In  a  small  proportion  of  cases  the  lesions  of  gout  are  present.  The  bones 
have  occasionally  shown  lesions  that  have  a  doubtful  relation  to  lead. 
Bone-marrow  changes  were  found  by  Cadwalader.  There  was  marked 
hyperplasia  of  the  marrow,  the  granular  myelocytes  were  numerous,  and 

*  International  Clinics,  vol.  iv,  Seventh  Series. 
'Deutsch.  Archiv.  f.  klin.  Med.  Bd.,  Ivii. 


CHRONIC  LEAD  POISONING  95 

many  nucleated  red  cells  often  collected  into  characteristic  erythroblastic 
areas  were  found. 

In  cases  with  nervous  lesions,  the  paralyzed  muscles  are  more  or  less 
atrophic  and  show  degeneration  of  the  muscle  cells  and  jn-oliferation  of 
the  nuclei;  Oppenheim  has,  indeed  found  marked  changes  in  non-para- 
lyzed muscles.  The  peripheral  nerves  whose  territory  was  involved  clini- 
cally have  been  many  times  investigated  and  always  found  degenerated, 
the  radial  being  the  most  common  seat  of  changes.  I'he  alterations  are 
usually  parenchymatous,  rarely  involve  the  connective  tissue  severely  as 
a  result  of  lead  alone,  and  are  situated  chiefly  in  the  peripheral  portions  of 
the  nerves.  Gombault  has  produced  these  changes  experimentally.  The 
nerve-cells  of  the  anterior  horns  of  the  spinal  cord  usually  show  no  note- 
worthy changes,  though  in  relatively  uncommon  instances  they  are  de- 
generated. Madam  Dejerine-Klumpke,^  and  later  Spiller,^  sifted  these 
down  to  five  or  six  reliable  cases,  besides  Spiller's  own  case,  in  which 
there  were  marked  alterations.  Nissl,  Schaft'er,  Stieglitz,  and  Rybakoff, 
produced  spinal  changes  experimentally.  Spiller's  case,  Philippe  and 
Eide's  case,  and  Steiglitz's  animals,  also  showed  lesions  of  the  ganglia  on 
the  posterior  roots.  The  usual  gross  cerebral  lesions  in  encephalopathy 
have  been  oedema  and  anaemia,  flattening  of  the  convolutions,  thickening 
of  the  pia,  and  small  hemorrhages.  Microscopical  studies  have  been  very 
few.  Quensel  found  marked  changes  of  the  cortical  cells,  and  prolifera- 
tion of  the  nuclei  in  the  vessel  walls  and  of  the  glia-cells  about  the  vessels. 
Similar  changes  were  found  by  McCarthy^  in  dogs,  and  Spiller  also  noted 
in  his  case  proliferation  of  the  endothelial  cells  on  the  surface  of  the  pia. 
Changes  have  been  observed  in  the  cerebrum  in  cases  without  enceph- 
alopathy; and  the  changes  in  the  nervous  system,  in  human  subjects  and 
various  species  of  animals,  are  not  peculiar  to  lead  poisoning. 

Mode  of  Entrance  and  Pathogenesis.— As  already  stated,  the  usual 
channels  of  entrance  are  ingestion  into  the  stomach,  or  inhalation  of  par- 
ticles into  the  respiratory  tract,  followed  by  solution  and  absorption  in 
either  of  these  places.  Skin  absorption  certainly  plays  some  part,  though 
just  how-  much  is  uncertain;  it  is,  indeed,  uncertain  whether  any  con- 
siderable part  is  played  by  inhalation,  for  ingestion  is  undoubtedly  the 
most  important  method.  Inhalation  of  the  actual  vapor  of  lead  is,  as  al- 
ready explained,  a  very  questionable  occurrence.  The  digestion  experi- 
ments of  Oliver,  Bedson,  and  Best,  make  it  appear  probable  that  most 
of  the  lead  that  reaches  the  tissues  is  transformed  into  chloride  in  the 
stomach,  and  absorbed  either  there  or  from  the  upper  intestine.  Prob- 
ably a  part  of  it  is  got  into  solution  in  the  intestine  by  means  of  bile  or 
organic  acids.  The  gastric  juice  dissolves  lead  quite  freely  through  the 
agency  of  the  hydrochloric  acid;  other  elements  of  the  gastric  contents 
play  no  part,  and  this  action  is  even  much  interfered  with  by  the  presence 
of  protein,  because  protein  either  forms  insoluble  lead  protein  com- 
pounds or  saturates  the  hydrochloric  acid,  and  thus  prevents  the  forma- 

^  Des  Polynevrites  en  general  et  des  Paralysies  Saturnines  en  particular, 
Paris,  Balliere  et  cie,  1889. 

^  Contributions  from  the  William  Pepper  Laboratory  of  Clinical  Medicine, 
1903. 

^Contributions  from  the  William  Pepper  Laboratory  of  Clinical  Medicine, 
1902. 


96  DISEASES  DUE  TO  CHEMICAL  AGENTS 

tion  of  lead  fhloride,  a  fact  of  considerable  importance  in  ))rophylaxis,  as 
it  shows  the  rationale  of  having  workers  in  lead  take  a  full  nienl  or  plenty 
of  milk  before  beginning  their  work  and  at  mid-day.  The  bile  dissolves 
lead  freely,  and  acitl  bacterial-decomposition  products  in  the  intestines 
may  also  dissolve-  a  considerable  (juantity.  It  seems,  indeed,  probable 
that  more  absorption  takes  place  in  the  intestine  than  the  authors  men- 
tioned indicate,  for  the  contents  of  the  small  intestine  are  usually  acid 
throughout.  Pancreatic  digestion  does  not  increase  the  solution  of  lead. 
The  form  in  which  lead  reaches  the  circulation  and  tissues  is  not  known; 
it  is  not  as  all)uminates  or  pejjtonates,  for  these  are  insoluble.  Blum, 
whose  original  article  \\as  inaccessible  to  the  author,  is  referred  to  by 
Bauer  as  having  found  that  a  part  becomes  insoluble  basic  carbonate 
upon  reaching  the  blood  and  tissue-fluids,  and  is  ])reci))itated  as  such, — 
whence  comes,  perhaps,  much  of  the  frequent  prolonged  immunity  from 
symptoms  when  only  small  amounts  are  taken.  Blum  finds  part  of  it 
in  the  blood  in  a  peculiar  stable  solution  that  is  not  precipitated  by 
hydrogen  sulphide;  this  apparently  "undergoes  a  reaction  with  the 
tissues"  and  produces  the  symptoms  of  poisoning.  Evidences  that 
definite  combinations  with  the  tissues  occur,  he  finds  in  his  observation 
that  after  poisoning  with  lead  salts  that  are  insoluble  in  ether,  ether- 
soluble  lead  compounds  may  be  extracted  from  the  brain.  It  seems 
probable  that  if  tissue  compounds  are  formed,  they  are  unions  of  lead 
with  the  lipoid  elements  of  the  nervous  tissues,  both  because  of  the 
affinity  of  lead  for  these,  and  because  this  is  definitely  known  to  be  the 
case  with  some  other  poisons  affecting  nervous  tissues  (chloroform, 
chloral,  etc.).  Blyth,  however,  found  most  of  the  lead  in  the  brain  in 
an  ether-insoluble  form,  and  probably  in  the  protein  fraction.  Except  for 
the  widely  quoted  but  somewhat  questionable  observations  of  Maier,  that 
the  cerebral  cortex  has  a  special  affinity  for  lead,  there  is  no  other  evi- 
dence of  a  direct  chemical  action  of  this  metal  on  the  tissues. 

The  greatest  amount  of  lead  has  been  found  in  the  liver,  by  all  ob- 
servers. Considerable  quantities  are  often  found  in  the  kidneys;  the 
brain,  cord,  nerves,  muscles,  bones,  and  other  tissues  contain  various 
amounts.  A  number  of  authors  list  the  various  organs  in  order,  according 
to  the  amount  that  they  usually  contain,  commonly  placing  the  brain  sec- 
ond to  the  liver;  but  such  an  arrangement  is  ill-advised,  for  the  order 
must  vary  greatly  in  individual  cases.  Certainly  in  many  instances  the 
brain  contains  little  or  no  demonstrable  lead,  even  in  encephalopathic  cases. 
In  three  of  these  the  Avriter  found  no  lead  in  portions  approximating 
one-third  of  a  hemisphere.  The  custom  of  speaking  of  a  special  affinity 
for  lead  on  the  part  of  the  nervous  system,  particularly  the  peripheral 
nerves,  is  based  almost  entirely  on  clinical  observation  and  histological 
alterations,  not  on  facts.  The  lesions  are  not  necessarily  the  result  of 
the  direct  action  of  lead. 

The  manner  in  which  lead  acts  is  in  many  points  a  subject  purely  of 
speculation  and  controversy.  Colic  seems  to  be  due  to  spasm  of  the 
bowel,  dependent  most  probably,  but  not  certainly,  upon  changes  in  the 
intestinal  ganglia.  The  changes  in  the  muscles,  together  with  the  pecul- 
iar localization  of  the  paralysis  and  the  absence  of  sensory  symptoms, 
led  to  the  now  relinquished  hypothesis  that  the  paralysis  is  due  to  muscular 
changes,  and  also  suggested  the  view,  that  is  still  not  wholly  disproved, 


CHRONIC  LEAD  POISONING  97 

that  it  is  spinal  in  origin.  Tlie  usual  absence  of  spinal  lesions  led  the 
supporters  of  the  spinal  hypothesis  to  the  conjecture  (Remak,  Ii^rbj  that 
it  may  result  from  undemonstrable  functional  changes  in  the  cord;  but 
most  observers  and  investigators  now  lean  to  the  view  that  the  peripheral 
changes  are  primary,  and  Remak  himself  grants  that  the  spinal  origin 
cannot  be  very  firmly  maintained.  The  constancy  of  peri[)heral  changes, 
and  the  infrequency  of  noteworthy  changes  in  the  cord,  make  the  periph- 
eral the  more  probable  theory;  but  if  it  is  correct,  there  is  as  yet  no 
explanation  of  the  almost  regular  escape  of  certain  muscles  from  the 
paralysis. 

Whether  the  lead  acts  directly  upon  the  nerves  and  other  tissues  in 
producing  the  symptoms,  or  indirectly  through  setting  up  disturbances  of 
metabolism,  cannot  now  be  determined.  The  first  view  is  difficult  to 
disprove  and  seems  rational;  but  there  are  certain  facts,  such  as  the 
apparent  absence  of  lead  from  the  brain  in  some  cases  of  encephalopathy 
and  its  presence  in  other  cases,  that  presented  no  cerebral  symptoms, 
that  make  the  other  view  wholly  possible.  Definite  opinions  upon  this 
point  are  at  present  based  on  mere  speculation. 

Disturbances  of  metabolism  do  occur,  though  they  have  not  been  ex- 
tensively studied.  Clinical  observation  demonstrates  the  common  ten- 
dency to  tissue  breakdown  and  emaciation;  and  destructive  increase  of 
metabolism  has  been  shown  to  occur  at  the  time  of  the  attacks.  Some 
changes  in  the  phosphates,  kreatinin,  hippuric  acid,  and  uric  acid,  which 
are  of  questionable  and  as  yet  undetermined  value,  have  been  recorded. 
Most  of  the  observations  on  urea  excretion,  upon  which  some  authors  lay 
stress,  have  been  practically  valueless;  and  the  effect  on  uric  acid  excre- 
tion is  unimportant  (Ltithje).  A  noteworthy  fact,  and  one  that  may  be 
of  much  interest  in  relation  to  basic  degeneration  of  the  red  blood  cells, 
is  the  frequent  occurrence  of  slight  grades  of  haematoporphyrinuria. 

Lead  is  excreted  chiefly  through  the  kidneys  and  may  be  present  in  the 
urine  long  after  the  exposure  has  ceased.  It  is  excreted  in  the  bile  in 
large  proportions  in  animals,  and  some  observations  (Mann)  indicate 
that  it  may  be  partially  excreted  in  the  human  faeces.  A  little  excretion 
occurs  through  the  sweat,  but  this  is  of  slight  importance.  It  has  also  been 
found  in  mother's  milk  (Bulland),  a  fact  of  interest  in  relation  to  the 
infants  of  lead  poisoned  women.  Lead  has  been  demonstrated  in  the 
parotid  glands  and  saliva.  The  minimum  dose  capable  of  producing 
poisoning  when  long  continued  is  not  clearly  determined.  Brouardel 
considered  that  1  mg.  daily  may  suffice. 

Symptoms. — ^The  clinical  course  of  plumbism  consists,  in  most  instan- 
ces, of  the  development  of  more  or  less  marked  but  indefinite  general 
symptoms,  followed  after  a  variable  time,  usually  at  least  several  weeks 
often  much  longer,  by  the  appearance  of  colic.  Less  commonly  but  still 
frequently,  paralysis  supervenes;  occasionally  the  graver  cerebral  mani- 
festations occur,  also  usually  after  previous  colic.  There  is,  however,  no 
constancy  in  the  course  of  the  symptoms:  violent  colic  may  open  the 
scene  soon  after  exposure  begins;  paralysis  may  develop  very  early;  and 
in  rare  cases,  without  preceding  noteworthy  symptoms,  coma,  or  an  out- 
burst of  convulsions  or  of  more  or  less  dangerous  delirium,  may  be  the 
first  recognized  evidence  of  poisoning;  and  occasionally  indefinite  ill  health 
without  distinctive  symptoms  lasts  for  years  and  ultimately  causes  death. 


98  DISEASES  DUE  TO  CHEMICAL  AGENTS 

usually  chiefly  from  chronic  renal  disease.  Cases  of  the  latter  form  are 
rare,  however,  if  histories  are  searchingly  taken.  Probably  a  fair  number 
of  subjects,  get  well  early  without  showing  characteristic  symptoms,  be- 
cause the  exposure  ceases;  lead  workers  often  change  their  occupation 
upon  the  appearance  of  slight  symptoms  of  ill  health. 

It  is  not  wholly  feasible  to  classify  the  signs  of  actual  poisoning  under 
the  early  and  the  late  symptoms,  since  no  symptoms  appear  at  regular 
times,  and  no  combinations  of  symptoms  are  at  all  constant.  It  is,  never- 
theless, important  to  recognize  that  general  symptoms  are  practically  always 
present.  In  the  earliest  stages  they  are,  usually,  chiefly  the  symptoms  of 
ill-defined  disturbances  of  the  gastro-intestinal  tract,  or  they  belong  to 
the  indefinite  sort  that  are  likely  to  be  termed  neurasthenia,  the  patient 
then  presenting  more  or  less  weakness,  restlessness,  insomnia,  headache, 
and  mental  depression.  Frequently  mild  or  pronounced  pains  in  the 
limbs  and  trunk  are  noteworthy  early  features.  A  little  later,  usually 
when  more  distinctive  symptoms  have  become  apparent  but  sometimes 
without  these,  an  earthy  or  sallow  pallor,  often  very  striking  and  not 
well  explained  by  the  moderate  grade  of  anjemia  usually  present,  emacia- 
tion, and  more  pronounced  weakness  appear,  producing  the  so-called  lead 
cachexia.  Still  later,  signs  of  renal  or  cardiovascular  sclerosis  often  become 
conspicuous,  if  the  poisoning  has  been  prolonged  and  severe;  and  at  times 
such  features  develop  long  after  the  distinctive  evidences  of  lead  poisoning 
have  vanished.  Progressive  interstitial  nephritis  is  probably  the  com- 
monest ultimate  cause  of  death,'  though  cardiovascular  incompetency  or 
the  cerebral  results  of  arteriosclerosis  are  frequent  causes. 

At  any  time  during  the  periods  previously  noted,  the  more  distinctive 
characteristics  of  lead  poisoning — colic,  paralysis,  or  cerebral  symptoms, 
— may  appear  with  the  general  symptoms.  Colic  almost  always  develops, 
and  usually  soon  after  the  first  signs  of  ill  health.  Paralysis,  when  it 
occurs,  commonly  comes  on  after  some  cachexia  has  appeared;  that  is 
after  poisoning  has  lasted  for  a  considerable  period.  Encephalopathies 
may  develop  early  if  the  poisoning  has  been  severe,  but  they  likewise  may 
occur  later. 

Two  conditions,  the  blue  line  on  the  sums  and  basic  granulation  of 
the  erythrocytes,  are  usually  present  at  all  stages  of  poisoning,  and  often 
even  when  there  are  no  actual  symptoms  of  intoxication.  Basic  granula- 
tion (Grawitz,  Moritz,  Stengel,  White  and  Pepper,  Cadwalader)  is  indeed, 
so  far  as  is  known,  constant  during  the  whole  time  that  lead  is  present  in 
the  system,  and  it  appears  even  when  exposure  has  been  extremely  brief; 
White  and  Pepper  ^  found  it  after  four  days'  industrial  exposure,  and  even 
twenty-five  hours  after  a  single  dose  of  7J  grs.  (0.5  gm.)  of  lead  acetate. 
Neither  of  these  signs  alone  constitutes  absolute  evidence  of  clinical  saturn- 
ism, and  basic  granulation  is  found  in  many  other  conditions;  but  both  are 
of  extreme  importance  in  suggesting  that  lead  is  being  absorbed,  and  are 
valuable  confirmatory  facts  in  the  presence  of  obscure  symptoms.  The 
blue  line,  when  characteristic,  is  certain  evidence  that  lead  has  been  ab- 
sorbed; while  basic  granulation  is  only  suggestive,  though  it  is  extremely 
so  under  circumstances  that  will  be  mentioned  directly. 

'  Contributions  from  the  William  Pepper  Laboratory  of  Clinical  Medicine, 


CHRONIC  LEAD  POISONING  '99 

The  blue  line,  sometimes  called  Burton's  line,  is  said  (Still6)  to  have 
been  noted  by  Spence in  1805,  but  his  description  does  not  seem  to  refer 
to  the  lead  line,  and  certainly  it  was  first  actually  studied  clinically  by 
Burton  in  1834,  and  practically  at  the  same  time  by  Tanquerel;  Gull, 
Fagge,  Stewart,  and  Ruge  have  made  important  observations  since  then. 
Clinically  it  appears,  upon  hasty  observation,  to  be  an  irregularly  linear, 
or  broader,  dark-blue  discoloration  of  the  margin  of  the  gum.  Closer 
inspection  shows  that  it  is  frequently  a  line's  breadth  from  the  edge  of 
the  gum,  though  if  the  latter  is  loosened  and  overhanging  or  is  atrophy- 
ing, the  line  is  often  on  the  very  edge.  It  may  appear  stippled  even  to 
the  naked  eye,  and  a  hand-lens  shows  that  it  is  made  up  of  fine,  nearly 
round  dots,  which  are  sometimes  discrete,  sometimes  closely  clumped 
together.  At  times  it  consists  of  a  few  isolated  dots  or  of  a  very  slight 
and  ill-defined  line,  especially  if  the  gums  and  teeth  are  in  good  con- 
dition. It  is  not  usually  continuous  from  one  tooth  over  the  next ;  the 
portion  of  the  gum  situated  between  the  teeth  shows  it  most  commonly, 
but  little  separate  arches,  or  partial  arches  may  form  over  the  bases 
of  the  individual  teeth.  It  is  especially  marked  about  the  incisors  and 
canines,  and  particularly  in  the  lower  jaw.  The  common  statement 
that  it  is  absent  if  the  teeth  have  been  lost,  Stewart  considered  inac- 
curate; he  repeatedly  saw  it  in  such  persons  when  the  gums  were  not 
atrophied.  Stewart  also  insists  that  in  its  slight  forms  it  is  nearly  always 
present,  even  when  the  gums  are  in  good  condition.  Blue  patches  are 
sometimes  seen  on  the  inside  of  the  lips  and  cheeks,  but  these  appear 
to  be  usually  due  to  a  different  cause;  i.  e.,  to  deposit  of  lead  sulphide 
from  the  buccal  cavity,  in  areas  that  have  been  more  or  less  denuded  by 
rubbing  against  accretions  of  tartar  on  the  teeth  opposite  to  them.  The 
blue  line  must  be  carefully  distinguished  from  deposits  on  the  surface  of 
the  gum  or  on  the  teeth.  This  is  best  done  by  the  aid  of  a  lens,  noting  the 
situation  beneath  the  surface  and  the  dotted  appearance;  also,  as  sug- 
gested by  Stewart,  by  pushing  a  small  slip  of  white  paper  between  the 
edge  of  the  gum  and  the  teeth,  this  making  the  characteristic  line  more 
distinct  and  excluding  deposits  on  the  teeth.  The  similar  line  produced 
by  silver,  though  relatively  very  unusual,  may  rarely  cause  confusion; 
this  is  less  likely  with  the  green  line  due  to  copper.  If  there  is  uncer- 
tainty it  may  be  overcome,  if  desired,  by  snipping  off  a  small  piece  of 
pigmented  gum  and  observing  that  the  pigment  turns  white  (lead  sul- 
phate) in  hydrogen  peroxide,  and  grows  blue-black  again  in  ammonium 
sulphide  (Grehant,  Ruge).  The  blue  line  persists  throughout  exposure, 
and  from  three  months  (Oliver)  to  a  year  or  more  after  all  symptoms  have 
vanished. 

Basic  granulation  of  the  erythrocytes  gives  the  appearance  of  a  stip- 
pling, with  granules  that  vary  in  size  from  fine  points  to  others  as  large  as 
eosinophile  granules;  it  is  evident  only  after  staining,  the  granulations 
taking  basic  stains.  They  are  seen  in  many  different  diseases,  but  it  is  of 
great  importance  to  note  that  in  lead  poisoning  they  are  constantly 
present,  are  usually  seen  in  many  erythrocytes,  individual  cells  often 
show  large  numbers  of  them,  and  the  granules  are  ordinarily  of  rather 
large  size.  The  latter  conditions  are  extremely  rare,  especially  in  diseases 
that  are  likely  to  be  confused  with  lead  poisoning,  provided  the  ordinary 
stains    (thionin-phenique,   hematoxylin-eosin)    are    used.     The    objects 


100  DISEASES  DUE   TO   CHEMICAL  AGENTS 

brought  out  (Cadwaluder ')  by  the  use  of  jiolychroine  methylene  blue 
are,  in  part  at  least,  probably  of  different  nature,  and  seem  to  be  very 
commonly  observed  in  large  numbers  even  in  normal  blood;  hence,  this 
stain  is  not  satisfactory  for  {)urposes  of  clinical  diagnosis,  and  it  is  doubt- 
ful, indeed,  whether  any  methylene  blue  stains  are  wholly  reliable  for 
this  purpose  (Stengel,  White).  Hematoxylin-eosin  does  not  bring  them 
out  pro])erly  unless  the  staining  is  prolonged.  They  apparently  persist 
throughout  the  whole  course  of  poisoning,  and  vanish  soon  after  lead 
disappears  from  the  system  (White  and  Pepper),  though  this  })oint  is  one 
that  has  not  been  sufficiently  studied. 

Together  with  the  basic  granulation  there  is  usually  some  anfemia. 
Oliver  states  that  he  often  meets  with  severe  grades;  but  counts  rarely 
show  the  red  cells  below  two  million,  and  they  are  below  three  million  in 
but  few  cases.  There  is  some  reduction  of  the  haemoglobin;  usually  not 
severe  and  rather  less  than  is  proportionate  to  the  decrease  in  red  cells. 
Nucleated  red  cells  are  frequently  present  in  small  numbers,  occasionally 
in  considerable  numbers  (Cadwalader).  Gilbert  finds  cosinophilia  com- 
mon in  the  earliest  stages;  but  this  has  not  been  confirmed,  and  Dr.  Cad- 
walader states  that  in  37  differential  counts  he  never  saw  the  eosinophiles 
above  4  per  cent.,  rarely  as  high  as  2  per  cent.;  the  leukocytes  show,  in- 
deed, no  noteworthy  changes.  On  the  whole,  the  blood  shows  few 
alterations  excepting  the  basic  granulation  and  some  normoblasts;  and 
in  this  lies  an  important  contrast  with  pernicious  anaemia,  in  which  dis- 
ease severe  basic  clegeneration  is  common. 

When  actual  symptoms  of  poisoning  appear  they  are  both  general 
and  local.  The  general  symptoms  not  referable  to  any  special  organs, 
such  as  the  so-called  neurasthenic  symptoms  and  the  cachexia,  have 
already  been  noted.  Slight  fever  (99.5°  to  100°  )  is  present  in  unusual 
cases,  and  at  times  may  be  somewhat  prolonged;  this  may  cause  con- 
fusion in  diagnosis.  In  somewhat  greater  detail,  the  most  important 
local  clinical  effects  are  as  follows: 

Digestive  Tract. — Anorexia,  unpleasant  and  often  sweet  or  metallic 
taste,  furred  tongue  and  offensive  breath,  are  frequent  even  early,  and  the 
latter  symptom  is  often  extreme  in  well-developed  poisoning  and  has  been 
insisted  upon  as  important,  though  it  is  probably  due  to  the  common  bad 
state  of  the  mouth  and  to  the  disordered  nutrition,  rather  than  to  any  direct 
influence  of  the  lead.  Nausea  and  vomiting  are  very  common  (Tan- 
querel,  Stewart);  and  Oliver  has  especially  noted  attacks  of  epigastric 
pain  which  may  be  violent.  Constipation  is  the  rule,  and  is  frequently 
extremely  obstinate,  especially  when  colic  has  developed;  occasionally 
constipation  alternates  with  diarrhoea,  and  rarely  there  is  persistent 
diarrhoea.  Sailer  has  noted  the  absence  of  hydrochloric  acid  from  the 
stomach  contents  in  seventeen  out  of  twenty-one  cases;  Stengel  and  the 
writer  had  observed  the  same  in  a  few  cases.  This  might  lead  to  confusion 
with  gastric  carcinoma,  if  gastric  symptoms  and  cachexia  were  present ;  the 
discussion  of  Sailer's  paper  shoAved  that  this  had  actually  occurred  in 
one  of  the  cases,  and  the  same  mistake  was  several  times  recorded  before 
examination  of  gastric  contents  became  a  customary  method  of  observa- 
tion.   Among  rarer  disorders  of  the  digestive  tract  are  salivation,  severe 

'  American  Journal  of  the  Medical  Sciences,  January,  1905. 


I 


CHRONIC  LEAD  POISONING  101 

stomatitis,  parotitis  (which  hitter  may  be  due  to  the  lead,  but  seems  cliiefiy 
dependent  upon  infections  travehng  from  iU-kcpt  mouths),  and  ulcera- 
tive colitis.  Some  authors,  on  questionable  grounds,  consider  appendi- 
citis especially  common  in  subjects  of  [)lumbism. 

Colic  is  the  symptom  of  chief  importance  referable  to  the  digestive 
tract.  It  is,  however,  not  due  to  disturbed  digestion,  but  apparently  to 
spasm  of  the  bowel  of  nervous  origin.  In  severe  accidental  poisoning, 
colic  may  appear  after  a  single  dose,  and  occasionally  in  industrial  poison- 
ing within  a  few  days.  Usually  weeks  or  months  of  poisoning  and  fre- 
quently similar  periods  of  indefinite  ill  health  precede  it.  Generally  the 
patient  has  been  constipated  beforehand,  often  severely  so,  and  commonly 
forebodings  of  pain  have  already  been  felt  when  the  first  attack  of  actual 
colic  comes  on.  Severe  pain  then  appears,  often  in  the  night,  in  parox- 
ysms lasting  for  a  few  seconds  or  minutes,  in  some  cases  even  for 
hours.  The  outbreaks  of  violent  pain  are  separated  by  intervals  which 
last  for  similarly  variable  periods,  in  which  there  is  comparative  com- 
fort; the  abdomen  is  often  tender  in  the  interval,  and  dull  pain  frequently 
persists,  and  is  sometimes  nearly  continuous,  but  violent  paroxysms  of 
pain  do  not  often  continue  for  many  hours  without  prolonged  remission. 
The  severity  of  the  pain  varies  a  good  deal ;  when  it  is  extremely  marked, 
the  patient  is  in  restless  agony,  or  is  almost  collapsed  from  suffering, 
with  a  weak,  small  pulse;  while  in  milder  cases  the  pain  is  extreme  but 
bearable,  the  pulse  small  and  of  high  tension,  probably  from  reflex 
stimulation.  The  quality  of  the  pain  in  severe  colic  seems  to  be  well 
described  by  the  centuries-old  German  name,  Hiittenkatze,  given  to  it, 
it  is  said,  by  the  miners  and  smelters  because  they  believed  the  wildcats  of 
the  mines  were  tearing  out  their  entrails.  It  is  usually  situated  chiefly 
about  the  umbilicus,  but  may  be  diffused  over  the  abdomen;  in  rare  in- 
stances it  is  focalized  in  such  a  way  as  to  resemble  somewhat  closely 
renal  or  hepatic  colic.  The  abdominal  walls  are  usually  hard  and  re- 
tracted during  the  paroxysm,  and  pressure  upon  them  ordinarily  gives 
relief,  though  in  a  minority  of  instances  these  statements  may  be  reversed. 
Vomiting  is  common  during  the  paroxysm,  and  constipation  is  usually 
most  obstinate  until  the  spasm  of  the  bowel  is  over;  and  it  is  frequently 
troublesome  long  after  the  pain  is  wholly  past.  The  secretion  of  urine  is 
much  reduced;  occasionally,  it  is  said,  it  may  be  suspended  for  many 
hours.  The  duration  of  an  attack,  with  the  paroxysms  and  remissions,  is 
sometimes  a  few  hours  only,  more  commonly  several  days,  frequently  ten 
days  or  a  fortnight.  The  severity,  however,  usually  decreases  continuously 
after  the  first  day  or  two  of  treatment.  Recurrences  are  the  rule  if  expo- 
sure continues.  They  may,  indeed,  occasionally  develop  long  after 
exposure  has  ceased. 

Respiratory  Tract. — Aphonia  and  dyspnoea  from  laryngeal  paralysis 
are  very  rare.  Asthma  is  an  occasional  though  uncommon  result  of  the 
intoxication.  Pulmonary  tuberculosis  is  unduly  common  in  subjects  of 
plumbism,  partly  as  a  result  of  inhalation  of  irritants,  partly  from  re- 
duced general  resistance. 

Cardiovascular  System. — Arteriosclerosis  is  common  in  lead  workers 
even  at  an  early  age,  and,  though  the  point  is  disputed,  it  seems  to  be 
a  result  of  plumbism.  A  considerable  number  of  those  poisoned  for  a 
long  time  ultimately  exhibit  the  symptoms  of  cardiovascular  incompe- 


102  DISEASES  DUE  TO  CHEMICAL  AGENTS 

tencv,  and  die  from  circulatory  failure,  or  occasionally  from  cerebral 
accidents. 

Genito-urinaxy  System. — A  little  albumin,  and  some  casts,  are  not 
uncommon  in  the  early  stages,  especially  if  the  dosage  has  been  large. 
They  are  frecjuently  present  during  an  attack  of  colic.  After  prolonged 
poisoning,  progressive  interstitial  nej)hritis  often  becomes  the  most  im- 
portant feature  of  the  case,  and  it  is  probably  the  commonest  late  cause 
of  death. 

Suppression  of  urine,  spasm  of  the  bladder  and  urethra,  and  sometimes 
retention  of  urine,  may  be  seen  with  colic.  Retention,  sometimes  with 
overflow,  also  incontinence,  have  several  times  been  observed  as  persistent 
symptoms  in  cases  with  pronounced  nervous  lesions  of  spinal  type  (J.  J. 
Putnam).  Uratic  urethritis  in  a  case  of  saturnine  gout,  neuralgia  of  the 
testicle,  epididymitis,  and  orchitis  are  rare  occurrences,  and  have  a 
somewhat  doubtful  relation  to  lead. 

The  influence  upon  the  generative  organs  is  seen  chiefly  in  woman. 
Menstruation  becomes  disturbed,  being  usually  excessive  and  irregular; 
and  pregnant  women  with  saturnism  are  extremely  likely  to  abort  or  to 
have  premature  labors.  In  the  latter  the  child  is  often  still-born,  or  it  is 
very  frail  and  usually  soon  dies.  After  exposure  has  ceased,  women  often 
pass  through  repeated  normal  labors.  These  facts  are  of  much  economic 
importance  in  Europe,  but  are  scarcely  so  in  America,  where  exposure  to 
poisoning  is  comparatively  very  rare  in  Avomen. 

Joints  and  Bones. — Gout  occasionally  occurs,  though  the  actual  rela- 
tionship to  plumbism  has  been  the  subject  of  warm  discussion,  many 
maintaining  that  its  occurrence  is  merely  coincidental,  many  holding  it  to 
be  causative.  The  literature  seems  to  indicate  that  those  who  see  little 
gout  find  it  uncommon  in  lead  workers;  while  those  who  see  much  gout 
see  it  with  relative  frequency  in  lead  workers.  The  positive  evidence  out- 
weighs the  negative,  but  it  seems  clear  that  other  predisposing  causes  are 
necessary  in  addition  to  plumbism.  Saturnine  gout  is  apparently  some- 
what peculiar  in  that  it  involves  joints  ordinarily  spared;  the  rapidity, 
too,  with  which  many  joints  are  attacked  is  often  striking.  Gubler's 
tumor,  so-called,  is  occasionally  seen  over  the  back  of  the  wrist  or  of  the 
metacarpal  bones  of  the  hand.  It  is  an  oviod  mass  due  to  swelling  of 
the  sheath  of  the  tendons,  or  sometimes  of  the  synovial  sac  of  the  wrist- 
joint,  and  occurs  chiefly  in  wrist-drop;  slight  subluxation  often  exagger- 
ates the  so-called  tumor.  Bone  lesions  have  been  described  but  have  a 
doubtful  relation  to  lead. 

Nervous  System. — Moderate  pain,  often  indefinitely  located,  is  com- 
mon in  both  the  extremities  and  the  trunk,  especially  in  early  stages. 
Whether  this  is  due  merely  to  impaired  general  nutrition,  or  to  essential 
nerve  involvement,  is  uncertain;  but  the  latter  is  the  probable  cause  of 
the  actual  neuralgic  pains,  which  are  not  uncommon,  and  also  of  the 
joint  pains.  These  pains  in  the  joints  appear  in  brief  or  more  prolonged 
paroxysms,  which  may  be  very  severe,  and  may  last,  with  intermissions 
of  varying  lengths,  for  days;  or  they  may  cjuickly  disappear.  They  are 
usually  most  marked  in  the  knees  or  ankles.  True  joint-pains  do  not  seem 
very  common;  Tanquerel  and  others,  who  have  found  "arthralgia" 
common,  include  under  this  term  all  pains  in  the  extremities  and  even  in 
the  trunk.     The  muscles  sometimes  ache  severely,  and  may  be  tender. 


CHRONIC  LEAD  POISONING  103 

especially  those  that  are  soon  to  become  paralyzed.  Other  sensory  symp- 
toms are  usually  slight.  There  may  be  partesthesias,  and  general  sensa- 
tion may  be  reduced  or  lost  over  the  back  of  the  forearm,  less  commonly 
over  the  front  of  the  leg  or  other  localized  areas.  Hyperalgesia  is  occa- 
sionally noted,  and  in  rare  instances  there  is  much  tenderness  over  the 
nerve  trunks.  Sometimes  actual  hysterical  symptoms  are  present,  with 
hemiansesthesia  or  other  characteristic  stigmatic  local  areas  of  anaesthesia. 
Cerebral  accidents  (hemorrhage,  etc.)  if  they  occur,  may  produce  hemi- 
ansesthesia. 

With  the  diffuse  pains,  or  sometimes  in  association  with  colic,  and  oc- 
casionally without  other  symptoms,  certain  muscles,  particularly  those  of 
the  calves,  may  go  into  mild  or  severe  cramp,  which  may  be  very  painful. 
This  is  not  very  common  in  adults,  but  seems  to  be  so  in  children  (Tur- 
ner). Gowers  and  Haenel  have  observed  recurring  spasm  that  closely  re- 
sembled tetany,  and  Gowers  has  seen  flexor  spasm  precede  extensor 
paralysis.  Fibrillary  twitching  of  the  affected  muscles  is  common  after 
paralysis  has  developed,  and  in  slight  and  localized  form  it  is  not  rare 
earlier.  Buber  has  described  a  case  in  which  myokymia  of  wide  distri- 
bution was  very  prominent. 

The  nervous  symptoms  so  far  mentioned,  except  indefinitely  localized 
pains,  are  mostly  rare  or  inconspicuous.  Indefinite  pain  is  frequent,  but 
more  common  and  more  important  than  any  other  nervous  symptom 
mentioned  is  tremor.  This  is  frequently  noted,  especially  in  old  cases. 
It  affects  chiefly  the  hands,  and  is  usually  of  slight  amplitude  and  not 
striking,  though  it  is  sometimes  coarse  and  may  resemble  the  tremor  of 
paralysis  agitans.  It  usually  increases  upon  any  emotional  excitement, 
and,  more  markedly,  upon  effort.  Its  chief  diagnostic  importance  is  in 
rendering  confusion  with  mercurial  poisoning  occasionally  possible,  if 
paralytic  symptoms  are  absent.  Stewart  has  seen  actual  paralysis  agitans 
follow  lead  poisoning,  and  he  also  observed  curious  paroxysmal  attacks 
of  severe  generalized  tremor  which  he  believed  were  not  hysterical. 

Most  important  of  all  the  nervous  symptoms,  however,  and  in  its  ordi- 
nary form  by  all  means  the  most  characteristic,  is  paralysis ;  and  with  its 
usual  distribution  is  of  itself  almost  distinctive  of  lead  poisoning.  When 
typical,  it  produces  so-called  "wrist-drop,"  which  is  bilateral.  There  is 
at  first  an  increasing  degree  of  weakness  in  the  extension  of  the  fingers  at 
the  metacarpo-phalangeal  joint  (paralysis  of  the  extensor  communis  digi- 
torum),  followed  by  weakness  and  often  complete  paralysis  of  the  ex- 
tensors of  the  wrist.  Palsy  often  begins  in  one  hand,  the  other  following 
within  a  fortnight  or  less;  frequently  the  hand  first  involved  has  been 
subjected  to  special  strain,  or  has  been  especially  exposed  locally  to  lead 
(in  lead  workers,  pottery  dippers,  etc.),  the  latter  point  constituting  one 
of  the  chief  arguments  in  the  questionable  claim  that  lead  exerts  local 
effects  through  the  skin.  Frequently,  in  the  beginning  of  the  paralysis  or 
later,  portions  of  affected  muscles  show  special  involvement;  for  example, 
extension  of  the  middle  and  ring  fingers  is  often  noted  first,  and  may  long 
remain  most  marked.  The  paralysis  is  usually  subacute  in  its  onset, 
reaching  a  marked  degree  within  from  a  few  days  to  a  fortnight;  occa- 
sionally it  progresses  very  slowly.  When  well  developed,  it  produces  the 
well-known  "wrist-drop,"  the  hand  being  in  flexion  at  the  wrist  from 
paralysis  of  the  extensors,  and  the  fingers  moderately  flexed  owing  to 


104  DISEASES  DUE  TO  CHEMICAL  AGENTS 

paralysis  of  their  long  extensor.  At  first,  the  distal  phalanges  can  be 
extended  if  the  proximal  phahmges  "be  first  passively  extended;  for  the 
interossei,  the  proper  extensors  of  the  distal  joints,  arc  then  uninvolved; 
the  thumb  muscles  also  usually  functionate  at  first.  Later,  the  in- 
terossei and  the  muscles  of  the  thumb  are  affected;  distal  extension  of  the 
fingers  and  extension  and  adduction  of  the  thumb  are  imperfectly  per- 
formed, or  impossible.  The  long  abductor  of  the  thumb  often  becomes  in- 
volved late,  but  in  early  stages  is  usuallyspared;  and  the  supinator  longus 
is  almost  never  included  in  the  common  type  of  ])aralysis,  a  point  that 
is  of  great  importance.  The  distinctive  characteristics  of  this  paralysis 
are,  that  it  is  almost  always  bilateral,  is  purely  extensor,  spares  tiie  long 
supinator  and  usually  tlie  long  abductor  of  the  thumb,  and  there  are 
rarely  any  sensory  symptoms,  except,  perhaps,  limited  cutaneous  anaes- 
thesia over  the  backs  of  the  forearms.  Atrophy  begins  soon  in  the 
affected  muscles,  especially  those  of  the  back  of  the  forearm;  marked 
reduction  or  loss  of  faradic  response  appears;  and  the  reactions  of  degen- 
eration develop.  As  a  rule,  some  of  the  muscles  other  than  those  distinctly 
paralyzed  are  weak,  and  may  even  show  degeneration  reactions.  The 
paralysis  ordinarily  soon  reaches  the  limit  of  its  intensity  and  extent. 
Fresh  cases  quickly  improve  within  a  few  weeks  after  proper  treatment 
is  started,  and  generally  recover  almost  completely  within  a  few  months 
if  they  are  not  extremely  severe.  In  older  cases  recovery  is  slow,  and 
dependent  upon  the  grade  of  the  palsy  and  its  duration ;  if  long  neglected 
and  severe,  compleie  recovery  is  not  common,  and  occasionally  very  little 
improvement  occurs.  Gowers  makes  two  classes  of  paralysis:  in  the  first, 
which  is  the  usual  one  and  of  good  prognosis,  the  palsy  is  distinctly 
primary,  atrophy  and  degeneration  reactions  follow,  and  the  progress 
toward  more  or  less  complete  paralysis,  and  afterward  toward  recovery, 
is  rapid;  in  the  second  class,  which  is  uncommon,  atrophy  occurs  from 
the  beginning  and  goes  hand  in  hand  with  the  palsy,  faradic  and  gal- 
vanic response  decrease  together,  pari  jjaasu  with  the  atrophy  and  the 
palsy,  increase  of  the  palsy  is  slower,  and  the  prognosis  for  its  recovery 
is  poor. 

Forms  of  paralysis  other  than  characteristic  wrist-drop  may  occur. 
The  Aran-Duchenne  type  is  occasionally  seen;  in  it  the  small  muscles 
of  the  hand,  the  interossei,  and  the  thenar  and  the  hypothenar  early 
become  atrophied  and  more  or  less  paralyzed  and  these  changes  ])roduce 
the  "simian"  hand.  This  is  not  a  clearly  individualized  type  in  lead  poison- 
ing, being  usually  associated  with  the  previously  described  form,  and 
simply  an  exaggeration  of  some  features  that  are  generally  present  ^yhen 
wrist-drcp  is  at  all  severe.  The  Aran-Duchenne  form  has  been  particu- 
larly noted  in  persons  whose  occupation,  such  as  file  making,  causes  a 
special  strain  on  the  small  muscles  of  the  hand.  The  upper  arm  or 
Duchenne-Erb  type,  in  which  the  deltoid,  often  the  biceps  and  the  bra- 
«hialis  anticus,  and  sometimes  the  supra-  and  infraspinati,  are  involved, 
occurs  occasionally.  In  it  the  arms  hang  by  the  side,  rotated  somewhat 
outward  and  incapable  of  abduction,  and  in  severe  cases  incapable  of 
flexion  at  the  elbow.  This  form  has  repeatedly  been  seen  as  a  separate 
condition,  though  it  is  usually  associated  with  paralysis  of  the  extensors 
of  the  fingers  and  wrist.  Contrary  to  the  conditions  in  the  ordinary  fore- 
arm type,  the  supinator  longus  is  likely  to  be  involved  in  this  variety.    Of 


CHRONIC  LEAD  POISONING  105 

this  group  of  muscles,  the  deltoid  is  especially  liable  to  paralysis,  and  it 
has  repeatedly  been  the  sole  muscle  palsied;  sometimes  it  has  been  para- 
lyzed on  one  side  only. 

The  lower  limbs  are  infrequently  affected  in  adults,  and,  when  they 
are,  the  arms  usually  suffer  also;  the  conditions  in  children  differ  mark- 
edly in  this  point,  as  will  be  noted  later.  In  the  legs,  the  peronei  and  the 
extensor  of  the  toes  are  the  tyj)ical  seat  of  paralysis,  the  tibialis  anticus 
almost  always,  like  the  su])inator  longus  in  the  arm,  being  spared.  In 
rare  instances  in  adults,  more  commonly  in  children,  the  tibialis  anticus 
is  paralyzed,  while  the  muscles  usually  affected  escape.  The  disease  in 
the  legs,  as  in  the  arms,  is  practically  always  bilateral.  The  small  muscles 
of  the  feet  occasionally  show  special  involvement;  Koster  has  described 
an  isolated  case  in  which  they  were  affected  severely  without  disease  of 
the  leg  muscles,  and  this  produced  a  condition  analogous  to  the  "ape- 
hand"  in  typical  Aran-Duchenne  paralysis  of  the  hands.  Rarely  the 
disease  is  situated  chiefly  in  the  muscles  of  the  thigh.  The  knee-jerk 
may  be  increased  when  the  legs  are  affected;  it  may  be  normal;  some- 
times it  is  reduced  or  lost. 

Paralysis  of  the  cranial  nerves  is  occasionally  noted ;  this  is  not  usually 
due  to  isolated  neuritis,  but  is  a  part  of  encephalopathic  symptoms.  In 
these  latter  cases,  the  cause  of  the  paralysis  is  not  certainly  known;  in- 
creased intracranial  pressure  from  congestion  or  oedema  is  often  present, 
but  direct  or  secondary  toxic  effects  of  the  lead  on  the  brain  substance  are 
probably  more  frequently  the  cause. 

The  nerve  most  frequently  involved  is  the  optic,  though  fortunately 
this  is  rare;  the  eye  symptoms  will  be  mentioned  later.  Laryngeal  paral- 
ysis, which  is  much  more  rare  (Remak  collected  only  twelve  cases),  has 
not  been  associated  with  cerebral  symptoms  in  most  instances,  and, 
while  human  pathological  studies  have  not  been  made,  the  condition  is 
probably  usually  a  neuritis;  this  view  is  supported  by  studies  of  horses, 
which  animals  were  noted  by  Tanquerel  and  by  many  since  his  time  to  be 
especially  subject  to  laryngeal  paralysis  after  prolonged  exposure  in  lead 
works.  The  paralysis  has  most  commonly  affected  the  adductors  and 
caused  hoarseness  or  aphonia,  though  the  abductors  have  repeatedly  been 
paralyzed  and  produced  marked  inspiratory  dyspnoea.  The  facial  nerve 
has  several  times  been  paralyzed,  once  (Bury)  with  the  peripheral  type  of 
distribution;  hence,  in  this  instance  there  was  probably  a  neuritis. 
Other  cranial  nerves  that  have  certainly  been  separately  paralyzed  as 
the  result  of  lead,  are  the  abducens  and  the  oculomotor;  and  the  clinical 
importance  of  these  nerves  has  been  materially  increased  recently  by  the 
large  series  of  cases  in  children  observed  by  Lockhart  Gibson;  paralysis 
of  these  nerves,  as  of  the  optic,  is  commonly  associated  with  cerebral  signs. 
Sometimes  several  ocular  and  other  cranial  nerves  have  been  involved 
coincidently,  usually  when  other  cerebral  symptoms  were  present.  Oph- 
thalmoplegia has  occurred. 

In  addition  to  the  localized  forms  of  paralysis,  cases  are  occasionally 
seen  in  which  generalized  paralysis  appears,  usually  advancing  from  the 
periphery  toward  the  trunk.  In  these  instances  it  is  probable  that  both 
spinal  and  peripheral  changes  are  frequently  present.  There  are  two 
important  varieties,  one  subacute  or  acute,  the  other  of  slow  progress;  a 
third  variety  is  distinguished  simply  by  the  presence  of  fever,  with  rapidly 


106  DISEASES  DUE  TO  CHEMICAL  AGENTS 

extending  paralysis.  The  slow  form  generally  supervenes  upon  a  pre- 
existing local  palsy,  usually,  of  course,  of  the  forearms;  but  it  may  be 
progressive  from  the  beginning.  The  rapid  form  is  likely  to  have  been 
preceded  by  enceplialo|)athy,  but  this  is  not  always  the  case.  Both  ordi- 
narily end  in  recovery,  the  acute  form  often  beginning  to  mend  very  rapidly 
within  a  few  weeks  or  less,  the  slower  form  disappearing  after  more  delib- 
erate progress.  Very  rarely  death  has  occurred  from  asphyxia.  In 
rare  instances,  paralysis  of  the  diaphragm  has  occurred,  even  without 
general  palsy.  A  few  cases  have  been  seen  of  diffuse  paralysis  following 
the  type  of  progressive  muscular  atrophy.  Some  cases  have  been  observed 
in  which  conspicuous  ataxia,  sometimes  absent  knee-jerks,  and  only  slight 
paralysis  or  none,  produced  some  resemblance  to  locomotor  ataxia. 
Remak  states  that  a  definite  pseudotabctic  form  has  not  been  observed; 
but  the  reports  of  Teissier,  Raymond,  Putnam,  Walton,  and  others,  show 
at  least  that  ataxia  may  be  severe  even  in  the  absence  of  paralysis.  There 
is  more  doubt  in  regard  to  the  type  resembUng  spastic  spinal  palsy,  its 
recognition  being  based  almost  entirely  upon  Putnam's  reports,  and  the 
diagnosis  in  these  cases  was  dependent  solely  upon  the  discovery  of  small 
amounts  of  lead  in  the  urine.  Bechtold,  however,  has  recently  reported 
a  rather  clear  case,  and  Oppenheim  mentions  its  occurrence. 

Cerebral  Symptoms. — E?icephalopatJiy. — Transitory  hemiplegia  (Da- 
Costa)  is  a  rare  observation;  as  is  persistent  hemiplegia  or  other  cere- 
bral paralysis,  except  late  in  the  course  in  old  cases  when  nephritis  and 
arteriosclerosis  may  cause  apoplexy.  Aphasia  has  been  noted  and  chorei- 
form movements  have  repeatedly  been  seen,  but  are  rare.  There  may  be 
hysterical  symptoms,  with  hemiansesthesias  and  other  stigmata,  or 
hysterical  outbreaks  of  excitement  or  convulsions,  especially  in  predis- 
posed young  women. 

The  most  common  and  striking  cerebral  symptoms  are  epileptiform 
convulsions,  delirium,  and  coma;  sometimes  a  picture  more  or  less  closely 
resembling  paretic  dementia.  In  Tanquerel's  1,217  cases,  encephalop- 
athy occurred  72  times.  Its  frequency  varies  according  to  the  dose,  and 
perhaps  according  to  the  nature  of  the  lead  compound  ingested.  In  Stew- 
art's chrome-bun  series  of  64  cases,  encephalopathy  occurred  15  times. 
These  latter  figures  are,  however,  perhaps  partly  due  to  the  fact  that 
many  children  were  affected.  The  outbreak  often  comes  suddenly; 
those  who  are  alcoholic  are  especially  liable,  and  the  author  has  several 
times  seen  cerebral  symptoms  appear  suddenly  after  sli-ght  indulgence 
in  alcohol.  Convulsions  or  delirium  usually  occur  first,  convulsions  being 
the  more  frequent;  if  coma  appears  it  usually  follows  delirium  or  con- 
vulsions, particularly  the  latter.  The  convulsive  attacks  are  epileptiform 
with  clonic  and  tonic  movements;  only  one  may  occur,  but,  as  a  rule,  the 
attacks  are  protracted  at  varying  intervals  over  days — rarely,  even  weeks. 
Epileptiform  attacks  have  occasionally  persisted,  though  this  is  decid- 
edly unusual,  and  their  relation  to  plumbism  has  not  been  very  certain. 
In  the  delirious  form  there  is  usually  active  excitement,  and  the  patient 
may  be  very  violent;  convulsions  not  uncommonly  interrupt  the  delirium, 
and  there  are  often  striking  changes  from  violent  intellectual  and  motor 
activity  to  hebetude  and  quiet.  Delusions  of  persecution,  and  particularly 
hallucinations,  especially  of  terrifying  character,  are  common;  though 
they  are  not  confined  to  such  subjects,  hallucinations  are  very  frequent 


CHRONIC  LEAD  POISONING  107 

in  those  who  are  also  alcohoUc,  and  with  marked  tremor  the  resemblance 
to  delirium  tremens  may  be  very  striking.  Fever  (100°  to  101°,  occa- 
sionally even  higher)  is  not  uncommon.  The  duration  may  be  extremely 
brief,  but  more  commonly  delirium  lasts  from  several  days  to  a  fortnight 
or  sometimes  longer;  in  unusual  instances  the  patient  remains  insane. 
The  fact  that  delirium  may  be  of  sudden  and  violent  onset  is  at  times  one 
of  grave  moment;  one  of  the  patients  in  the  Episcopal  Hospital,  Phila- 
delphia, who  had  previously  shown  very  slight  symptoms  of  saturnism 
(mild  colic),  aroused  the  ward  suddenly  in  the  night  with  wild  cries  of  fear, 
and  almost  immediately  leaped  from  a  third-story  window  and  was 
killed;  a  few  days  later  a  similar  but  not  fatal  accident  occurred  to  one  of 
Dr.  Tyson's  patients  at  the  University  Hospital  of  Philadelphia.  Acute 
encephalopathies  are  very  dangerous;  Tanquerel  saw  16  deaths  in  72 
cases,  and  as  a  rule  the  mortality  is  put  higher  than  this.  Death  usually 
occurs  in  convulsions,  in  coma,  or  from  general  exhaustion;  broncho- 
pneumonia is  also  quite  common. 

Symptoms  of  general  paresis  have  been  observed  in  a  considerable 
number  of  cases,  and  it  is  probable  that  lead  can  cause  this  disorder, 
though  many  cases  reported  under  this  heading  appear  to  have  been 
other  conditions,  such  as  marked  exhaustion  resulting  from  acute  delirium 
or  from  cachexia  and  marasmus,  sometimes  a  state  approaching  that  in 
Korsakow's  polyneuritis  psychosis.  When  the  symptoms  resemble 
general  paresis,  differences  usually  exist,  in  that  the  onset  is  very  rapid, 
speech  is  less  disturbed  than  in  ordinary  paretic  dementia,  moral  vagaries 
are  less  common,  and  recovery  often  occurs  even  from  extreme  states. 

Eye  Symptoms. — Disease  of  the  external  ocular  nerves  produces  the 
corresponding  muscular  paralyses.  Nystagmus  has  been  observed. 
Hemianopsia,  usually  homonymous,  once  heteronomous,  may  appear 
rarely.  Transitory  blindness  may  develop  suddenly,  usually  in  encephalo- 
pathic  cases;  this  blindness  commonly  disappears  rapidly  and  com- 
pletely. Vision  may  gradually  become  impaired,  with  the  symptoms 
common  in  other  forms  of  amaurosis,  and,  of  these,  probably  at  least  one- 
half  show  persistent  structural  changes  in  the  optic  nerve  (De  Schweinitz). 
Ophthalmoscopically,  the  transitory  cases  may  show  nothing;  the  changes 
found  in  other  cases  are  those  common  in  amaurosis,  except  that  lead 
subjects  show  especially  marked  vascular  lesions ;  and  it  is  also  noteworthy 
that  in  optic  neuritis  the  lesions  are  not  confined  to  the  parenchyma,  as 
they  are  in  the  nerves  of  the  extremities,  but  are  also  interstitial  and 
perineuritic.  Serious  eye  symptoms  are  fortunately  rare;  De  Schweinitz 
saw  only  3  instances  in  over  15,000  eye  cases. 

Lead  Poisoning  in  Children. — Plumbism  in  infancy  and  early  child- 
hood commonly  shows  such  wide  clinical  divergence  from  that  in  adults 
that  a  brief  separate  mention  of  it  is  demanded.  It  is,  naturally,  not  com- 
mon in  the  very  young,  since  it  is  always  accidental  in  them;  but  it  is 
probably  somewhat  more  common  than  is  usually  thought,  and,  in  a  con- 
siderable proportion  of  the  cases  that  occur,  it  is  almost  certainly  not 
recognized.  J.  J.  Putnam  first  directed  especial  attention  to  its  peculiari- 
ties, and  Newmark,  Chapin,  Sinkler,  Stewart,  Brown,  Variot,  Hahn,  and 
others  have  added  interesting  observations,  the  remarkable  reports  of 
Turner  and  Gibson  of  its  widespread  occurrence  in  Queensland  being 
particularly  noteworthy,  especially  in  some  of  their  clinical  features. 


lOS  DISEASES  DUE  TO  CHEMICAL  AGENTS 

Symptoms. — It  is  prohahlc  that  some  of  the  sickly  infants  of  mothers 
with  pliunbisni  have  lead  ])oisoiiino;  and  die  of  it.  Infants  seem,  as  is  to 
be  exi)ected,  prone  to  convulsions  when  poisoned  by  lead  from  this  or 
other  sources.  Colic  is  likewise  a  commonly  noted  symptom  in  proved 
or  suspected  cases  in  infants,  although  in  them  it  alone  is,  of  course,  not 
good  evidence  of  actual  poisoning.  In  older  children  there  is  a  striking 
frequency  of  cerebral  symptoms,  though  colic  and  paralysis  are  more 
imj)ortant.  The  spasms  of  colic  may  be  of  the  same  general  character 
as  in  adults,  but  colic  alone  rarely  suggests  plumbism  in  children.  The 
fact,  however,  that  colic  occurs  repeatedly  throughout  more  or  less 
prolonged  periods,  and  that  it  may  show  a  lack  of  dependence  upon 
dietetic  error  or  evitlent  digestive  derangement,  is  suggestive.  Turner 
refers  to  the  marked  frequency  of  jiains  in  the  legs,  or  severe  cramps, 
with  colic,  these  cramps  being  often  the  most  marked  symptoms. 

In  paralysis  in  children  the  legs  are  almost  regularly  affected,  and  usually 
show  the  most  severe  lesions  when  the  arms  are  included;  and  a  further 
peculiarity,  as  compared  with  adults,  is  noted  by  Turner:  the  peroneal 
muscles  usually  affected  in  adults  often  escape,  while  the  tibialis  anticus 
is  usually  paralyzed.  There  is  not  a  great  probability  of  mistaking  these 
cases  for  poliomyelitis  if  they  are  carefully  observed;  but  the  likelihood  of 
considering  them  dii)htheritic  or  other  infectious  peripheral  palsies,  is 
evident. 

Of  cerebral  symptoms,  convulsions  have  been  noted  by  the  largest 
number  of  observers,  but  there  is  a  very  suggestive  interest  in  the  reports  of 
Gibson  and  Turner  of  twenty-four  instances  in  which  the  chief  symptoms 
were  prolonged  rigidity  of  the  neck,  retraction  of  the  head,  and  ocular 
symptoms.  Of  the  latter,  paralysis  of  the  abducens  and  the  oculomotor 
were  most  frequent,  though  ophthalmoplegia  was  repeatedly  observed, 
and  blindness  was  common;  sometimes  the  latter  disappeared,  and  some- 
times it  became  permanent  from  progressive  optic  atrophy.  These  cases 
were  at  first  reported  as  chronic  basal  meningitis;  later  the  regular  re- 
covery of  general  health  after  removal  from  the  homes  or  from  demon- 
strated sources  of  lead,  the  frequent  discovery  of  a  blue  line,  and  of  lead 
in  the  urine  in  the  cases  examined  for  this,  demonstrated  that  many  of 
them  at  least  were  lead  poisoning. 

The  blue  line  is  said  by  Brown  and  Turner  to  be  frequently  absent. 
Their  evidence  is  not  given  in  wholly  convincing  form,  and  is  somewhat 
opposed  to  certain  otlier  observations;  but  the  lead  line  appears  to  be 
at  least  less  common  than  in  adults. 

Diagnosis. — Proper  knowledge  of  the  sources  of  lead  poisoning,  and 
alert  attention  to  details  in  the  history  indicative  of  exposure,  will  often 
give  an  immediate  suggestion  of  the  nature  of  the  case,  even  when  the 
symptoms  are  unusual.  Colic  and  wrist-drop,  however,  are  of  course 
much  the  most  common  results,  and,  when  characteristic,  are  sufficient 
to  bring  up  the  diagnosis  at  once.  Their  association  with  a  clear  source 
of  poisoning,  and  especially  with  a  blue  line,  makes  the  diagnosis  practi- 
cally certain.  The  absence  of  a  known  source  of  lead  is  not  of  much  diag- 
nostic importance,  if  the  other  signs  are  definite;  and,  even  if  the  blue  line 
is  absent  (which  is  unusual),  bilateral  wrist-drop  without  involvement 
of  the  supinator  longus,  and  with  no  affection  of  the  flexors  and  no  note- 
worthy sensory  symptoms,  is  nearly  decisive,  though  to  be  completely  so 


CHRONIC  LEAD  POISONING  109 

it  needs  confirmation  through  finding  lead  in  the  urine.  The  search  for 
lead  in  any  case  should  be  undertaken  early  ih  the  treatment  and  after 
giving  potassium  iodide  for  a  few  days.  A  positive  result  then  does  away 
with  the  occasional  possibility  of  confusion  with  the  unusual  instances  of 
similar  palsy  due  to  alcohol  or  other  poisons,  or  to  spinal  disease,  such  as 
poliomyelitis;  a  negative  result,  unless  the  examination  has  been  care- 
fully and  capably  carried  out,  means  nothing,  even  early,  and  is  never 
of  importance  late  in  the  case.  The  slight  and  fragmentary  forms  of  the 
blue  line,  which  may  require  a  lens  to  determine  their  nature  accurately, 
should  be  carefully  sought  when  a  more  characteristic  line  is  absent. 
Basic  granulation  that  is  very  marked  (with  hematoxylin-eosin,  or 
thionin  stain),  and  that  is  not  associated  with  profound  changes  of  other 
kinds  in  the  blood  cells,  is  extremely  suggestive,  and  may  lead  to  a  correct 
diagnosis.  It  is  not  yet  certain  whether  other  metallic  poisonings  pro- 
duce basic  granulation;  Lowenthal  had  suggestive  results  with  tin,  but 
he  considers  his  experiments  of  doubtful  value;  and,  too,  he  used  methy- 
lene blue  staining. 

Cerebral  cases  and  the  slight  or  more  unusual  forms  of  paralysis  are 
much  more  likely  to  be  misinterpreted.  If  they  are  of  industrial  origin 
attention  to  the  nature  of  the  occupation  usually  suggests  the  diagnosis 
quickly,  and  a  search  for  the  blue  line  and  for  basic  granulation  fur- 
nishes more  direct  evidence.  It  is  to  be  remembered,  however,  that 
neither  of  the  latter  signs  constitutes  final  evidence  that  unusual  varieties 
of  paralysis  are  due  to  lead,  and  if  distinctive  symptoms  are  absent,  or  a 
source  of  poisoning  is  not  known,  recourse  must  always  be  had  to  exam- 
ination of  the  urine;  and  in  any  doubtful  case  the  diagnosis  must  depend 
upon  this.  The  chief  source  of  error  in  the  blue  line  is  in  the  fact  that  it 
may  persist  even  for  years  after  lead  poisoning  has  disappeared,  and  it 
may,  therefore,  be  present  with  other  conditions  that  have  developed  later. 
When  convulsions  or  eye  symptoms  are  present  the  possibility  of  uraemia 
must  be  considered.  In  cases  with  only  general  symptoms  the  finding  of 
lead  in  the  urine  is  the  sole  reliable  source  of  diagnosis.  In  a  search  for 
lead  in  the  urine  the  rougher  clinical  m^ethods,  such  as  the  magnesium- 
band  test,  or  the  observation  of  a  black  precipitate  of  lead  sulphide  after 
adding  albumin  and  an  alkali  and  heating,  may  be  tried  if  desired.  If  a 
precipitate  is  formed  and  confirmatory  tests  show  it  to  be  lead,  this  suf- 
fices; but  these  tests  are  usually  negative  even  when  lead  is  present. 
The  only  satisfactory  method  is  to  oxidize  the  organic  matter  by  heating 
as  much  as  500  c.  c.  of  urine  with  one-tenth  its  amount  of  hydrochloric 
acid  and  two  or  three  grams  of  potassium  chlorate,  subsequently  driving 
off  the  chlorine  and  concentrating  by  evaporation.  The  lead  is  then  re- 
covered by  electrolysis,  or,  as  sulphide,  by  means  of  hydrogen  sulphide. 

Prognosis. — General  disorders  that  have  not  caused  serious  organic 
lesions,  colic,  and  the  mild  and  recent  palsies,  recover  entirely  under 
proper  treatment.  The  older  and  more  severe  forms  of  paralysis  have  a 
prognosis  as  to  complete  recovery  that  is  directly  related  to  their  dura- 
tion and  intensity,  severe  protracted  cases  rarely  getting  wholly  well. 
Persistent  atrophy  and  progressive  decrease  or  entire  loss  of  response  to 
electricity  are  bad  signs.  Cerebral  symptoms  are  always  dangerous, 
coma  being  particularly  so;  if,  however,  the  patient  escapes  death  frpm 
encephalopathy,  serious  consequences  rarely  follow.    Eye  symptoms,  of 


110  DISEASES  DUE   TO  CHEMICAL  AGENTS 

slow  onset  especially,  are  of  very  doubtful  prognosis.  About  half  of  them 
have  persistent  optic  atrophy,  and  this  goes  on  to  blindness  in  a  large  pro- 
portion of  cases. 

The  progno.sis  as  to  future  attacks  depends  almost  entirely  upon  the 
discovery  and  exclusion  of  the  source  of  poisoning,  renewed  outbreaks 
from  old  lead  deposits  in  the  body  being  very  unusual.  If  the  exposure 
continues,  recurrences  arc  probable  and  are  of  worse  prognosis  than  the 
original  attacks. 

In  renal,  cardiovascular,  and  other  changes  resulting  from  lead  poison- 
ing, the  prognosis  is  dependent  upon  the  severity  and  stage  of  these  lesions. 
If  the  further  absorption  of  lead  is  stopped,  the  progress  of  the  lesions 
that  have  resulted  is  of  course  slower. 

Prophylaxis  and  Treatment.— Were  the  industries  that  cause  expos- 
ure subjected  to  reasonable  regulations  and  these  actually  enforced,  and 
were  the  workmen  not  only  given  opportunity  to  keep  themselves  clean, 
but  required  to  do  so,  industrial  lead  poisoning  would  largely  disappear. 

Cleanliness  is  the  most  important  point  in  prophylaxis,  and  the  most 
difficult  one  to  carry  out,  owing  to  the  utter  carelessness  of  most  workmen. 
Much  of  this  is  due  to  a  lack  of  proper  comprehension  of  the  dangers  and 
the  methods  of  avoiding  them,  and  many  poisonings  are  avoided  in  those 
works  where  the  policy  of  instruction  is  adopted  instead  of  the  narrow 
custom  of  belittling  the  danger.  But  many  workmen  will  not  voluntarily 
keep  properly  clean,  and  hence  those  at  all  seriously  exposed  should  be 
required  to  do  so.  The  effect  of  such  regulations  is  seen,  for  example,  in 
one  large  plant,  in  which  lead  poisoning  at  one  time  even  greatly  endan- 
gered the  success  of  the  industry,  but  in  which  the  workmen  are  now 
provided  with  attractive  facilities  for  cleanliness  as  to  person  and  clothes, 
are  required  to  use  these  facilities  under  penalty  of  discharge,  and  are 
given  full  pay  for  the  time  consumed  in  daily  bathing,  etc.  Lead  poison- 
ing has  now  nearly  disappeared  from  this  plant.  Most  of  the  details  of 
the  hygiene  of  construction  and  operation  of  plants  in  this  country  are 
dependent  upon  the  wisdom  and  philanthropy  of  the  operator;  they 
should  be  controlled  by  law.  The  regulations  existing  in  a  number  of 
European  countries  ^  are  examples  of  what  needs  to  be  done ;  the  most 
important  of  these  regulations  are  those  that  demand  certain  forms  of 
ventilation,  height  of  ceiling,  isolation  of  the  most  dangerous  parts  of  the 
work  from  the  other  portions  of  the  plant,  apparatus  for  the  exclusion  of 
dust  or  for  the  removal  of  that  which  escapes  into  the  atmosphere,  daily 
cleansing,  and  such  construction  of  the  walls  and  floors  as  to  permit  of 
easy  and  thorough  cleaning,  the  provision  of  separate  eating-rooms  and 
of  free  baths,  the  exclusion  of  women  and  children  from  the  dangerous 
parts  of  the  work,  limitation  of  the  hours  of  work  and  of  continuous  ex- 
posure of  the  same  individuals  to  the  most  dangerous  parts  of  the  work, 
and  the  services  of  a  physician  who  has  power  to  "lay  off"  any  suspicious 
cases  from  w^ork  and  who  must  report  such  cases.  In  some  countries  it  is 
also  required  of  the  workmen  that  they  change  their  clothes  and  bathe 
after  working,  wear  gloves  or  rub  their  hands  with  grease  when  at  work, 
and  do  not  eat,  drink  alcoholic  beverages,  or  smoke  or  chew  tobacco  in  the 

'  See  Gesundheitsgefahrliche  Industrien;  Firgau,  Gijte  and  Stark  Wirkende 
Arzneimittel,  Berlin,  Haering,  1901  (German  laws,  etc.) ;  Poisons  Industrielles, 
Dangerous  Trades,  ed.  by  Oliver. 


CHRONIC  LEAD  POISONING  111 

workrooms.  The  enforcement  of  these  laws  is  sometimes  unfortunately 
lax.  There  are  in  several  countries  very  specific  regulations  governing 
the  specific  dangers  in  different  industries.  Simple  examples  of  this  are 
the  requirement  that  lead  colors  be  ground  wet,  that  {)ottery  glaze  be 
properly  fritted,  etc.;  indeed,  the  English  law  concerning  the  latter  point 
is  so  rigid  that  Prof.  Orton  states  it  is  exceedingly  difficult  to  comply 
with  it  and  continue  manufacturing.  A  more  elaborate  instance  of  spe- 
cific regulations  is  seen  in  the  fact  that  in  Germany  the  production  of 
electric  storage  batteries  is  governed  by  twenty-eight  regulations,  and 
many  of  these  apply  purely  to  the  apparatus,  material,  and  building  con- 
struction to  be  used  in  this  particular  industry. 

Of  the  simpler  preventive  measures,  proper  cleansing  is  by  far  the  most 
important.  Respirators  are  of  little  use  because  the  men  usually  will  not 
wear  them;  sulphuric  acid  lemonade  is  of  some  value,  though  lead  sul- 
phate is  absorbed  to  a  slight  extent.  Theoretically  proper,  and  practi- 
cally very  valuable,  is  the  free  use  of  protein  food  before  beginning  work 
or  at  mid-day;  milk  is  provided  free  in  a  considerable  number  of  plants, 
and  in  several  it  has  gained  the  reputation,  which  is  too  favorable,  of 
being  an  almost  certain  preventive.  Fats,  such  as  olive  oil,  also  seem  to 
have  some  preventive  action;  one  plant  in  Philadelphia  has  long  required 
the  men  to  take  olive  oil  before  beginning  work  and  at  the  mid-day  meal, 
and  excellent  results  are  claimed  from  this.  Exercise  in  the  open  air, 
by  increasing  eliminative  functions  and  general  resistance,  has  a  most 
important  influence;  companies  owning  their  workmen's  houses  have 
repeatedly  built  them  at  a  distance  in  order  to  necessitate  a  daily  walk  to 
and  fro,  and  with  very  useful  results. 

When  poisoning  has  developed,  exclusion  of  the  source  is  the  first 
imperative  necessity.  In  industrial  cases  this  means  of  course,  a  change  of 
occupation,  or,  if  necessary,  cessation  of  work;  in  accidental  poisoning 
it  often  means  painstaking  and  extended  search  for  the  source.  If  the 
water  is  at  fault  lead  service  pipes  should  be  replaced,  if  possible.  In 
towns  where  this  often  cannot  be  generally  done,  the  whole  supply  can 
be  rendered  nearly  harmless  by  adding  chalk  or  lime  to  the  reservoirs,  or 
by  sand  filtration;  or  the  individual  may  do  this  himself,  or  filter  the  water 
through  charcoal,  though  these  measures  are  more  successful  if  done  be- 
fore the  water  passes  through  the  lead  pipe.  The  water  should  also  be 
allowed  to  run  a  long  time  before  any  is  taken  for  drinking  or  cooking 
purposes,  as  that  which  stands  in  the  pipe  becomes  specially  laden  with 
lead. 

The  active  treatment  consists  in  elimination  of  the  lead  and  of  general 
products  of  metabolism,  and  in  combating  general  or  local  symptoms. 
The  initial  action  in  any  case  should  be  to  expel  any  lead  present  in  the 
gastro-intestinal  tract,  preferably  by  means  of  saline  purges ;  purgatives 
that  act  largely  through  increasing  peristalsis  should  not  be  used.  Pur- 
gation is  frequently  difficult  to  accomplish,  for  the  constipation  is  often 
obstinate  if  there  is  colic  and  sometimes  when  there  is  not.  In  such  cases 
it  is  often  necessary  to  use  large  and  frequent  doses  of  salines  (which 
may  have  to  be  combined  with  simple  enemas,  or  enemas  containing  a 
half  ounce  or  an  ounce,  15  to  30  gm.,  of  magnesium  sulphate),  and  to 
give  with  the  purgatives,  to  control  the  intestinal  spasm,  moderate  doses 
of  atropine,  pilocarpine  or  other  antispasmodic.    Large  oil  enemas  are  also 


112  DISEASES  DUE  TO  CHEMICAL  AGENTS 

very  useful  and  entirely  harmless.  In  cases  with  severe  colic  a  movement 
may  sometimes  be  secured  only  by  giving,  before  the  purgatives,  moder- 
ate doses  of  morphine.  Control  of  the  constipation  is  one  of  the  most 
important  features  of  the  treatment  of  colic,  and  colic  is  the  commonest 
symptom  demanding  treatment.  After  the  bowels  are  once  opened  they 
should  be  moved  at  least  once  (better  two  or  three  times)  a  day  until  the 
local  symptoms  disaj)pear,  in  order  to  encourage  elimination  and  pre- 
vent return  of  the  spasm.  Water  should  be  drunk  freely,  and  if  the  secre- 
tion of  urine  is  low  diuretics  should  be  used.  After  the  bowels  have  been 
moved,  potassium  iodide  should  be  given  in  doses  of  5  grains  (0.3  gm.) 
three  times  daily.  If  increased  beyond  this  it  should  be  carefully  watched, 
as  some  observers  believe  that  it  may  temporarily  exaggerate  the  symp- 
toms by  getting  more  lead  into  solution.  The  manner  of  action  of  this 
drug  is  still  a  subject  of  controversy,  but  it  is  quite  as  probable  that  its 
influence  is  indirect,  through  its  alterative  effect  and  through  increasing 
general  elimination,  as  that  it  acts  directly  by  formation  of  the  soluble 
double  iodide  of  lead  and  potassium;  the  latter  action  in  the  body  is 
purely  hypothetical.  It  seems,  however,  to  be  in  all  forms  of  lead  poison- 
ing the  best  eliminative  available.  Baths  of  potassium  sulphuret  have 
been  recommended  by  a  number  of  Avriters;  the  patient  is  immersed  for 
twenty  minutes  in  a  bath  tub  containing  about  six  inches  depth  of  water 
in  which  six  or  seven  ounces  of  potassium  sulphuret  have  been  dis- 
solved. The  pains  of  lead  colic  should  be  controlled  by  hot  applications, 
or,  if  severe,  by  w^arm  baths  or  hypodermics  of  atropine  or  pilocarpine, 
avoiding  morphine  unless  the  pain  is  so  extreme  and  uncontrollable  that 
it  must  be  used;  though  it  controls  the  immediate  symptoms,  morphine 
interferes  with  the  ultimate  purpose  of  treatment  in  that  it  reduces  elimi- 
nation of  lead  and  of  general  metabolic  products  through  the  kidneys,  and 
usually  interferes  with  bowel  movements,  and,  in  rare  instances,  it  has 
brought  on  dangerous  or  even  fatal  cerebral  symptoms,  probably  due  to 
uraemia.  Oliver  warmly  recommends  monosulphite  of  soda  in  doses  of 
5  grains  (0.3  gm.)  for  both  colic  and  paralysis  in  mild  cases;  my  results 
with  it  have  been  unsatisfactory. 

Paralysis  should  be  treated  by  the  general  principles  used  in  managing 
peripheral  neuritis.  Active  treatment  should  be  begun  only  when  the 
acute  progress  of  the  palsy  has  ceased.  The  most  important  measures  are 
electricity,  carefully  graduated  massage  wnth  passive  exercises,  and,  so 
far  as  possible,  very  slowly  increased  active  exercise.  The  treatment 
must  be  continued  for  montlxs,  and  if  complete  recovery  does  not  occur 
it  should  not  be  stopped  until  all  improvement  has  ceased  for  months. 
Since  there  is  usually  decided  impairment  of  the  general  health  in  these 
cases,  general  treatment  is  almost  as  important  as  local.  Moderate 
general  exercise,  provided  the  paralysis  permits  of  it,  as  it  nearly  always 
does,  should  be  used  after  a  preliminary  rest  in  bed;  fresh  air,  sun- 
shine, and  a  generous  diet,  must  be  insisted  upon  at  all  times  when  they 
can  be  had.  Bitter  tonics  are  useful.  Strychnia  is  not  in  as  good  repute  as 
a  cure  for  paralysis  as  it  once  w^as,  but  is  an  excellent  general  tonic  and 
stomachic,  and  certainly  will  do  no  harm  if  used  only  after  evidences  of 
increase  in  the  paralysis  have  clearly  ceased.  The  anaemia  that  is  usually 
present  needs,  especially,  fresh  air  and  food;  but  small  doses  of  arsenic 
(loo   grain    continued    for   only  short    periods,    as   arsenic   also   causes 


CHRONIC  LEAD  POISONING  113 

nerve-degeneration)  will  often  improve  both  the  anjemia  and  general 
nutrition.  Iron  is  not  very  effectual  in  such  anaemias,  and  if  given  should 
be  used  sparingly,  lest  it  disturb  digestion  and  increase  constipation. 
The  general  measures  mentioned  are  likely  to  be  necessary  in  any  case, 
w^hether  paralysis  is  present  or  not,  in  order  to  secure  recovery  of  good 
general  health. 

Cerebral  symptoms  need  to  be  managed  with  much  care.  There  is  so 
much  danger  of  exhaustion  that  severe  eliminative  measures  should  not 
be  used.  The  bowels  must  be  kept  moderately  active,  and  diuresis  should 
be  stimulated,  especially  by  free  water  drinking  and  by  enteroclysis  with 
large  amouuts  (a  quart  or  more)  of  normal,  or  preferably  half-normal, 
salt  solution  at  115°  or  120°  F.  Convulsions  or  delirium  should  be  treated 
with  large  doses  of  bromides,  combined  with  hyoscine  or  chloral.  Mor- 
phine should  not  be  used  except  as  a  last  resort,  and  then  with  care,  because 
of  its  interfering  with  elimination.  Moderate  venesection  is  a  more 
suitable  measure  in  actively  severe  cases  than  is  generally  taught;  there 
is  sufficient  evidence  of  cerebral  congestion  to  justify  it  in  such  cases. 
Good  results  have  several  times  been  obtained  from  lumbar  puncture, 
and  it  is  possible  that  it  is  reasonable  to  use  it  if  the  symptoms  are  persist- 
ent and  urgent,  but  only  in  such  cases. 

In  both  prophylaxis  and  treatment  it  is  of  the  greatest  importance  to 
exclude  alcohol  absolutely. 


CHAPTER  VI. 

CHRONIC  ARSENIC   POISONING. 
By  DAVID  L.  EDS  ALL,  M.  D. 

The  intense  general  interest  in  chronic  poisoning  by  arsenic,  that  was 
at  one  time  exhibited  by  the  lay  public  as  well  as  the  medical,  has  well- 
nigh  disappeared;  and  with  good  reason,  because  the  opportunities  for 
poisoning  are  now  far  less  numerous  and  less  obscure.  At  present,  with 
the  exception  of  arsenical  beer,  which  is  of  interest  chiefly  in  Great 
Britain,  the  occasion  for  poisoning  is  given  almost  solely  by  a  limited 
number  of  occupations,  by  criminal  or  suicidal  use,  or  by  the  therapeutic 
administration  of  the  drug.  There  are  still  a  small  number  of  articles 
used  by  the  public  in  the  manufacture  of  which  arsenic  is  employed  in  such 
quantities  as  to  make  them  somewhat  dangerous  to  those  who  purchase 
them;  but  this  is  at  present  of  small  moment  as  compared  with  the  past. 
To  the  clinician  chronic  arsenic  poisoning  remains,  nevertheless,  and 
will  continue  to  be,  of  constant  and  rather  especial  interest  because,  unless 
somewhat  cautious  in  the  use  of  arsenic,  he  may  see  chronic  poisoning  as  a 
result  of  his  own  administration  of  the  drug;  he  is  indeed,  much  more 
likely  at  present  to  see  intoxication  from  this  source  than  from  any  other 
that  acts  through  prolonged  ingestion  of  small  quantities,  unless  he  has  an 
unusual  situation  in  regard  to  occupations  that  cause  exposure.  The  con- 
dition is,  however,  also  of  special  interest  because  chronic  sequels  of 
acute  poisoning  occur  not  infrequently.  Most  of  the  chemicals,  such  as 
lead,  that  produce  chronic  disease,  if  taken  for  a  long  time  in  small 
amounts,  rarely  cause  lesions  of  prolonged  or  persistent  course  when  only 
a  single  large  dose  or  a  few  such  doses  are  taken.  Local  effects  of  direct 
irritation — gastro-enteritis  and  the  like — may,  of  course,  remain;  but  the 
patient  otherwise,  usually  gets  entirely  well  without  general  disorder,  if  he 
escapes  such  accidents  with  his  life.  A  few  of  these  chemicals,  however, 
do  cause  chronic  general  evil  effects  as  a  consequence  of  acute  poisoning, 
and  of  this  group,  arsenic  is  a  prominent  member;  arsenical  neuritis  not 
uncommonly  results  from  a  single  dose  taken  by  accident  or  in  an  at- 
tempt at  suicide. 

Etiology. — Because  of  the  subtle  danger  to  the  public  at  large,  more 
interest  has  been  exhibited  in  poisoning  from  various  articles  in  domestic 
use  than  from  any  other  source.  Wall  paper  in  particular  caused  many 
cases  of  poisoning  and  excited  lively  general  apprehension.  The  danger 
from  this  source  was  pointed  out  by  Gmelin,  in  1839,  but  aroused  no 
special  interest  until  Basedow,  in  1846,  demonstrated  its  clinical  import- 
ance; and  his  observations  caused  the  passing  of  a  Prussian  law  forbid- 
ding the  use  of  arsenic  in  dyeing  paper.  It  was  not  until  many  years 
later  that  active  attention  was  given  to  the  subject  in  this  country  and 

114 


CHRONIC  ARSENIC  POISONING  115 

England.  Chiefly  as  a  result  of  the  reports  of  Draper/  Wood,"  J  J. 
Putnam,  C.  P.  Putnam,  Shattuck  and  others,  so  much  interest  was 
excited  in  this  country  that  manufacturers  were  soon  forced  into  greater 
caution;  but  it  was  only  in  1900  that,  following  the  lead  of  most  European 
countries,  a  law  was  passed  in  Massachusetts  strictly  limiting  the  amount 
of  arsenic  permissible  in  papers  and  articles  of  dress.  This  permits  only 
0.01  grain  per  square  yard  in  dress-goods,  stockings,  etc.,  and  0.1  grain 
per  square  yard  in  papers  and  fabrics  other  than  dress  goods.  As  a  result 
of  this  excitement  and  legislation,  the  conditions  in  the  country  at  large 
have  become  almost  free  from  danger.  Haywood  and  Warner  have 
made  a  series  of  nearly  eight  hundred  quantitative  tests  of  wall  paper  and 
in  only  four  did  the  amount  exceed  the  limit  of  the  Massachusetts  state 
law.  Two  of  these  were  from  England,  one  of  the  few  European  coun- 
tries that  has  no  laws  limiting  the  amount  of  arsenic  in  papers  and  fabrics; 
and  of  five  samples  that  were  very  close  to  the  limit,  four  came  from 
abroad.  These  observations  are  like  those  of  others;  Dr.  Charles  Har- 
rington states  that  he  and  others  in  Massachusetts,  who  have  examined 
many  hundreds  of  samples,  find  regularly  less  than  1  per  cent,  that 
exceed  the  limit  of  the  state  law. 

The  danger  of  arsenical  poisoning,  however,  was  by  no  means  confined 
to  wall  paper;  the  greatest  variety  of  substances  colored  with  arsenic 
produced  poisoning.  It  was  caused  by  papers  of  other  kinds,  used  for 
wrapping  purposes,  for  making  paper  flowers,  playing  cards,  and  for 
various  other  purposes;  it  was  seen  as  a  result  of  the  use  of  arsenical 
book  covers,  crayons,  arsenical  paint  used  for  interior  work,  and  numer- 
ous other  objects  of  diverse  kinds,  particularly  bedroom  hangings  and 
clothing  of  various  sorts — stockings,  hat  bands,  gloves,  and  dress  goods 
of  numerous  kinds.  It  is  not  to  be  wondered  at  that  the  public  became 
excited  and  apprehensive.  There  was,  and  to  some  extent  still  is,  an 
impression  that  green  is  the  chief  or  only  color  likely  to  be  arsenical. 
This  is  a  wholly  wrong  impression.  Red  was  very  commonly  arsenical, 
and  various  other  colors  frequently  so;  in  Charles  Putnam's  remarkable 
observations  of  poisoning  in  infants,  the  cause  was  the  blue  dresses  worn 
by  the  nurses.  The  danger  from  this  source  also  is  now  slight  as  com- 
pared with  the  conditions  a  decade  or  two  ago,  but  Haywood  and  Warner 
found  in  1904  that  over  11  per  cent,  of  samples  of  dress  goods  and  over 
29  per  cent,  of  stockings  contained  amounts  that  were  excessive  though 
not  highly  dangerous.  Goods  colored  red  are  particularly  likely  to  contain 
large  amounts,  though  black  and  green  goods  often  yielded  considerable 
quantities.  Another  source  that  is  evidently  of  some  importance  at  present 
is  furs  and  rugs,  which  are  cured  with  arsenic;  8  samples  of  rugs  were 
found  to  contain  over  J  grain  of  arsenic  per  square  yard,  6  of  these  con- 
tained over  1  grain,  and  in  one  the  amount  exceeded  5  grains,  while  in 
one  it  was  just  below  17  grains  per  yard.  The  greatest  danger  from  furs 
is  local  irritant  action  because  of  the  manner  in  which  they  are  worn; 
but  general  poisoning  may,  of  course,  occur. 

Foods,  in  earlier  times,  were  a  frequent  source  of  danger,  and  repeatedly 
caused  both  acute  and  chronic  poisoning,  arsenic  having  been  used  to 
preserve  the  color  of  foods,  to  keep  them  from  decomposing,  and  also  to 

^Report  of  State  Board  of  Health  of  Massachusetts,  1872, 
Ubid.,  1884, 


116  DISEASES  DUE   TO   CHEMICAL  AGEXTS 

provide  attractive  artificial  colors.  Large  epidemics,  such  as  those  at 
Wiirzburg,  Bronicn,  Paris,  Hyores,  and  clsewiiere,  resulted  at  times,  and 
isolated  cases  were  not  uncommon.  At  present  this  danger  has  practically 
disappeared  as  foods  are  now  too  closely  watched. 

There  are  a  t'tw  other  sources  of  accidental  poisoning  that  are  still 
occasionally  active.  Acute  cases  sometimes  occur  from  arsenical  fly 
paper  or  rat  poisons  and  may  have  chronic  results.  Kebler  has  suggested 
that  chronic  poisoning  might  occur  from  the  use  of  certain  common  drugs 
that  are  likely  to  contain  small  amounts  of  arsenic  as  an  impurity;  sodium 
sulphate,  for  instance,  may  contain  appreciable  amounts,  and  this 
drug  is  often  used  daily  throughout  years.  INIr.  Haywood  states  that,  in 
investigating  a  factory  which  tlischarged  arsenical  fumes,  he  found  that 
appreciable  quantities  of  arsenic  were  recoverable  from  the  water  of 
neighboring  streams  even  when  collected  several  miles  from  the  plant; 
under  such  circumstances  the  drinking  water  might  readily  be  the  source 
of  chronic  poisoning.  The  fear  that  the  use  of  arsenic  as  an  insecticide, 
more  particularly  the  use  of  Paris-green  against  potato  bugs,  might  result 
in  poisoning  through  eating  the  potatoes,  seems,  from  the  investigations 
of  Kedzie,^  to  be  groundless. 

Beer  drinking  has  been  an  extremely  important  and  very  disquieting 
source  of  poisoning  recently  in  Great  Britain,  Kelynack  and  Kirkby"  in 
particular  having  studied  this  point  extensively.  The  arsenic  was  derived 
from  the  sulphuric  acid  used  in  manufacturing  the  glucose  that  is  em- 
ployed in  making  beer.  The  conditions  in  regard  to  this  point  have  not 
been  investigated  in  this  country,  but  probably  if  there  is  any  such  danger 
here,  it  is  very  much  less  than  in  Great  Britain;  the  sulphuric  acid  used 
in  the  latter  country  has  heretofore  been  manufactured  largely  from 
markedly  arsenical  iron  pyrites  while  in  this  country  iron  pyrites  is  much 
less  used,  and  when  used  it  is  much  less  arsenical.  Most  of  the  sulphuric 
acid  used  in  this  country  is  manufactured  from  brimstone  or  by  the  con- 
tact method,  and  is  then  free  from  arsenic. 

The  occupations  that  cause  danger  are  more  limited  in  number  than 
they  were.  In  those  that  remain  dangerous,  poisoning  can  be  very 
largely  prevented  by  insisting  upon  proper  cleanliness  and  by  instituting 
measures  to  control  dust,  etc.  The  mines  at  Deloro,  Ontario,  for  example, 
have  become  quite  distinguished  for  the  care  adopted  in  protecting  the 
workmen,  and  for  the  success  obtained.  The  chief  dangerous  occupa- 
tions are  the  mining  and  smelting  of  arsenical  compounds  and  of  ores 
containing  considerable  quantities  of  arsenic,  among  the  latter  being 
particularly  zinc,  silver,  and  lead.  Those  engaged  in  Avorking  upon  the 
skins  of  animals  and  birds,  some  hat  makers,  and  dye  makers,  are  also 
exposed  to  poisoning.  In  occupational  poisoning,  skin  symptoms  are  the 
most  common  chronic  results. 

The  chief  sources  of  poisoning,  however,  are  at  present  suicidal  or 
accidental  ingestion  of  toxic  amounts  of  arsenic,  or  large  or  prolonged 
dosage  for  therapeutic  purposes.  This  source  in  particular  has  been 
frequently  discussed  in  this  country  and  abroad,  and  extensive  collections 
of  the  literature  have  been  made  by  Irabert-Gourbeyre,  Brouardel,  and 

'  Report  of  State  Board  of  Health  of  Michigan,  1875. 

^Arsenical  Poisoning  in  Beer  Drinkers,  Ballidre,  Tindall  &  Cox,  London, 
1901. 


CHRONIC  ARSENIC  POISONING  117 

Marik.  Poisoning  from  therapeutic  use  of  arsenic  has  usually  occurred 
in  cases  of  skin  disease,  chorea,  pernicious  aniemia  and  other  severe 
anaemias,  or  Hodgkin's  disease,  in  which  conditions  the  drug  is  likely  to 
be  used  for  a  long  time  and  in  large  doses.  It  should  be  remembered  that 
patients  with  skin  diseases  particularly,  have  many  times  produced 
chronic  intoxication  in  themselves  by  continuing  the  use  of  arsenic  with- 
out the  continued  advice  of  a  physician,  and  they  should  be  warned  con- 
cerning this  point. 

The  practice  of  eating  arsenic  for  the  purpose  of  increasing  the  powers 
of  general  physical  endurance,  to  stimulate  sexual  capacity,  or  to  improve 
the  condition  of  the  skin  and  scalp,  has  been  much  discussed  in  connec- 
tion with  the  peasants  in  Styria  in  particular;  the  people  of  some  parts  of 
Hungary,  India,  and  elsewhere  have,  however,  carried  out  the  practice, 
and,  in  a  lesser  degree,  it  has  also  been  prevalent  in  some  countries 
among  women  of  higher  social  station.  Doubt  was  cast  upon  the  exist- 
ence of  the  practice  by  publications  that  followed  v.  Tschudi's  descrip- 
tion of  it,  but  observations  by  Marik, ^  Friedrich  Miiller,  and  others  have 
clearly  shown  that  it  was  once  common  in  Styria,  and  was  being  con- 
tinued only  a  few  years  ago  in  spite  of  legal  restrictions.  It  is  not  so  free 
of  bad  results  as  it  was  once  popularly  considered  to  be,  Marik  and  Miiller 
having  studied  many  cases  that  showed  actual  chronic  poisoning  as  a 
consequence. 

Pathology. — The  lesions  produced  in  chronic  poisoning  have  not  been 
extensively  studied;  opportunity  for  investigating  them  occurs  indeed 
only  rarely,  as  death  is  an  unusual  result  of  chronic  poisoning.  Even 
severe  symptoms  are  usually  recovered  from,  more  or  less  completely, 
and  if  remnants  remain,  postmortem  observations  of  them  are  rarely 
made  until  long  after  the  original  attack.  Skin  lesions,  ansemia,  and 
changes  in  the  nervous  system,  are  most  common.  Gastro-enteritis, 
nephritis,  and  fatty  change  of  the  liver,  vascular  system,  and  muscles,  are 
conspicuous  in  the  acute  poisoning,  but  much  less  so  in  the  chronic  form. 
Of  the  skin  lesions,  pigmentation  is  much  the  most  interesting  from  the 
pathological  as  well  as  the  clinical  standpoint.  It  is  due  to  a  deposit, 
most  marked  in  the  lymphatics  of  the  papillse,  of  a  pigment  that  is  of  some- 
what uncertain  origin;  it  has  not  been  satisfactorily  determined  whether 
or  not  it  is  derived  from  hsemoglobin. 

The  nervous  lesions  have  been  studied  by  Erlicki,  Rybalkin,  Henschen 
and  Hildebrand  in  human  subjects,  and  experimentally  by  Schaffer  and 
others.  The  effects  are,  in  the  severe  cases  at  any  rate,  probably 
exerted  on  both  the  peripheral  nerves  and  the  spinal  cord.  In  the  cord, 
arsenic  produces  chiefly  degeneration  and  atrophy  of  the  cells  of  the 
anterior  horns,  sometimes  degeneration  of  the  white  matter.  Schaffer 
described  changes  in  rabbits  that  he  considered  somewhat  peculiar  to 
arsenic,  but  there  is  nothing  distinctive  of  the  lesions  as  a  rule.  In  human 
subjects  the  peripheral  nerves  suffer  most  markedly;  they  show  degen- 
eration of  the  myelin,  which  is  often  of  segmentary  form,  and  may 
leave  the  axis  cylinder  entirely  uninvolved.  The  latter  is,  however,  often 
affected,  and  at  times  so  much  so  that  it  can  be  distinguished  only  "v\dth 
difficulty. 

'  Wien.  Klin.  Woch.,  1891,  Nos.  31-40. 


118  DISEASES  DUE  TO  CHEMICAL  AGENTS 

Mode  of  Entrance  and  Pathogenesis.— The  commonest  mode  of 
entrance  is  thenijXHitic,  suicidal,  or  accidental  administration  by  the  mouth. 
It  has,  however,  been  clearly  shown  that  severe  general  lesions  may  be  pro- 
duced by  means  of  external  application;  this  lias  occurred  with  arsenical 
"cancer  cures."  ■  Arsenic  may  also  be  inhaled  as  dust  in  some  occupations, 
and  the  volatile  compomids  of  arsenic  are,  of  course,  readily  taken  in  by 
respiration.  Chronic  poisoning  from  wall  paper  proved  to  be  of  much  inter- 
est in  the  latter  regard.  It  was  by  many  thought  to  be  due  to  arsenical  dust 
from  the  paper,  but  it  was  demonstrated  by  the  work  of  Fleck,  Selmi, 
Hamberg,  Sanger,  and  others,  particularly  by  Gosio,  that  the  view  that  a 
volatile  compound  was  formed,  is  correct.  Poisoning  from  this  source  was 
probably  due  chiefly  to  this  fact.  The  volatile  compound  is  apparently 
arseniuretted  hydrogen  and  is  ])roduced  by  a  number  of  moulds,  among 
which  pcniciUium  hrcvicanh  is  the  most  important.  The  energetic  capacity 
of  the  latter  organism  to  produce  this  volatile  arsenical  compound  has  since 
been  used  to  a  considerable  extent  as  a  means  of  demonstrating  the  pres- 
ence of  arsenic  in  organic  matter,  especially  in  toxicological  work,  exceed- 
ingly minute  amounts  thus  becoming  apparent.  The  moulds  act  well  at 
room-temperature  and  in  the  presence  of  oxygen,  and  their  growth  is  fur- 
thered by  moisture  and  by  the  adhesive  paste  used  in  fastening  the  paper 
to  the  wall. 

The  manner  in  which  arsenic  acts  on  entering  the  system  is  a  subject 
chiefly  of  speculation,  but  some  suggestions  that  have  been  made  are 
interesting.  In  small  doses,  it  seems  to  stimulate  the  bone-marrow  to 
blood-formation ;  in  large  doses,  to  produce  degeneration  of  the  marrow 
and  cause  anaemia.  Very  large  doses  set  up  general  tissue  destruction. 
The  effect  upon  the  nervous  system,  as  well  as  some  other  effects,  are 
thought  by  certain  authors  to  be  due  to  the  formation  of  arsenic  acid  from 
arsenious  acid,  and  to  the  substitution  of  the  phosphoric  acid  in  lecithin 
by  this  arsenic  acid.  Many  of  the  local  effects  are  due  to  excretion;  this 
occurs  chiefly  through  the  kidneys,  but  also  through  the  skin  and  various 
mucous  membranes  and  glands,  such  as  the  liver  and  the  breasts. 
Mother's  milk  has  caused  fatal  poisoning  of  infants.  Many  instances  of 
disease  of  the  skin,  conjunctiva,  etc.,  are  due  to  excretion,  though  many 
are  due  to  direct  external  local  action. 

Individual  susceptibility  plays  a  large  part  in  determining  the  occur- 
rence of  poisoning.  Less  than  a  fluid  ounce  of  Fowler's  solution  taken 
over  a  period  of  a  few  weeks  has  caused  severe  intoxication;  while 
large  doses  are  definitely  known  to  have  been  taken  for  therapeutic 
purposes  for  even  thirty  years  or  longer  without  ill  effects,  and  arsenic 
eaters  have  apparently  accustomed  themselves  to  frequent  doses  of 
several  grains,  continued  with  impunity  for  very  many  years.  Some 
animals  have  considerable  natural  immunity,  and  in  some  birds  the 
immunity  is  possibly  complete.  There  is  still  a  certain  degree  of  ques- 
tion whether  a  natural  immunity  can  be  increased  in  animals  or  man. 
It  has  appeared  altogether  probable  that  in  some  instances  this 
does  occur,  but  the  work  of  Cloetta  suggests  that  the  apparent 
immunity  is  due  to  lack  of  absorption  of  the  solid  preparations  by  the 
mucous  membrane.  In  animals,  accustomed  to  taking  large  quantities 
by  mouth,  subcutaneous  injection  of  amounts  ordinarily  toxic  produced 
poisoning,  so  that  there  seemed  to  be  no  real  tissue  immunity. 


CHRONIC  ARSENIC  POISONING  119 

Symptoms. — Peripheral  neuritis  and  skin  lesions  are  the  most  impor- 
tant as  well  as  the  most  common  results.  If  these  are  severe  they  may 
cause  secondary  disturbance  of  the  general  health.  In  many  instances, 
indeed,  some  degree  of  general  disorder  develops  coincidently  with  the 
local  lesions,  or  before  them;  but  not  infrequently  marked  disease  of  the 
skin  or  nervous  system  occurs  without  other  noteworthy  disturbance  of 
health.  If  general  symptoms  are  present,  they  are  chiefly  anaemia,  ema- 
ciation, general  weakness,  irregularity  or  weakness  of  the  heart  action, 
and  vasomotor  disturbance.  There  is  also  more  or  less  disorder  of  the 
gastro-intestinal  tract,  occasionally  evidences  of  chronic  nephritis  are 
present,  and  exceptionally  other  symptoms,  but  one's  attention  is  ordinarily 
directed  chiefly  to  the  skin  or  the  nervous  system. 

Vasomotor  changes  are  probably  the  chief  cause  of  one  of  the  frequent 
and  somewhat  important  skin  manifestations ;  namely,  hyperidrosis.  This 
is  often  very  marked  and  may  lead  to  severe  maceration  of  the  skin, 
especially  that  of  the  palms  and  soles,  in  which  situations  hyperidrosis, 
as  is  usually  the  case,  is  most  pronounced.  The  condition  resembling 
erythromelalgia  which  was  repeatedly  seen  by  Kelynack  and  Kirkby  in 
beer  drinkers,  and  occasionally  by  other  observers,  is  probably  due  chiefly 
to  vasomotor  changes,  though  often  associated  with  arteriosclerosis;  in 
this  condition,  painful  patches  of  dusky-red  or  purple  color,  usually  with  a 
well-defined  border,  appear  particularly  on  the  soles  and  sides  of  the  feet. 
This  condition  is  often  but  not  always,  associated  with  signs  of  neuritis. 
Herpes  is  an  occasional  skin-lesion,  and  is  sometimes  very  severe  and 
refractory;  it  may  occur  on  the  trunk  or,  at  times  on  the  face,  extremities, 
or  prepuce.  It  has  frequently  been  associated  with  neuritis.  Workers  in 
arsenic  in  particular,  sometimes  also  those  poisoned  by  ingestion  of  the 
drug,  have  a  marked  tendency  to  ulcers  of  the  parts  especially  exposed, 
particularly  those  parts  subject  to  attrition;  and  these  ulcers,  as  a  rule, 
heal  very  slowly  and  are  often  very  distressing.  Glossiness  of  the  skin  is 
also  common. 

The  most  striking  skin  symptoms  are  keratosis  and  pigmentation. 
Keratosis  occurs  chiefly  on  the  palms  and  soles;  it  may  be  diffuse,  or 
localized  in  small  areas,  and  may  be  of  any  grade  up  to  the  most  severe. 
Ordinarily  marked  desquamation  takes  place  in  connection  with  the  kera- 
tosis and  this  may  occur  even  in  large  scales  or  plates.  The  localized 
horny  areas  have  some  tendency  to  become  epitheliomatous. 

Pigmentation  is  extremely  important  clinically.  It  should  be  watched 
for  when  arsenic  is  being  freely  administered,  as  it  is  both  a  warning  of 
the  possible  early  appearance  of  the  graver  nervous  lesions  if  the  drug  is 
continued,  and  is  also  itself  very  disfiguring  and  at  times  very  distressing 
to  the  patient.  Furthermore,  it  has  repeatedly  been  mistaken  for  other 
forms  of  pigmentation,  such  as  that  of  Addison's  disease.  It  varies  in 
intensity  from  a  slight  yellowish-brown  tint  to  a  deep  brown,  and  it  may 
be  diffused  over  the  whole  surface,  when  it  is  usually  of  moderate  or  slight 
degree ;  or,  more  frequently,  it  is  collected  in  local  areas,  particularly  on 
exposed  surfaces,  or  in  the  folds  of  the  joints,  as  the  axilla,  regions  exposed 
to  pressure,  or  in  parts,  such  as  the  nipples,  that  are  normally  pigmented. 
Sometimes  small  spots  of  pigmentation  may  occur,  somewhat  resembling 
moles.  The  mucous  membranes  may  show  pigmentation.  Deep  pig- 
mentation may  be  present  in  local  areas,  together  with  a  higher  degree  of 


120  DISEASES  DUE   TO   CHEMICAL  AGEXTS 

diffuse  discoloration.  As  a  rule,  the  pigment  slowly  disappears  after  ces- 
sation of  the  poisoning,  but  it  may  remain  permanently,  to  a  greater  or 
less  degree. 

A  variety  of  other  lesions  of  the  skin  also  occur.  Erythema  has  very 
frequently  been  seen  and  it  often  shows  bilateral  symmetry;  papular, 
vesicular,  and  bullous  eruptions,  pustules,  and  boils,  are  common,  as  are 
thickening,  brittleness,  and  roughness  of  the  nails,  loss  of  hair,  occasionally 
urticarial,  psoriasis-like,  and  other  eruptions. 

Among  the  manifestations  suggestive  in  diagnosis  is  the  condition  of 
the  exterior  of  the  eyes.  There  is  often  puffiness  of  the  eyelids;  the  con- 
junctiva is  congested  and  frequently  somewhat  swollen;  there  may  be 
marked  chemosis,  and  there  is  often  marked  running  from  the  eyes.  These 
eye  symptoms  have  been  particularly  noted  in  the  cases  due  to|external 
action  of  the  arsenic  or  to  drinking  arsenical  beer;  alcohol  is  probably 
an  associated  factor  in  the  latter  instances. 

Of  the  symptoms  referable  to  the  nervous  system,  paralysis  is  much 
the  most  important,  though  a  considerable  variety  may  be  met.  These 
symptoms  are  nearly  always  the  result  of  internal  use  of  arsenic.  Paral- 
ysis following  a  large  toxic  dose  usually  appears  a  week  or  ten  days,  or 
even  more,  after  the  poisoning,  when  the  acute  symptoms  due  to  disturb- 
ance of  the  gastro-intestinal  tract  and  other  direct  irritative  symptoms 
have  more  or  less  subsided.  A  number  of  cases  have  been  described, 
however,  in  which  transitory  palsy  appeared  within  a  few  hours  or  a  very 
few  days,  and  in  rare  instances  even  severe  paralysis  has  begun  to  de- 
velop within  three  or  four  days  after  the  acute  poisoning.  On  the  other 
hand,  the  paralysis  may  be  delayed  several  weeks,  and  the  patient  may 
show  no  symptoms  in  the  interval  following  the  acute  symptoms.  Par- 
alysis has  even  been  delayed  for  a  year  (Perkins),  the  interval  in  this  in- 
stance having  been  filled  with  distressing  pains.  In  chronic  poisoning 
the  time  of  appearance  of  paralysis  depends,  of  course,  upon  the  dose,  and 
upon  individual  susceptibility.  It  has  developed  after  three  or  four 
weeks' use  of  arsenic,  but,  naturally,  it  often  appears  much  later. 

Paralysis  is  usually  preceded  by  disturbances  of  sensation.  Contrary 
to  the  conditions  in  lead  palsy,  paresthesias  and  particularly  pain  are 
very  common.  Pain  is  strikingly  frequent  and  extremely  distressing, 
both  before  the  paralysis  appears  and  for  some  time  after  it  has  developed; 
its  frequency  and  severity  constitute,  indeed,  important  indications  of 
arsenic  poisoning.  The  nerve  trunks,  also,  are  frequently  sensitive  to 
pressure,  and  the  skin  may  be  extremely  hyperalgesic  upon  touch  or  pres- 
sure. With  the  progress  of  the  palsy,  all  qualities  of  skin  sensation  be- 
come reduced  or  lost,  the  legs  and  feet  usually  showing  the  most  marked 
changes.  Curious  anomalies  of  sensation — polysesthesia,  allochiria,  etc., 
— have   been   seen. 

Motor  palsy  usually  develops  subacutely  in  cases  which  follow  acute 
poisoning;  in  rare  instances  it  appears  very  suddenly.  It  may,  however, 
develop  slowly  even  when  due  to  acute  poisoning,  and  in  chronic  poison- 
ing this  is  generally  the  case.  Like  the  anaesthesia,  it  is  most  marked  and 
most  common  in  the  legs.  Writers  who  have  collected  large  series  of 
cases  agree  in  the  statement  that  the  legs  are  almost  always  affected,  that 
they  are  often  paralyzed  when  the  arms  are  not,  and  that  they  frequently 
suffer  alone.    The  paralysis  has,  however,  a  marked  tendency  to  involve 


CHRONIC  ARSENIC  POISONING  121 

all  extremities.  The  motor  and  the  senstny  j)al,sy  alike  affect  the  distal 
portions  of  the  extremities,  and  very  rarely  extend  above  the  knees  and 
elbows;  while  the  upper  arms,  the  thighs,  the  trunk  muscles,  and  the 
sphincters,  escape.  Both  the  extensors  and  flexors  an;  involved  and  there 
is  no  tendency  to  spare  certain  muscles  as  in  lead  palsy,  all  muscles  of  the 
areas  affected  suffering.  The  extensors  are,  however,  usually  more 
severely  diseased  than  the  flexors.  It  is  very  unusual  for  the  arms  to  be 
affected  without  the  legs,  and  paralysis  localized  to  one  extremity  is  rare, 
though  it  has  occurred. 

The  knee-jerks  are  almost  always  lost  when  palsy  is  at  all  marked. 
Degeneration  reactions  are  present,  and  the  response  to  faradism  is  re- 
duced or  lost.  Atrophy  develops  within  a  few  weeks  and  often  becomes 
extremely  marked.  Contractures  of  much  severity  are  frequent  when 
well-developed  poisoning  has  been  present  for  some  time. 

Cases  of  rapidly  fatal  progress  are  almost  unknown,  but  the  disability 
that  develops  may  be  extreme  and  death  may  occur  with  the  appearances 
of  general  cachexia.  Unless,  however,  the  paralysis  is  very  severe  or  has 
been  long  neglected,  improvement  usually  begins  after  a  few  months  at 
most,  and  it  progresses  in  most  cases  to  complete  or  almost  complete 
recovery,  though  occasionally  marked  disability  remains  permanently. 

In  very  rare  instances,  single  cranial  nerves  have  been  diseased  alone; 
aphonia  from  laryngeal  paralysis  has,  for  example,  been  reported  by 
Morell  Mackenzie  and  Brouardel;  ptosis  has  occurred  and  other  exter- 
nal eye  muscles  have  been  paralyzed.  Lagophthalmus  has  been  described. 
Amblyopia  and  amaurosis  occasionally  appear.  Cloudiness  of  the  lens 
has  been  reported  after  acute  poisoning,  and  is  said  to  occur  as  a  result 
of  chronic  poisoning. 

There  is  an  interesting  and  important  group  of  cases  to  which  attention 
was  directed  by  Dana,^  in  which  ataxia,  particularly  of  the  legs,  is  so 
conspicuous  a  feature  that  it  may  readily  lead  to  a  diagnosis  of  tabes 
dorsalis,  unless  the  mode  of  onset,  the  presence  of  neuritis,  and  the  ab- 
sence of  involvement  of  the  sphincters,  are  carefully  noted.  Psychic 
symptoms  sometimes  occur,  more  especially  in  severe  and  prolonged  cases. 
They  are  chiefly  loss  of  memory  and  general  weakness  of  intellect  that 
may  progress  to  pronounced  dementia.  Sometimes  hallucinations  are 
conspicuous. 

Diagnosis. — If  a  source  of  poisoning  is  recognized  and  the  nature  of  the 
case  thereby  suggested,  there  is,  as  a  rule,  little  difficulty  in  diagnosis. 
With  skin  lesions  particularly,  and  more  especially  with  keratosis  or  pig- 
mentation, arsenic  should  be  considered  and  a  source  sought  for.  If  sug- 
gestive symptoms  develop  in  a  patient  who  has  been  under  treatment  for 
chronic  skin  disease,  malaria,  anaemia,  glandular  enlargement,  chorea, 
or  other  disorders  in  which  arsenic  is  frequently  used  freely,  the  possi- 
bility of  poisoning  should  always  be  suspected.  This  will,  of  course, 
occur  to  the  attendant  if  he  is  himself  giving  arsenic.  The  pains,  since 
they  may  occur  without  any  paralysis,  or  may  long  precede  paralysis,  are 
likely  to  be  mistaken  for  neuralgia  dependent  upon  other  causes,  or  be  put 
under  the  crude  class  of  "rheumatic  pains."  These  mistakes  are  avoid- 
able only  by  a  proper  investigation  of  the  nature  of  any  persistent  pains. 

1  Brain.,  vol.  ix,  1886-87. 


122  DISEASES  DUE  TO  CHEMICAL  AGE}^TS 

Tlic  paralysis  may  have  to  be  distinguished  from  lead  palsy,  alcoholic 
neuritis,  and  neuritis  due  to  various  infections  and  other  causes.  Lead 
palsy  is  usually  readily  excluded  by  the  severe  pains  and  other  sensory 
disturbance,  the  more  marked  involvement  of  the  legs  than  the  arms,  the 
distal  localization,  and  the  paralysis  of  muscles  that  escape  in  lead  poison- 
ing. The  other  conditions  will  be  excluded,  as  a  rule,  only  by  finding  a 
source  of  arsenic,  or  by  searching  for  arsenic  in  the  urine.  If  a  person 
^yho  has  no  history  of  alcoholic  or  infectious  cause  for  a  neuritis,  develops 
j)eri{)heral  palsy,  particularly  associated  with  severe  pains  and  the  other 
characteristics  of  arsenical  paralysis,  a  source  of  arsenic  should  be  carefully 
searched  for,  and  the  urine  should  be  examined  for  it.  A  negative  result 
of  the  latter  examination  is  not  distinctive,  for  arsenic  is  not  constantly 
present  in  the  urine  even  when  it  is  in  the  system,  and  it  is  usually  entirely 
excreted  within  about  two  weeks  of  the  time  that  ingestion  ceases;  for 
the  latter  reason,  it  may  have  permanently  disappeared  from  the 
urine,  even  though  severe  symptoms  are  still  present.  A  distinctly  posi- 
tive result  by  Reinsch's  test  is  of  much  importance;  this  test  may  be 
carried  out  by  any  one  who  has  a  little  skill  in  laboratory  technique;  500 
to  1,000  c.c.  of  urine  should  be  evaporated  at  a  low  temperature  to  about 
one-fourth  the  original  bulk;  one-fifth  part  of  hydrochloric  acid,  free  from 
arsenic,  and  a  piece  of  copper  foil,  are  added  and  the  fluid  boiled  for  fifteen 
minutes.  If  arsenic  is  present  the  surface  of  the  copper  becomes  grayish, 
or,  if  there  is  a  large  quantity,  it  turns  a  deep  blackish-gray.  The  fact 
that  arsenic  is  present  may  then  be  definitely  determined  by  the  sublima- 
tion test,  which  gives  a  crystalline  mirror  of  arsenious  acid.  If  this  test 
gives  a  doubtful  result,  a  trained  chemist  must  be  called  in  to  decide  the 
question. 

Cases  due  to  arsenical  wall  paper,  carpets,  dress  goods,  etc.,  are  now 
very  rare;  the  diagnosis  will  depend  solely  upon  chemical  investigation 
of  suspicious  objects  and  of  the  urine.  In  this  class  the  symptoms  have 
often  been  obscure,  and  if  so,  whatever  the  source  of  the  arsenic,  the  diag- 
nosis is  likely  to  be  suspected  only  in  case  there  is  a  careful  consideration 
and  search  for  all  possible  causes  of  the  disorder. 

Prognosis. — The  main  points  concerning  the  course  of  the  poisoning 
have  already  been  discussed.  General  symptoms,  unless  very  severe  and 
protracted,  usually  disappear  gradually  if  properly  treated ;  and,  if  the 
poisoning  ceases,  the  skin  disorders  are  usually  recovered  from,  though 
often  slowly.  Keratosis  or  ulcers  occasionally  become  epitheliomatous  or 
run  a  very  long  course  in  spite  of  exclusion  of  the  cause.  Pigmentation, 
as  a  rule,  greatly  improves  or  disappears,  though  at  times  disfigurement 
remains  permanently.  The  nervous  symptoms  are,  in  general,  of  good 
prognosis;  like  all  toxic  paralyses,  however,  those  due  to  arsenic  are  oc- 
casionally permanent,  or  show  little  improvement  if  they  have  reached  a 
severe  grade,  and  especially  if  treatment  is  long  delayed.  Marked  psychic 
symptoms  are  unusual;  since  they  are  commonly  due  to  advanced  or  pro- 
tracted poisoning,  they  are  of  very  doubtful  prognosis  but  severe  stages 
may  be  recovered  from. 

Prophylaxis  and  Treatment. — The  prophylaxis  of  industrial  poisoning 
should  follow  the  principles  discussed  under  lead  poisoning.  When  these 
are  properly  used  they  prevent  a  very  large  proportion  of  the  evil  results. 
Intoxication  from  therapeutic  use  of  arsenic  can  usually  be  avoided  by 


CHRONIC  ARSENIC  POISONING  123 

care  in  administration;  even  in  diseases  such  as  pernicious  anaemia,  in 
which  large  doses  are  often  necessary  for  a  long  time,  severe  symptoms 
can  be  prevented  by  watching  for  gastro-intestinal  disturbance,  signs  of 
renal  irritation  and,  particularly,  by  observing  slight  pigmentation  and 
other  mild  chronic  toxic  effects. 

The  treatment  must  be  regulated  according  to  the  conditions  to  be 
cared  for.  Potassium  iodide  in  moderate  doses,  5  grains  (0.3  gm.) 
after  meals,  is  generally  considered  a  useful  eliminant,  but  there  is  no 
specific  treatment.  Skin  lesions  should  be  managed  in  accordance  with 
the  individual  case,  and  paralysis  should  be  treated  as  multiple  neuritis 
is  treated.  In  the  earlier  stages  of  the  latter,  pain  will  frequently  be  a 
troublesome  feature,  and  will  require  symptomatic  treatment,  the  ex- 
tremities being  protected  from  pressure  of  bedclothes,  etc.,  the  pains 
controlled  by  warm  applications,  hot  baths,  or  if  necessary,  coal  tar  prep- 
arations or  opiates.  Rest  is  essential  until  all  irritative  symptoms  are 
past.  Carefully  graduated  massage,  electricity,  and  passive  movements, 
with  slowly  increased  active  exercise,  must  be  used  persistently.  Avoid- 
ance of  alcohol  and  careful  regulation  of  the  hygiene  of  life  are  to  be  in- 
sisted upon. 


CHAPTER  VII. 

OTHER    METALLIC    POISONS,    MERCURY,    PHOSPHORUS, 

ETC. 

By  DAVID  L.  EDSALL,  M.D. 
CHRONIC  MERCURY  POISONING. 

Under  this  heading  will  not  be  considered  the  acute  and  subacute 
symptoms  included  under  the  term  ptyalism,  but  only  those  disorders 
that  are  of  more  direct  interest  to  the  medical  clinician. 

The  fact  that  mercury,  besides  causing  ptyalism,  may  produce  chronic 
poisoning  has  certainly  been  known  since  the  early  part  of  the  Christian 
era  and  it  has  been  recognized  in  medical  writings  for  at  least  twelve 
centuries.  Marechal,  in  reviewing  the  history  of  chronic  mercurialism, 
refers  to  distinct  medical  evidence  that  it  was  known  as  far  back  as  850 
A.  D.;  and  according  to  Dieterich,  Rhazes  recognized  clearly  that  it  may 
produce  nervous  symptoms.  Lively  interest  in  the  subject  was  not 
awakened,  however,  until  the  controversy  between  the  mercurialists  and 
the  antimercurialists,  in  the  sixteenth  century,  showed  its  importance; 
and  the  first  distinct  description  of  tremor,  disturbance  of  speech,  and 
other  nervous  disorders,  as  direct  effects  of  mercury,  is  said  by  Marechal 
to  have  been  written  in  1519,  by  a  layman,  the  chevalier  Ulrich  von  Hutten, 
who  observed  them  in  his  own  person  as  a  result  of  treatment  for  syphilis. 
In  such  cases  even  to  the  present  time,  there  is  doubt  whether  the  symp- 
toms were  due  to  the  mercury  or  to  the  syphilis;  but  Fernel,  in  1557,  de- 
scribed a  case  in  which  chronic  poisoning  occurred  in  a  man  who  was  not 
syphilitic  and  who  had  not  taken  mercury  medicinally,  but  who  had 
worked  with  the  metal.  Occupational  poisoning,  with  nervous  symp- 
toms, was  recognized  by  Ramazzani.  Jussieu,  in  1719,  described  the 
conditions  in  the  mines  at  Almaden;  Astruc,  in  1738,  contributed  an 
elaborate  and  valuable  description;  and  in  the  century  that  has  just 
passed,  there  were  numerous  observations  and  studies,  among  which  that 
of  Kussmaul  is  classical. 

Etiology. — The  importance  of  chronic  mercurial  poisoning  has  largely 
decreased  in  recent  years,  partly  because  much  greater  care  is  now  exer- 
cised in  using  mercury  medicinally,  but  much  more  because  in  a  number 
of  industries  in  which  mercury  poisoning  was  once  common,  this  metal  is 
not  now  used,  or  the  industries  themselves  have  given  way  to  others  that 
accomplish  the  same  purpose.  In  mirror  making,  for  example,  mercury 
has  been  replaced  by  silver;  and  fire  gilding  and  silver  plating  with  the 
aid  of  mercury  have  almost  or  quite  disappeared,  electroplating  and  roll 

124 


OTHER  METALLIC  POISONS  125 

plating  having  taken  their  place.  Besides  the  occupations  mentioned, 
the  preparation  of  mercurial  pigments,  their  use  in  paints,  in  the  making 
of  artificial  flowers,  dyes,  etc.;  the  use  of  amalgams  in  making  gold  and 
silver  jewelry;  the  exhausting  of  incandescent  light  bulbs  with  mercury 
pumps;  the  preparation  of  fulminate;  the  manufacture  of  fireworks;  the 
production  of  some  aniline  colors;  and  the  preparation  of  the  skins  of 
animals  and  birds,  has  produced  chronic  poisoning.  Mercury  has  been 
used  in  all  these  processes,  and  in  some  parts  of  the  world  is  still  used  in 
many  of  them.  Most  of  these  occupations,  however,  are  at  present  of 
very  little  consequence  in  this  regard. 

The  chief  industries  in  which  this  poisoning  is  now  seen  are  mercury 
mining  and  smelting,  the  manufacture  of  thermometers,  barometers,  and 
other  physical  apparatus  of  which  mercury  is  an  essential  part,  and  the 
manufacture  of  felt  hats,  the  acid  nitrate  of  mercury  being  used  in  the 
latter  in  treating  the  felt. 

Mercury  mines  have  long  been  recognized  as  a  fruitful  source  of  saliva- 
tion and  chronic  poisoning:  the  mines  at  Almaden  and  Idria  have  fur- 
nished the  basis  of  a  goodly  part  of  the  literature  on  this  subject,  and 
there  have  always  been  many  cases  among  those  working  in  mercury 
mines.  It  is  even  stated  that  those  living  near  the  mines,  but  not  working 
in  them,  sometimes  show  chronic  poisoning,  and  it  is  said  that  through  a 
fire  in  the  Idria  mines  in  1803,  the  atmosphere  in  the  surrounding  regions 
became  so  laden  with  the  vapor  of  mercury  that  nine  hundred  or  more 
persons  exhibited  mercurial  tremor.  Since  mercury  volatilizes  at  ordinary 
temperatures,  this  danger  could  be  controlled  only  by  ventilation  that  is 
constant  and  thorough,  an  exceedingly  difficult  problem  in  mercury  mines. 
Dr.  Jamison,  of  New  Almaden,  California,  states  that  poisoning  is  still 
very  common  among  the  workmen  in  the  great  mines  there,  but  is  less 
so  than  it  was,  partly  because  the  ore  is  less  rich.  Among  special  sources 
of  salivation,  which  may  also  be  sources  of  chronic  poisoning,  he  mentions 
drinking  water  about  the  mines,  which  is  usually  charged  with  the  metal, 
entering  a  drift  too  soon  after  a  blast,  w^hen  the  air  is  filled  with  fine  par- 
ticles of  mercury,  and  standing  over  the  furnaces  to  free  them  of  wet  ore 
that  has  become  clogged.  Because  of  the  comparatively  small  number 
of  men  employed  in  mercury  mining,  this  source  of  poisoning  is  of  lim- 
ited clinical  importance,  and  the  restriction  of  this  industry  to  a  few  places 
also  serves  to  make  it  of  relatively  little  importance  to  the  profession  at 
large. 

In  this  country  there  are  but  a  few  persons  who  are  exposed.  How- 
ever, these  occupations  are  of  much  interest  to  the  medical  clinician 
when  he  comes  in  contact  with  them,  because  a  considerable  proportion 
of  those  exposed  develop  more  or  less  severe  chronic  poisoning,  and  also 
because  proper  hygienic  arrangements  will  prevent  a  very  large  percentage 
of  these  cases. 

Hat  making,  because  of  the  comparatively  large  number  of  persons 
employed  at  it  and  because  of  the  fact  that  it  is  a  widely  distributed 
industry,  is  of  more  direct  interest  to  the  profession  in  general.  It  has 
been  impossible  to  obtain  any  satisfactory  figures  as  to  the  number  of  per- 
sons in  this  industry  w^ho  are  exposed  to  mercury  poisoning;  it  is  generally 
known,  however,  that  many  cases  of  poisoning  occur.  A  few  years  ago  at 
the  Episcopal  Hospital,  Philadelphia,  employees  from  one  factory  fre- 


126  DISEASES  DUE  TO  CHEMICAL  AGENTS 

quently  appeared  in  the  out-patient  department  or  in  the  wards;  they  are 
now  cared  for  by  special  j)rovision  of  the  proprietors  of  this  factory.  The 
danger  occurs  in  handUng  the  felt  after  the  solution  of  acid  nitrate  of 
mercury,  with  which  it  has  been  treated,  has  dried;  and  poisoning  occurs 
chiefly  through  the  dissemination  of  small  particles  of  dust  in  the  course 
of  cutting  and  fitting  the  felt,  etc.,  possibly  also  through  some  volatiliza- 
tion and  through  tlae  skin  in  handling  the  felt.  Chronic  mercurialism 
also  occurs  among  men  engaged  in  the  production  of  various  salts  of  mer- 
cury in  chemical  plants,  though  to  what  extent  is  difficult  to  determine. 
Salivation  is  not  uncommon  among  them  and  chronic  poisoning  must 
occur  occasionally,  but  it  is  probably  quite  rare. 

Poisoning  from  the  medicinal  use  of  mercury  occurred  not  infrequently 
until  the  danger  became  thoroughly  and  generally  recognized.  At  present, 
chronic  mercurial  poisoning  of  this  source  is  extremely  rare.  It  is  almost 
always  preceded  by  more  or  less  ptyalism,  and  this  is  of  course  sufficient 
to  lead  almost  certainly  to  the  withdrawal  of  the  drug  before  chronic 
mercurialism  appears. 

Accidental  intoxication  very  rarely  occurs  now,  but  it  has  developed  in 
most  curious  and  interesting  ways.  One  of  the  most  striking  of  these  is 
the  story  of  the  ship  "Triumph,"  that  in  1810  sailed  with  a  cargo  includ- 
ing much  mercury  that  was  held  in  containers;  some  of  the  latter  burst, 
and  in  three  weeks,  it  is  said,  many  of  the  persons  on  board  had  some 
of  the  phenomena  of  chronic  mercury  poisoning.  There  are  also  on 
record  instances  of  persons  having  been  poisoned  by  living  in  buildings 
where  mercury  was  used  for  industrial  purposes,  even  when  their  living- 
rooms  were  separated  by  several  stories  from  the  workrooms;  and  there 
is  an  instance  in  which  persons  who  lived  in  a  tenement  developed  mer- 
curial poisoning,  which  investigation  showed  to  be  due  to  the  fact  that 
the  rooms  had  previously  been  used  as  a  mirror  factory.  In  the  last  men- 
tioned series,  the  mercury  had  dropped  through  cracks  in  the  floor  and 
its  continual  volatilization  produced  the  poisoning;  much  mercury  was 
discovered  when  the  floor  was  torn  up.  The  previously  mentioned  wide- 
spread poisoning  from  the  fire  in  the  Idria  mine  is  another  striking 
instance  of  accidental  poisoning. 

Pathology. — So  little  work  has  been  done  on  the  pathology  that  it  can- 
not be  satisfactorily  discussed.  Wising  has  described  degeneration  and 
atrophy  of  the  myelin  in  the  lateral  columns  of  the  cord  and  reduction  in 
the  number  of  fibers,  and  Brauer  has  noted,  experimentally,  degenerative 
changes  in  the  cells  of  the  anterior  horns,  using  the  Nissl  stain.  Letulle 
and  Heller  describe  experimental  neuritis  after  sublimate  injections, 
but  Brauer  considers  this  to  have  been  due  to  the  local  effects  of  the 
injections,  not  to  the  general  action;  and  it  is  probable  that  chronic  mer- 
cury poisoning  rarely  or  never  produces  neuritis.  Prolonged  medicinal 
use,  and  sometimes  occupational  poisoning,  may  cause  ansemia  and 
marked  emaciation,  with  more  or  less  severe  fatty  degeneration  in  various 
organs,  and  chronic  gastro-enteritis  is  quite  a  common  result.  The  occa- 
sional ansemia  and  cachexia,  the  profound  changes  sometimes  seen  after 
severe  acute  poisoning,  especially  in  the  kidneys  and  bowel,  and  the  re- 
markable influence  of  mercury  on  syphilitic  tissues  show  that  it  may  exert 
an  extremely  important  effect  upon  nutritive  processes.  C.  W.  Miller  and 
the  writer  recently  studied  the  influence  upon  autolysis  and  have  contrib- 


OTHER  METALLIC  POISONS  127 

uted  evidence  that  mercury  increases  autolysis.  Probably  this  is  one  way 
at  least  in  which  the  metal  acts  upon  nutrition. 

Mode  of  Entrance. — There  is  overwhelming  evidence  that  mercury 
may  enter  the  system  through  inhalation  as  vapor,  and  it  is  probably  the 
chief  way  in  which  occupational  })oisoning  occurs,  though  absorption 
through  the  skin  seems  to  play  a  role  of  considerable  importance;  and  in 
the  manufacture  of  hats,  the  preparation  of  skins,  and  similar  processes  in 
which  much  dust  is  created,  inhalation  of  actual  particles  occurs.  There 
are  always  ready  opportunities  for  inhalation  poisoning  when  mercury 
itself  is  used,  since  it  volatilizes  at  ordinary  temperatures,  and  further- 
more the  heating  processes  necessary  in  most  of  these  industries  largely 
increase  the  volatilization.  Frequent  ingestion  of  small  particles  is 
probably  a  factor  of  much  importance,  even  in  occupational  poisoning. 
Workers  in  mercury,  like  others  exposed  to  similar  dangers,  grow  sur- 
prisingly careless,  and  one  may  see  them  eating  food  or  fruit,  or  smoking 
cigars  or  pipes,  on  which  there  are  visible  globules  of  mercury;  the  super- 
intendent of  a  large  thermometer  factory  directed  the  attention  of  the 
writer  to  the  fact  that  those  whose  work-tables  were  kept  neat  and  who 
were  careful  as  to  cleanliness  of  the  person  escaped  poisoning  in  a  large 
proportion  of  cases,  even  though  engaged  in  especially  dangerous  parts 
of  the  work. 

Symptoms. — It  is  a  striking  and  generally  recognized  fact  that  saliva- 
tion and  stomatitis  are  very  often  absent  in  the  chronic  cases.  In  exam- 
ining the  mouths  of  a  series  of  cases  in  which  there  were  marked  nervous 
symptoms,  the  writer  found  in  almost  every  instance  that  the  gums  and 
teeth  were  in  fairly  good  condition  for  persons  of  their  social  class  except 
that,  as  is  often  the  case  in  mercury  workers,  the  teeth  showed  blackish 
discoloration.  Sometimes,  however,  persistent  ptyalism  does  develop, 
generally  before  the  nervous  symptoms.  In  the  early  stages  of  poisoning 
and  when  the  condition  is  more  pronounced,  the  patients  often  complain 
of  headache,  restless  sleep  and  marked  depression  and  weakness,  par- 
ticularly in  the  morning;  the  latter  sensation  may  pass  off  later  in  the 
day  so  that  they  often  feel  quite  well  toward  evening.  Several  subjects 
of  mild  poisoning  stated  that  they  had  a  most  abnormal  dread  of  the  ex- 
ertion of  going  to  work  in  the  morning;  later  on,  this  passed  off  and  the 
remainder  of  the  day  they  felt  entirely  cheerful.  Sometimes  anaemia  de- 
velops and,  in  severe  cases,  a  condition  of  general  cachexia  occasionally 
appears.  Gastro-intestinal  disturbance,  particularly  of  the  stomach,  is 
also  not  uncommon,  though  less  frequent  than  one  would  expect.  Neu- 
ralgic pains,  especially  in  the  territory  of  the  trigeminus,  are  quite  common 
in  both  early  and  advanced  stages  and  joint  pains  also  occur.  Dr.  Jami- 
son has  frequently  seen  loss  of  sexual  power,  which  usually  improves  upon 
treatment. 

But  the  most  striking  and  common  features  of  chronic  mercurial  poison- 
ing are  the  tremor  and  the  emotional  disturbance  or  erythism.  These  are 
usually  associated  with  each  other  in  greater  or  less  degree  from  the  begin- 
ning. The  tremor  in  early  stages  is  absent  when  the  subject  is  quiet  but 
appears  upon  voluntary  effort,  especially  upon  finely  coordinated  move- 
ment; and  emotional  influences  usually  have  an  intense  effect  in  increasing 
the  tremor,  bringing  it  out  when  not  otherwise  present.  For  example,  upon 
attempting  to  write  his  name,  particularly  in  the  presence  of  witnesses,  a 


128  DISEASES  DUE   TO   CHEMICAL  AGEXTS 

man  who  is  ordinarily  free  from  tremor  but  who  is  in  the  early  stages  of 
poisoning  may  develop  tremor  at  once.  This  may  be  shght  and  of  small 
amplitude,  but  is  more  likely  to  be  rapid,  gross  movement,  and  is  fre- 
quently so  severe  that  it  at  once  becomes  wholly  impossible  for  the  man 
to  write  legibly.  After  a  few  moments  the  tremor  and  excitement  decrease 
and  within  a  short  time  they  have  nearly  or  quite  vanished.  The  hands 
and  lips  are  chiefly  affected  at  this  stage  and  usually  more  severely  than 
other  parts  at  all  stages;  if  the  condition  is  marked,  however,  most  of  the 
facial  muscles  are  involved  and  all  the  extremities  frequently  show  tremor. 
All  grades  of  severity  may  be  seen,  and  the  phenomenon  in  bad  Ccises  is 
most  remarkable.  ^Yhen  the  tremor  has  grown  actually  troublesome  it  is 
ordinarily  present  in  some  degree  even  when  the  patient  is  at  rest;  it  may 
be  constantly  very  marked  and  in  extreme  cases  may  interfere  with  almost 
all  coordinate  muscular  action;  the  patient  may  become  unable  to  feed 
himself  or  to  stand,  and  cases  have  been  described  that  were  of  such  se- 
verity that  the  patient  had  even  to  be  strapped  in  bed  to  avoid  injury  from 
the  violent  and  general  movements.  Frequently,  however,  the  tremor  is 
comparatively  slight  at  most  times,  even  though  the  response  to  muscular 
action  or  emotional  excitement  is  very  severe.  For  instance,  without  his 
knowing,  the  writer  watched  a  man  blow  spherical  thermometer  bulbs 
of  various  sizes  that  were  necessarily  very  accurately  graduated.  He  had 
slight  tremor  but  it  did  not  interfere  with  this  fine  work,  but  when  spoken 
to,  he  instantly  went  into  general  tremor;  he  could  then  scarcely  hold 
the  tubing  in  his  hands,  the  lips,  facial  muscles,  and  orbicular  muscles 
showed  violent  twitchings  and  contortions,  and  there  was  general  severe 
tremor  of  the  body  and  legs  which  were  so  marked  that  had  he  not  been 
sitting  he  would  have  dropped  to  the  floor.  A  few  minutes  later  he  was 
calmly  at  work  again.  The  tremor  in  bad  cases  may  persist  during  sleep 
but  often  does  not. 

Physical  examination,  even  in  severe  cases,  usually  shows  nothing  be- 
yond the  tremor  except,  perhaps,  slight  or  moderate  muscular  weakness. 
Occasionally  weakness  is  very  marked  even  when  other  symptoms  are 
absent.  Nystagmus  has  been  described  but  is  very  rare.  A  point  of  im- 
portance and  one  that  has  sometimes  caused  confusion  with  multiple 
sclerosis  is  that  owing  to  the  involvement  of  the  muscles  of  articulation 
the  speech  is  frequently  much  disturbed.  It  may  be  of  somewhat  the  same 
irregularly  staccato  type  seen  in  multiple  sclerosis;  but  it  is  usually  evi- 
dent that  the  disturbance  of  speech  is  due  merely  to  the  severe  tremor  of 
the  lips  and  facial  muscles.  Another  point  that  sometimes  lends  resem- 
blance to  multiple  sclerosis  is  the  fact  that  vertigo  is  a  frequent  complaint 
and  at  times  is  so  severe  as  to  cause  the  patient  to  fall. 

Sometimes  there  are  choreiform  movements,  chiefly  in  severe  and  ad- 
vanced cases,  and  in  the  same  t}'pe,  disturbances  of  sensation — usually 
anaesthesia — may  sometimes  be  seen.  Paralysis  also  occasionally  occurs 
in  bad  cases;  it  is  likely  to  be  localized  and  incomplete  and  is  often  not 
permanent.  Choreiform  movements,  anaesthesia,  and  paralysis  are  likely 
to  be  irregularly  distributed  and  limited  to  one  extremity  or  to  one  side. 

Convulsive  attacks  are  described  and  may  be  of  true  epileptic  type, 
though  it  is  not  certain  that  epilepsy  is  ever  due  to  mercury.  Two  other 
forms  of  convulsions  have  been  attributed  directly  to  mercury.  One  of 
them  is  tonic  and  follows  violent  movements  or  hard  work  and  affects 


OTHER  METALLIC   POLSON^  129 

chiefly  the  flexors  of  the  forearm.  This  tonic  spasm  comes  on  chiefly  in 
painful  paroxysms  but  may  persist  to  some  extent  in  the  interval.  During 
the  attack  the  patient  grasps  anything  at  hand  with  all  his  might,  and  at 
the  end  of  the  spasm  he  is  often  for  some  time  unable  to  let  go.  In  the 
other  type  the  convulsions  are  clonic  and  of  the  form  described  by  Rous- 
sel  as  occurring  somewhat  frequently  at  Almaden  and  called  there  calam- 
hres.  These  occur  in  paroxysms  that  are  said  to  have  some  likeness  to 
malarial  chills.  There  is  marked  oscillation  of  the  head  with  movements 
of  the  eyelids  and  eyeballs,  the  facial  muscles,  and  the  arms  and  legs. 
The  violence  of  the  attacks  at  times  makes  it  necessary  for  several  persons 
to  hold  the  patient.  The  attacks  are  often  painful  but  there  is  no  loss  of 
consciousness.  A  large  proportion  of  the  subjects  of  these  are  said  to  die 
within  a  year  after  the  attacks  appear. 

In  addition  to  the  disorders  mentioned,  neuritis  has  been  described. 
Leyden  discussed  it  in  1893;  Remak  narrows  down  Leyden's  cases  to  at 
most  three  that  are  reliable  and  even  these  seem  to  me  somewhat  doubt- 
ful as  direct  results  of  mercury  because  of  their  association  with  violent 
dysentery  in  two  and  with  gastro-enteritis  and  gonorrhoea  in  the  other 
instance.  A  few  cases  have  been  described  in  which  there  was  severe  ataxia. 
Kussmaul  has  described  aphonia  from  laryngeal  paralysis  but  this  is 
extremely  rare.  There  may  be  exaggeration  of  the  special  senses;  the 
least  noise,  for  example,  may  be  intensely  disagreeable.  Shivering  feelings 
and  sensations  of  cold  are  common. 

The  chief  other  disturbance  is  of  the  emotional  nature.  This  is  closely 
associated  as  a  rule  with  the  tremor.  Sometimes,  however,  it  is  very 
marked  when  there  is  little  or  no  tremor,  or  it  may  be  very  inconspicuous 
as  compared  with  the  tremor.  Most  of  the  patients  notice  this  emotional 
disturbance  before  anything  else;  many  of  them  describe  it  by  saying 
they  first  notice  that  they  have  "lost  their  nerve."  Any  sudden  occur- 
ence, even  of  the  most  trivial  nature,  throws  them  into  tremor,  usually 
accompanied  by  a  sudden  sense  of  powerlessness,  or  of  fright.  In  bad 
cases  the  feeling  of  weakness  causes  the  patient  to  drop  into  the  nearest 
seat  or  grasp  the  nearest  support,  lest  he  should  fall.  These  persons  come 
to  dread  the  least  disturbance  and  they  often  avoid  company  because 
little  conventionalities  bring  on  this  embarrassing  excitement;  several 
men  have  stated  to  the  author  that  they  would  walk  around  a  block  if  they 
saw  a  friend  on  the  street  because  they  dreaded  the  mere  sign  of  recog- 
nition in  passing.  At  first  their  attitude  toward  this  disturbance  is  merely 
one  of  perfectly  natural  annoyance  with  themselves  because  of  what  they 
term  their  own  silliness ;  later  they  may  become  morbid,  and  in  severe  and 
advanced  cases  may  develop  a  distinct  psychosis,  which  varies  in  nature  but 
seems  usually  to  be  dementia.  Actual  psychosis  seems,  however,  to  be 
rare  now;  its  frequency  has  probably  decreased  since  Kussmaul  made 
his  classical  study,  improved  hygiene  being  chiefly  responsible  for  this. 

The  relation  of  this  emotional  disturbance  to  hysteria  is  interesting, 
particularly  in  regard  to  the  question  whether  hysterical  symptoms  are 
directly  due  to  a  toxic  agent,  or  are  dependent  upon  a  psychic  anomaly  m 
the  individual  and  are  merely  brought  out  by  some  toxic  agent.  Cer- 
tainly if  these  symptoms  in  mercurial  poisoning  are  due  to  an  essential 
anomaly  in  the  individual,  this  anomaly  must  be  pretty  widely  distributed; 
it  looks  rather  in  this  instance  as  if  the  poisoning  produced  the  sjTuptoms 


130  DISEASES  DUE   TO  CHEMICAL  AGENTS 

directly,  for  they  occur  in  an  extremely  larjic  ])r()portion  of  cases.  In  ex- 
amining and  questioning  a  series  of  patients  who  showed  various  degrees 
of  chronic  poisoning,  the  same  emotional  condition  was  usually  found, 
and  yet  nearly  all  were  well-built,  healthy-looking  men,  who  in  other 
respects  showed  not  a  shade  of  the  a]:)pearance  of  hysteria. 

Diagnosis. — The  chief  conditions  that  are  likely  to  cause  confusion 
are  disseminated  sclerosis,  paralysis  agitans,  general  paresis,  alcoholism 
and  lead  j)oisoning. 

The  nature  of  the  occupation  and  the  knowledge  and  determination  of 
the  fact  that  mercin-y  is  used,  if  necessary  the  demonstration  that  mer- 
cury is  present  in  the  urine,  are  the  most  important  ])oints,  and  as  a  rule, 
settle  the  diagnosis  jiretty  thoroughly.  The  wide  amplitude  and  irregular- 
ity of  the  movements,  the  remarkable  effect  of  emotional  influences,  the 
absence  of  nystagmus  and  of  any  evidence  of  focal  cercbrosj)inal  lesions, 
and  the  strikingly  tremulous  and  emotional  character  of  the  stammering, 
distinguish  the  condition  from  multiple  sclerosis.  The  rapid  appearance 
or  marked  increase  of  the  tremor  upon  movement  or  emotional  stimulus, 
the  lack  of  persistent  rigidity  and  of  the  peculiar  expressionless  appearance 
of  the  features  separate  it  from  Parkinson's  disease.  General  paresis  is 
excluded  by  the  absence  of  focal  signs  of  cerebrospinal  changes,  and  by 
the  lack  of  delusions  of  grandeur  and  changes  of  the  moral  sense;  also 
by  the  fact  that  tremor  is  usually  by  all  means  the  most  pronounced 
feature.  Frequently  alcoholism  is  actually  associated  with  mercurial 
poisoning;  in  such  cases  the  very  severe  tremor,  the  peculiar  erythism, 
and  the  extremely  marked  influence  of  the  latter  upon  the  tremor  indi- 
cate the  double  poisoning.  When  alcoholism  is  not  present  it  may  be 
excluded  by  the  history  and  by  the  absence  of  all  signs  of  it  except  tremor 
and  excitability,  and  the  last  mentioned  features  differ  in  the  two 
conditions.  Lead  poisoning  will  almost  always  be  indicated  by  the  occupa- 
tion, by  attacks  of  colic  and  by  the  blue  line,  even  if  evidences  of  charac- 
teristic lead  neuritis  are  absent.  Basic  degeneration  is  also  probably  an 
important  distinction,  but  this  has  not  been  definitely  determined  in 
relation  to  chronic  mercurial  poisoning.  Lead  poisoning  and  mercurial 
poisoning  may  be  combined,  but  this  is  unusual;  in  such  cases  it  is 
necessary  to  determine  that  mercury  is  used  in  the  work  or  is  present  in 
the  urine. 

Prognosis. — If  the  tremor  has  not  become  constant  and  there  is  no 
marked  cachexia,  recovery  practically  always  occurs  under  proper  sur- 
roundings. Even  severe  and  persistent  tremor  usually  disappears  ulti- 
mately, as  does  the  emotional  disturbance.  If  there  is  paralysis,  mental 
disturbance,  or  severe  cachexia,  the  outcome  is  doubtful.  Sometimes 
even  moderate  tremor  never  wholly  disappears,  and  in  any  instance 
recovery  is  likely  to  be  very  slow.  Prognosis  depends  largely  upon  free- 
dom from  further  exposure  and  upon  abstinence  from  alcohol  and  excesses 
of  all  kinds.  Some  persons  have  recovered  from  very  marked  symptoms 
Avhile  continuing  at  the  same  work,  but  this  was  only  when  unusual  care 
was  exercised,  and  as  a  rule  is  not  possible. 

Prophylaxis  and  Treatment. — As  in  almost  all  similar  conditions,  the 
majority  of  cases  of  poisoning  can  be  prevented  if  employers  properly 
protect  their  workmen.  The  results  of  the  energetic  and  successful  efforts 
of  Wollner  in  enforcing  proper  hygiene  in  the  mirror  factories  at  Fiirth 


CHRONIC  MERCURY  POISONING  131 

are  profoundly  impressive  in  this  regard.  Thorough  ventilation  is  the 
most  essential  point,  as  is  shown  by  Wollner's  experience.  A  large  manu- 
facturer who  is  interested  in  two  factories,  one  old  and  with  poor  hygienic 
arrangements,  the  other  new  and  well-ventilated,  states  that  men  have 
acquired  severe  chronic  poisoning  in  the  old  factory  and  have  recov- 
ered in  the  new  while  doing  the  same  work.  Cement  floors  and  other 
forms  of  construction  that  permit  of  thorough  cleanliness  and  prevent 
the  accumulation  of  particles  of  mercury,  the  use  of  hoods  whenever 
possible  and  of  well-covered  containers  for  the  mercury,  with  the  require- 
ment that  the  employees  shall  be  extremely  careful  to  cleanse  themselves 
before  eating,  to  cleanse  their  persons  thoroughly,  and  to  protect  their 
hands  with  rubber  gloves  while  at  dangerous  work,  are  also  of  the  great- 
est importance.  Free  and  nutritious  diet,  abstention  from  alcohol  and 
from  sexual  and  other  excesses,  with  a  generous  amount  of  exercise,  in 
the  open  air,  if  possible,  are  of  the  utmost  value  in  prophylaxis  and  treat- 
ment. Many  workmen  take  small  doses  of  potassium  iodide  at  frequent 
intervals  as  a  prophylactic,  particularly  if  they  have  already  had  slight 
symptoms,  and  a  number  have  recovered  from  marked  poisoning  without 
cessation  of  work  by  treating  themselves  in  the  manner  indicated.  Turk- 
ish baths  and  frequent  hot  baths  are  also  useful. 

The  measures  mentioned  are  the  most  important  in  any  stage  of  poison- 
ing, as  well  as  in  prophylaxis.  Sometimes  the  severity  of  special  symptoms 
particularly  the  tremor,  may  demand  medicinal  treatment.  Sedatives  such 
as  derivatives  of  opium,  chloral,  bromides,  and  also  belladonna  and 
pilocarpine  have  been  found  useful.  Musk  has  been  very  highly  praised 
by  some  authors  of  experience. 

PHOSPHORUS  POISONING. 

The  history  of  phosphorus  poisoning  practically  begins  with  the  inven- 
tion of  phosphorus  matches  in  1833.  A  little  more  than  a  decade  later 
the  descriptions  of  Lorinser,  Heyfelder,  Strohl,  and  particularly  of  v. 
Bibra  and  Geist,  of  the  distressing  effects  of  phosphorus  upon  workers  in 
match  factories,  aroused  most  intense  interest,  and  their  studies,  together 
with  others  that  followed,  have  resulted  in  some  of  the  most  remarkable 
advances  in  the  history  of  humanitarian  industrial  reforms.  A  number  of 
European  countries  have  forbidden  the  use  of  poisonous  white  or 
yellow  phosphorus  in  making  matches,  and,  as  a  consequence,  non- 
poisonous  matches  are  now  made  in  enormous  and  increasing  numbers 
in  these  and  other  countries.  Business  sagacity  and  philanthropy  have 
led  in  this  country  as  well  as  in  Europe  to  marked  improvements  in  the 
hygiene  of  match  factories  and  the  care  of  the  health  of  the  workmen; 
in  Europe  legal  enactments  have,  to  some  extent,  enforced  such  measures; 
the  result  is  that  the  danger  in  many  plants  that  still  use  white  phosphorus 
has  been  greatly  reduced  and  in  some  it  has  almost  disappeared.  Clin- 
ical interest  in  chronic  poisoning  has,  therefore,  become  greatly  lessened. 

Acute  phosphorus  poisoning  has  likewise  come  to  be  largely  past  his- 
tory as  a  matter  of  clinical  importance  in  most  parts  of  the  world,  and  it 
never  was  of  much  consequence  in  this  country.  Hence  phosphorus 
poisoning  demands  but  brief  discussion.    Acute  poisoning  is  still  common 


132  DISEASES  DUE  TO  CHEMICAL  AGENTS 

in  a  few  countries,  sucli  as  Sweden,  and  among  cities  Prague  has  a  most 
unfortunately  large  recent  record  of  deatlis  from  this  cause.  Phosphorus 
necrosis  also  still  occurs  with  some  frecjuency  in  a  small  number  of 
European  countries  in  which  workmen  have  little  or  no  legal  j^rotection 
and  the  hygienic  conditions  are  poor.  It  is  not  improbable  that  cases 
occur  in  Japan,  where  matches  are  manufactured  in  large  quantities.  In 
general,  however,  both  acute  and  chronic  cases  are  now  few,  and  the 
industrial  cases  are  chiefly  cared  for  by  specially  trained  medical  em- 
])loyees  of  corporations,  so  that  the  subject  is  of  little  interest  to  the  general 
profession. 

Etiology. — Industrial  (chronic)  poisoning  has  occasionally  occurred  in 
the  manufacture  of  phosphorus  itself,  but  is  almost  always  due  to  the  much 
more  dangerous  exj)osure  that  occurs  in  the  use  of  the  crystalline  white 
or  yelfow  ])hosphorus  in  making  matches.  Phos])horus,  of  course, 
volatilizes  at  room-temperature,  and  in  dipping  and  packing  the  matches, 
exposure  to  the  vapor  inevitably  occurs  unless  the  workrooms  are  large, 
extremely  well-ventilated,  and  kept  scrupulously  clean.  The  most  serious 
results  have  occurred  in  the  small  and  wretchedly-equipped  house  indus- 
tries of  European  countries,  which  are  now  fast  disappearing,  but  larger 
factories  with  poor  equi])ment  have  naturally  furnished  many  cases.  The 
degree  to  which  the  danger  may  be  overcome  is  shown  by  the  experi- 
ence of  Dr.  Knowlton  of  Akron,  Ohio,  who  has  charge  of  over  two 
thousand  employees  of  one  company.  This  company  now  provides  com- 
modious workrooms  that  have  excellent  ventilation  and  are  kept  thor- 
oughly clean;  separate  eating  rooms  are  also  furnished,  the  employees 
are  given  facilities  for  personal  cleanliness,  and  much  of  the  work  pre- 
viously carried  out  by  hand,  is  now  done  by  machinery.  The  condition  of 
the  mouth  and  teeth  of  the  workmen  is  rigidly  inspected  and  local  disease 
is  at  once  treated  and  the  subject  removed  from  further  danger.  Dr. 
Knowlton  writes  that  he  has  at  present  in  this  large  number  of  em- 
ployees only  two  cases  of  necrosis  and  these  are  mild.  A  general  idea  of 
the  earlier  as  well  as  the  present  conditions  in  other  countries  may  be 
obtained  from  Dangerous  Trades,  the  publications  of  the  British  Home 
Office,  and  the  articles  of  Bauer,  Holzer,  Kaup,  G.  H.  Wood  and  others 
in  Gesundheifsgefdhrliche  Industrien. 

"White"  phosphorus,  which  becomes  "yellow"  phosphorus  on  exposure 
to  light,  forms  amorphous  "red"  phosphorus  if  subjected  to  a  high  tem- 
perature in  an  atmosphere  free  of  oxygen.  This  red  phosphorus,  which 
is  used  in  making  most  safety  matches,  is  almost  harmless  to  those  work- 
ing with  it,  even  if  swallowed,  apparently  because  of  its  slight  volatility 
and  solubility. 

Accidental  chronic  poisoning  has  been  reported  in  rare  instances,  for 
example,  as  a  result  of  the  phosphorus  vapor  produced  by  storing  a  large 
number  of  matches  near  a  stove.  Purely  accidental  acute  poisoning  has 
occurred  in  a  few  cases,  but  as  a  rule  is  due  to  attempts  at  suicide,  gener- 
ally by  swallowing  match  heads.  Children  have  also  unknowingly  poisoned 
themselves  with  matches;  twenty-five  match  heads  usually  contain 
enough  phosphorus  to  cause  grave  or  even  fatal  poisoning  of  an  adult. 
The  very  large  doses  of  phosphorus  that  were  once  recommended  for 
therapeutic  purposes,  especially  in  treating  rickets,  caused  fatal  poisoning 
in  a  number  of  instances.    Finally,  Kobert  has  suggested  that  some  cases 


CHRONIC  MERCURY   POISONING  133 

of  icterus  gravis,  or  acute  yellow  atrophy,  may  be  actual  instances  of 
phosphorus  poisoning  resulting  fronn  reduction,  chiefly  in  the  intestinal 
tract,  of  the  phosphorus  compounds  contained  in  such  substances  as 
lecithin  and  nucleins.  He  and  others  have  conducted  interesting  experi- 
ments concerning  this  point,  but  have  not  as  yet  demonstrated  its  truth. 

Pathology.— Experimental  chronic  poisoning  has  produced  hepatic 
cirrhosis  and  chronic  interstitial  nephritis.  The  result  of  chronic  poison- 
ing in  human  subjects  is  almost  always  necrosis  of  the  jaw  with  subse- 
quent sequestruni  formation  and  suppuration  of  the  bone  and  the  nearby 
tissues,  the  lesions  being  very  extensive  in  cases  not  treated  early. 
General  fragility  of  the  bones  has  been  described. 

The  changes  in  acute  poisoning  have  led  to  some  of  the  most  important 
observations  and  experiments  in  the  history  of  pathology.  In  brief,  they 
are  reduction  or  loss  of  coagulability  of  the  blood,  diffusely  scattered  small 
or  larger  hemorrhages,  icterus,  loss  of  elasticity  of  the  vessels,  fatty 
changes  in  the  muscles,  heart,  kidneys,  stomach,  and  duodenum,  en- 
largement of  the  spleen,  and  very  extensive  changes  in  the  liver;  the 
latter  organ  is  enlarged,  of  saffron  color,  a  typical  fatty  icteric  liver,  the 
acini,  large  and  easily  seen,  and  microscopically  there  is  an  extensive 
deposit  of  fat,  while  some  of  the  liver  cells  are  merely  filled  with  fat, 
others  are  undergoing  destruction  or  have  been  entirely  destroyed.  Much 
work  has  been  done  on  the  question  of  the  source  of  the  fat  by  Lebedeff, 
Pfliiger,  Athanasiu,  A.  E.  Taylor,  Kraus,  Sommer,  and  others,  and  it  is 
now  fairly  clear  that  it  does  not  come  from  transformation  of  protein  into 
fat,  but  from  deposit  of  fat  that  is  transferred  from  depots  elsewhere. 
If,  as  has  often  been  the  case,  the  phosphorus  is  taken  for  the  purpose  of 
producing  abortion,  there  are  usually  hemorrhages  into  the  cavity  of  the 
uterus,  there  is  frequently  abortion,  and  the  organs  of  the  foetus  may  show 
the  same  changes  as  those  of  the  mother. 

The  alterations  in  the  chemistry  of  the  organism  are  very  striking  and 
their  study  has  led  up  to  a  considerable  part  of  a  body  of  knowledge  that 
has  caused  profound  changes  in  the  teaching  concerning  many  normal  and 
pathological  processes.  Oxidative  processes  are  reduced,  as  are  syn- 
thetic processes,  such  as  glycogen  production  in  the  liver  and  muscles, 
and  the  supposed  synthesis  of  hippuric  acid  by  the  kidneys,  while  the  work 
of  Jacoby  has  shown  a  marked  increase  of  autolytic  processes.  Inter- 
mediate products  of  metabolism  in  abnormal  amounts  or  substances  that 
are  entirely  abnormal — leucin,  tyrosin,  cystin,  sarcolactic  acid  and 
peptone-like  or  ptomaine-like  substances — are  found  in  the  blood  and 
urine;  glycosuria  often  occurs;  there  is  very  excessive  acid  production 
and  the  power  of  oxidizing  acids  is  reduced.  As  a  consequence,  the  am- 
monia of  the  urine  is  greatly  increased  while  the  urea  is  diminished.  The 
last-mentioned  conditions  are  due  chiefly  to  the  acid  intoxication,  not  to 
the  loss  of  the  liver's  function  of  producing  urea. 

The  action  of  phosphorus  seems,  as  was  stated  in  1869  by  Schultzen 
and  Riess,  to  be  like  that  of  a  ferment:  in  what  manner  its  results  are 
produced,  whether  through  furtherance  of  the  effects  of  bacteria  or  of 
their  growth,  or  through  exciting  processes  that  are  normally  resident  in 
the  cells,  is  not  wholly  certain,  but  recent  knowledge  makes  it  much 
more  probable  that  its  chief  action  is  to  accelerate  certain  ferment 
processes. 


134  DISEASES  DUE  TO  CHEMICAL  AGENTS 

Symptoms. — Acute  poisoning  bears  a  very  close  resemblance  to  "idio- 
pathic" icterus  gravis  and  acute  yellow  atrophy;  it  is  therefore  of  much 
interest  to  the  medical  clinician  in  tiie  few  regions  where  it  occurs  fre- 
quently. Some  hours  after  taking  phosj)horus,  vomiting  and  often  diar- 
rhoea appear;  and"  the  vomitus  may  be  phosphorescent.  The  symptoms 
remit  after  the  digestive  tract  is  emptied,  and  for  two  or  three  days  the 
patient  seems  almost  or  quite  well.  After  this,  vomiting  returns  and 
icterus  develops,  as  do  epigastric  pains,  tenderness  of  the  whole  trunk, 
and  distressing  pains  in  the  muscles,  which  are  probably  in  large  part 
the  result  of  hemorrhage  into  the  tissues.  Blood  is  often  ])resent  in  the 
vomit  and  stools,  and  petechiii?  occur  in  the  skin  and  mucous  membranes. 
The  liver  enlarges  a  day  or  two  after  the  return  of  the  symptoms  and 
grows  tender;  later  it  may  decrease  in  size,  but  usually  it  does  not  unless 
recovery  occurs.  The  patient  becomes  apprehensive,  sleepless  and  pros- 
trated. There  is  much  less  tendency  to  severe  cerebral  disturbance  than 
in  acute  yellow  atrophy  or  icterus  gravis,  but,  in  some  instances,  marked 
somnolence,  coma,  or  maniacal  excitement  appears  a  day  or  two  before 
death. 

Phosphorescence  of  the  breath  and  urine  has  been  described,  appar- 
ently with  somewhat  doubtful  accuracy.  The  urine,  when  poisoning  is 
well  developed,  contains  much  sarcolactic  acid,  at  times  leucin,  cystin,  oc- 
casionally tyrosin.  The  ammonia  of  the  urine  is  greatly  increased,  the 
urea  is  usually  diminished;  the  total  nitrogen  excretion  is  ordinarily 
increased  beyond  the  intake. 

In  fatal  cases,  the  end  generally  occurs  after  about  a  week,  sometimes 
earlier.  Fully  half  the  cases  die.  If  recovery  takes  place  the  symptoms 
gradually  subside,  the  liver  decreases  in  size,  and  it  may  ultimately 
shrink  to  less  than  its  normal  dimensions.  There  may  be  sequelae  such 
as  neuritis  and  paralysis  from  cerebral  hemorrhage. 

Chronic  poisoning  consists  almost  entirely  of  necrosis  of  the  jaw  and 
neighboring  tissues,  and  the  consequences  of  this  local  disease.  General 
disturbance  of  health  without  necrosis  is  described  by  some  observers, 
but  is  not  conspicuous  at  best.  Necrosis  occurs  particularly  in  those 
whose  mouths  and  teeth  are  in  bad  condition ;  it  is  not  the  efi'ect  of  phos- 
phorus alone,  but  of  bacterial  action  also,  and  hence  conditions  that  favor 
bacterial  growth  favor  necrosis.  It  begins  usually  about  a  single  tooth, 
most  commonly  in  the  loAver  jaw,  with  local  decay  and  abscess  forma- 
tion. If  not  treated  quickly,  the  disease  spreads  and  the  gums  become 
loosened.  If  the  tooth  is  removed,  exceedingly  foul  pus  is  discharged 
from  the  alveolus,  the  necrosis  advances  to  neighboring  teeth  and  to 
further  portions  of  the  jaw-bone,  sequestra  form,  the  suppuration  extends 
to  neighboring  tissues,  sometimes  burrowing  deeply  into  the  neck,  fre- 
quently breaking  through  the  skin;  the  patient  becomes  weak  and 
anaemic  and  is  likely  to  develop  amyloid  disease,  phthisis,  basal  menin- 
gitis, or  general  septicaemia.  Frightful  disfigurement  has  been  produced 
in  some  cases,  and,  with  the  dreadful  odor,  has  made  the  subjects  almost 
outcasts.  Occasionally  other  bones  besides  those  of  the  jaw  become 
necrotic,  and  instances  have  been  reported  in  which  ten  or  more  of  the 
cranial  bones  were  involved.  A  series  of  cases  is  on  record  in  which 
there  was  general  fragility  of  the  bones,  and  this  was  believed  to  be  due  to 
phosphorus;  in  some  cases,  also,  wounds  involving  bones  of  the  limbs 


CHRONIC  MERCURY  POISONING  135 

have  been  followed  by  necrosis  of  these  bones.  It  has  been  repeatedly 
observed  that  necrosis  may  make  its  first  appearance  even  years  after 
the  subject  has  ceased  working  in  phosphorus.  If  local  treatment  is 
instituted  very  early  the  necrosis  is  sometimes  controlled  without  serious 
surgical  measures;  and  if  the  disease  is  distinctly  developed  but  not  ad- 
vanced, resection  of  the  bone  usually  checks  it.  In  severe  cases  even 
extensive  surgical  measures  may  not  stay  its  progress. 

Diagnosis. — Acute  poisoning  is  distinguished  from  acute  yellow  atro- 
phy chiefly  by  the  history  of  poisoning;  by  the  appearance  of  jaundice, 
and  of  other  severe  symptoms  two  or  three  days  after  temporary  gastric 
symptoms,  while  in  acute  yellow  atrophy,  the  grave  symptoms  are  usually 
preceded  for  some  time  by  signs  of  catarrhal  or  obstructive  jaundice;  by 
the  enlargement  of  the  liver;  by  the  fact  that  leucin,  and  more  particularly 
tyrosin,  are  less  common  and  less  abundant  than  in  acute  yellow  atro- 
phy. Cerebral  symptoms  are  also  much  less  frequent.  None  of  these 
distinctions  is  absolute  or  constant.  Phosphorus  necrosis  is  diagnosed 
chiefly  by  means  of  the  occupational  history,  with  persistent  and  advanc- 
ing necrosis  of  the  jaw. 

Prognosis. — Acute  poisoning  is  always  very  grave,  one-half  or  more  of 
the  cases  ending  in  death.  The  prognosis  depends  largely  upon  the 
promptness  with  which  the  stomach  is  emptied  and  further  treatment  in- 
stituted. If  severe  symptoms  develop,  it  depends  upon  their  duration; 
with  each  day  beyond  three  or  four  that  such  symptoms  continue,  the 
outlook  grows  much  more  grave.  The  course  of  necrosis  depends  upon 
the  rapidity  and  thoroughness  of  treatment.  Early  resection  is  usually 
successful.  Advanced  disease  and  long-postponed  treatment  renders  the 
prospects  doubtful  as  to  recovery,  and,  at  best,  the  disfigurement  is  likely 
to  be  severe. 

Prophylaxis  and  Treatment.— Phosphorus  necrosis  would  practically 
disappear  were  the  use  of  white  phosphorus  in  making  matches  every- 
where forbidden.  While  this  has  been  done  in  several  countries,  it  is 
doubtful  whether  it  can  ever  be  generally  carried  out  with  success,  and 
at  present  it  certainly  cannot.  Constant  and  thorough  care  of  employees' 
mouths  and  teeth  and  of  the  hygienic  conditions  in  the  workrooms,  with 
the  use,  whenever  possible,  of  machinery  in  place  of  handwork,  will,  as 
shown  by  recent  records  here  and  in  England,  almost  entirely  prevent 
serious  results. 

The  treatment  of  the  necrosis  consists  in  removing  the  subject  from 
danger  upon  the  development  of  the  slightest  signs  of  necrosis,  immedi- 
ate dental  treatment  of  the  local  disease,  and,  if  it  does  not  yield,  or  ad- 
vances in  spite  of  this,  early  resection  of  the  jaw.  Acute  poisoning  should 
be  treated  by  the  immediate  administration  of  copper  sulphate,  both  for 
its  emetic  effect  and  because  it  forms  a  coating  over  the  phosphorus 
match  heads  and  prevents  much  of  the  absorption.  The  stomach  should 
be  washed  out,  using  potassium  permanganate  solution  (2  per  cent,  to 
3  per  cent.)  or  hydrogen  peroxide  (1  per  cent,  to  3  per  cent.)  for  their 
oxidative  action,  since  the  oxides  of  phosphorus  are  little,  if  at  all,  poi- 
sonous. If  diarrhoea  is  not  present  a  purge  should  be  given,  avoiding 
castor  oil  since  oils  increase  the  solution  of  phosphorus.  Old,  ozon- 
ized turpentine  should  be  given  in  doses  of  0.5  c.c.  (7^  m.)  three  or 
four  times  daily  for  a  week  or  more,  as  it  is  supposed  to  favor  oxidation  of 


136  DISEASES  DUE  TO  CHEMICAL  AGENTS 

the  phosphorus.  Alkalies  should  be  administered.  If  there  arc  severe 
symptoms,  tiie  dose  of  alkali  should  be  very  large  in  order  to  combat  the 
acid  intoxication,  and  intravenous  administration  of  alkaUes  may  be 
used  as  in  diabetic  coma. 


CHRONIC  SILVER  POISONING  OR  ARGYRIA. 

Argyria  is  of  two  forms,  local  and  general.  The  former  occurs  in  those 
who  handle  silver  in  their  occupations,  when  it  is  seen  chiefly  in  the  skin  of 
the  hands,  a  condition  first  described  by  Lewin.^  It  may  be  due  to  pro- 
longed use  of  silver  preparations,  particularly  in  hair  dyes,  or  in  treating 
diseased  mucous  membranes  of  the  eye,  throat,  and  other  parts;  recently, 
however,  de  Schweinitz-  and  others  have  directed  attention  to  the  danger 
accompanying  long-continued  use  in  this  way  of  the  newer  silver  prepara- 
tions, such  as  protargol. 

General  argyria  has  also  occurred  in  a  few  instances  from  prolonged 
occupational  contact  with  silver,  and,  in  a  smaller  number  of  cases,  from 
its  protracted  local  application.  Kobert,  indeed,  urgently  insists  that  we 
are  likely  to  enter  upon  a  new  era  in  the  history  of  argyria  because  of  the 
freedom  with  which  the  newer  preparations  of  silver  are  now  being  used 
locally  by  gcnito-urinary,  ophthalmic,  and  other  surgeons,  and,  even  more, 
because  of  the  recent  frequent  use  of  some  of  these  preparations  in  com- 
paratively strong  solution  in  the  treatment  of  local  disease  of  the  bowel,  or 
intravenously  in  septic  and  other  conditions.  In  a  great  majority  of  in- 
stances, however,  argyria  has  been  due  to  the  therapeutic  internal  use  of 
silver  nitrate.  In  slight  degree  the  condition  has  been  set  up  by  as  little 
as  2  grams  (30  grains),  administered  in  the  course  of  two  months;  but 
when  marked  general  discoloration  occurred,  the  amount  has  generally 
been  much  larger— 15  grams  (^  ounce)  or  more.  The  comparatively  fre- 
quent occurrence  of  argyria  in  earlier  times,  and  the  very  unfortunate 
results,  led  to  such  general  and  emphatic  warnings  against  the  possible 
production  of  it  that  the  condition  became,  and  still  is,  quite  uncommon. 
Many  recent  graduates  in  medicine,  however,  seem  to  have  an  insuffi- 
cient appreciation  of  the  danger.  In  the  past  three  years  the  writer  has 
seen  7  cases,  3  of  which  were  of  recent  origin. 

General  argyria  has  occurred  through  accident;  Lewin  saw  a  case  as  a 
result  of  accidental  swallowing  of  a  stick  of  silver  nitrate  under  circum- 
stances that  prevented  its  removal  before  it  was  absorbed. 

Pathology. — Argyria  consists  of  a  deposit  of  silver,  in  the  skin  or  mu- 
cous membranes  alone,  in  the  local  form;  in  the  internal  organs  also,  in 
the  general  form.  In  argyria  due  to  internal  use  of  silver,  the  pigment  is 
found  in  the  papillae  of  the  skin  and  in  the  glands,  but  not  in  the  epithelium ; 
in  occupational  cases,  in  which  it  enters  from  the  exterior,  it  may  be 
found  in  the  epidermis.  In  generalized  argyria  most  of  the  organs  may 
show  pigmentation,  but  it  is  ordinarily  most  marked  in  the  kidneys,  liver, 
and  choroid  plexus.  The  pigment  is  situated  in  the  vessel  walls  and  the 
nearby  tissues.    In  the  early  stages  it  is  first  found  in  the  leukocytes. 

'  Berl.   klin.   Woch.,  1886,  p.  17. 

^  Transactions  of  the  American  Ophthalmological  Society,  1903. 


CHRONIC  MERCURY  POISONING  137 

Silver  salts,  when  absorbed,  form  an  albuminate;,  and  this  is  gradual!}' 
deposited  and  reduced;  the  reduction  occurs  through  photochemical 
action  in  surfaces  exposed  to  light,  while  in  the  internal  organs  it  is  accom- 
plished by  the  activity  of  the  cells  (Loew). 

Chronic  interstitial  changes  in  the  liver,  lungs,  and  kidneys,  have  been 
described  as  a  result  of  the  prolonged  presence  of  the  pigment  in  the 
tissues. 

Symptoms. — ^The  condition  consists  of  a  more  or  less  disfiguring  pig- 
mentation without  any  subjective  symptoms.  Gastric  ulcer,  chronic 
nephritis,  pulmonary  tuberculosis,  headache,  and  weakness  of  memory, 
have,  without  clear  justification,  been  attributed  to  prolonged  use  of 
silver;  and  an  isolated  case  of  neuritis  with  symptoms  resembling  the 
forearm-extensor  palsy  of  lead  poisoning  is  mentioned  by  Gowers. 
Marked  mental  depression  and  abnormal  shyness  may  naturally  result 
from  the  very  marked  disfigurement.  As  a  rule,  however,  pigmentation 
is  the  sole  result.  When  this  is  due  to  local  application  or  to  occupation, 
the  discoloration  begins  in  the  areas  that  come  directly  in  contact  with 
the  silver,  and  in  such  it  usually  remains  localized.  If  it  results  from 
internal  use  of  silver,  the  first  pigmentation  is  almost  always  seen  in  the 
form  of  a  line  on  the  edge  of  the  gum  that  resembles  the  lead  line,  but  is 
of  a  more  violet  color.  This  line  is  of  diagnostic  importance  and  also 
serves  as  an  important  warning,  since  it  appears  well  before  the  pigmenta- 
tion of  the  skin,  and  indicates  the  necessity  of  stopping  the  use  of  silver  at 
once.  When  skin  pigmentation  develops  from  internal  use,  it  is  at  first  in 
patches,  chiefly  in  areas  much  exposed  to  light;  the  patches  afterward 
coalesce  and  the  whole  surface — skin,  conjunctiva,  and  other  visible 
mucous  membranes — ultimately  shows  more  or  less  pigmentation. 
Slight  grades  resemble  moderate  degrees  of  cyanosis;  in  more  severe 
cases  there  is  a  very  striking  and  characteristic  slate-gray  color  that 
makes  the  appearance  of  the  individual  extremely  conspicuous.  The 
color  is  often  spoken  of  as  resembling  the  complexion  of  the  Moorish 
race,  but  it  is  really  more  of  a  bluish-gray.  If  distinct  pigmentation  is 
allowed  to  develop  while  silver  is  still  being  administered,  the  discolora- 
tion usually  grows  more  marked  after  the  drug  is  discontinued,  because  a 
considerable  amount  of  unreduced  silver  is  always  present  in  the  body 
under  such  circumstances,  and  reduction  goes  on  for  some  time.  The 
color  may  indeed  continue  to  deepen  slightly  for  many  months;  in  one 
case  known  to  the  writer  it  apparently  continued  to  grow  darker  for  years. 

Diagnosis.— The  discoloration  may  be  mistaken  for  cyanosis,  and  the 
line  on  the  gums  may  be  confused  with  the  lead  line.  The  nature  of 
the  condition  is  determined  by  the  history,  or,  if  desirable,  by  excising 
small  portions  of  skin  and  finding  that  in  sections  the  pigment  granules 
disappear  after  treating  with  potassium  cyanide  or  concentrated  nitric 
acid,  and  reappear  upon  adding  ammonium  sulphide.  There  is  no 
practical  likelihood  of  mistaking  the  condition  for  anything  else  when  the 
color  has  once  been  seen  and  recognized. 

Prognosis. — Once  developed,  the  pigmentation  is  permanent.  If  there 
is  merely  a  line  on  the  gums,  disfigurement  of  the  skin  may  usually  be 
avoided  by  discontinuing  the  use  of  silver  at  once.  If  the  skin  already 
shows  discoloration,  this  generally  deepens  somewhat,  even  if  the  drug  is 
stopped. 


138  DISEASES  DUE  TO  CHEMICAL  AGENTS 

Prophylaxis  and  Treatment. — Tlu  jirophylaxis  consists  in  the  exercise 

of  great  care  in  prescribing  silver  nitrate,  not  giving  more  than  one-fourth 
grain  doses  and  not  continuing  it  for  more  than  six  weeks.  If  it  is  desired 
to  use  the  chiig  further  in  the  same  patient,  there  should  then  be  an  inter- 
mission of  several  -weeks.  Patients  should  not  be  given  solutions  of  silver 
to  use  without  the  supervision  of  a  physician,  and  they  should  be  warned 
against  the  danger  of  having  prescriptions  for  internal  use,  or  external 
application,  refilled. 

There  is  no  treatment  for  argyria,  all  practicable  methods  of  combating 
the  pigmentation  being  entirely  unsuccessful. 


CHRONIC    ZINC,    COPPER,    BRASS,    TIN    AND    MANGANESE 

POISONING. 

Whether  any  of  these  substances  produce  chronic  systemic  disease  is 
an  unsettled  question.  There  is  little  doubt  that  most  of  them  may  pro- 
duce digestive  disturbance;  and  the  presence  of  zinc,  copper  or  tin  in 
preserved  foods  should  therefore  be  considered  prejudicial  to  health. 
There  is  likewise  no  doubt  that  the  respiratory  tract  may  be  damaged  by 
inhalation  of  dust  in  the  manufacture  of  any  products  of  these  metals. 
Chronic  systemic  effects  have,  however,  been  but  rarely  observed,  and 
it  has  never  been  clearly  shown  that  the  systemic  effects  described  were 
not  due  to  other  unquestionable  systemic  poisons,  particularly  lead  and 
arsenic,  that  are  known  to  be  frequently  present  in  the  metals  under 
discussion,  or  to  sulphurous  and  sulphuric  acid,  carbon  monoxide,  and 
other  fumes  that  are  given  off  in  the  heating  of  these  metals.  Character- 
istic lead  poisoning  is  definitely  known  to  occur  occasionally  in  workers 
in  zinc  and  copper  mines  and  furnaces,  and  has  been  seen  as  a  result  of 
holding  brass  nails  in  the  mouth.  The  opinion  is  now  almost  general 
that  systemic  poisoning,  due  specifically  to  zinc  and  copper,  does  not 
occur  in  those  exposed  to  these  metals.  Workers  in  copper,  for  example, 
may  have  so  much  of  this  metal  in  their  stomachs  that  at  almost  any 
time  a  draught  of  weak  sulphuric  acid  produces  vomiting  from  the  copper 
sulphate  formed  (Wollner),  and  they  may  work  in  so  much  dust  that, 
like  the  employees  of  the  bronze  factories  at  Fiirth,  they  "  resemble  walking 
bronze  statues"^  and  yet  they  do  not  show  poisoning.  The  writer  has  spent 
many  years  in  the  immediate  neighborhood  of  large  zinc  mines  and  furnaces 
and  knows  of  no  zinc  poisoning  in  the  men  at  these  works;  and  Mr.  G. 
G.  Convers,  of  Bethlehem,  Pennsylvania,  whose  opportunities  and  obser- 
vations have  given  him  exceptional  knowledge  in  this  matter,  states 
that  the  men  who  work  with  the  oxide  of  zinc,  which  has  of  course  been 
largely  freed  from  impurities,  never  show  any  signs  of  systemic  poisoning 
even  though  they  spend  hours  every  day  in  an  atmosphere  containing  much 
zinc  oxide  dust.  There  is  also  no  evidence  that  drinking-water — which  is 
in  some  places  carried  through  zinc  pipes  and  in  such  instances  is  known 
to  contain  frequently  considerable  amounts  of  zinc — has  caused  chronic 
poisoning.  Gimlette  attributed  digestive  disturbance  and  emaciation 
to  water  collected  from  zinc  roofs,  but  his  view  was  not  convincingly 

^  Mayer,  Penzoldt  and  Stintzing's  Handbuch. 


CHRONIC  MERCURY  POISONING  139 

proved  even  though  the  water  did  contain  zinc.  Kobert  has  found  that 
zinc  workers  often  excrete  large  amounts  of  zinc  for  months  without  any 
evidence  of  poisoning. 

Professor  Koenig,  who  had  been  much  interested  in  the  question  of 
copper  poisoning  in  the  employees  of  the  great  copper  companies  in  Mich- 
igan, has  found  no  evidence  of  it  in  them,  or  in  the  people  who  live  in  the 
regions  about  the  mines  and  who  drink  water  that  often  contains  copper. 
Similar  observations  have  been  made  by  many  other  writers;  ancJ  hence 
even  soluble  copper  salts  apparently  do  not  cause  chronic  poisoning. 

Certain  chronic  local  symptoms,  however,  have  been  ascribed  to 
these  metals.  Zinc  chloride  may  produce  severe  skin  irritation  through 
external  action;  Gimlette  considered  the  epidemic  mentioned,  in  which 
there  was  gastro-intestinal  disturbance  and  emaciation,  to  be  due  to 
zinc;  and  systemic  effects  such  as  colic,  anaemia,  paralyses,  and  tabetic 
symptoms  have  been  ascribed  to  zinc  by  Schlokow  and  others.  Popoff  has 
attributed  similar  symptoms  to  working  with  bronze,  while  Schnitzler, 
Seeligmiiller  and  others  have  reported  neuritis  which  they  considered  to 
be  due  to  copper,  but  Walton  and  Carter^  however  themselves  suggest 
that  in  their  cases  pressure  may  have  been  the  actual  cause  of  the  symp- 
toms. Suckling  reported  neuritis  in  brass  workers,  and  he,  Hogben,  and 
Raymond,  have  described  ataxia  in  brass  workers.  Murray  observed 
cases  in  brass  workers  in  which  there  was  colic,  anaemia,  gastro-intestinal 
disturbance,  emaciation,  and  even  haemoptysis.  Brass  workers  also 
occasionally  show  marked  respiratory  disturbance  and  the  condition  that 
has  been  termed  "brass  workers'  ague,"  in  which  chills,  fever,  and  sweats 
occur  occasionally  and  may  somewhat  resemble  malaria.  It  is  not  prob- 
able that  these  conditions  are  produced  by  the  constituents  of  pure  brass. 

Copper  is  known  to  produce  some  disfigurement,  however,  through 
greenish  discoloration  of  the  teeth,  the  hair,  and  occasionally  the  skin  of  the 
face  and  other  parts.  Even  a  green  color  of  the  sweat  has  been  described. 
At  times  other  bones  than  the  teeth  show  this  color  markedly  at  necropsy 
or  upon  exhuming  a  body. 

The  cases  of  tin  poisoning  that  have  been  described  were  probably  in 
most  instances  intoxication  from  decomposed  canned  foods.  There  are 
no  cases  on  record  that  were  clearly  instances  of  chronic  tin  poisoning. 
Ungar  and  Bodlander^  have,  however,  produced  gastro-intestinal  symp- 
toms, heart  weakness,  emaciation,  paralysis,  ataxia,  and  coma,  in  animals, 
through  subacute  and  chronic  experimental  poisoning,  and  the  possibility 
of  chronic  poisoning  in  man  must  be  recognized,  for  tin  is  quite  extensively 
employed  in  weighing  fabrics ;  and  tin  vessels  are,  of  course,  used  to  an 
enormous  extent  in  preserving  foods,  and  acid  contents  of  such  vessels 
may  contain  appreciable  amounts  of  tin.  This  poisoning  must,  however, 
be  very  rare,  if  it  occurs.  It  is  apparently  of  little  clinical  importance 
(K.  B.  Lehmann)  and  we  have  at  any  rate  practically  no  definite  clinical 
knowledge  of  it. 

There  are  no  diagnostic  signs  of  any  of  the  poisonings  under  discus- 
sion, as  they  are  not  positively  known  to  occur.  In  cases  in  which  these 
metals  were  suspected  of  producing  poisoning,  the  prognosis  seems  to 

^  American  Journal  of  the  Medical  Sciences,  July,  1892. 
^Zeitsch.  f.  Hygiene,  Bd.  ii. 


140  DISEASES  DUE  TO  CHEMICAL  AGE^^TS 

have  been  much  Hkc  that  in  lead  poisoning;    and  the  treatment  should 
follow  the  same  principles. 

Chronic  manganese  poisoning  is  mentioned  separately  because,  while 
it  has  been  little  studied,  it  seems,  from  the  observations  of  Embden,  to 
be  perhai)s  of  coiisiderable  importance  in  the  limited  group  of  persons 
who  are  exposed  to  it.  Embden  described  a  series  of  cases  in  which  there 
was  oedema,  general  weakness  or  pareses  without  atrophy  or  degenera- 
tion reaction,  mask-like  appearance  of  the  face,  disturbance  of  speech 
and  of  the  voice,  gross  tremor  of  the  head  and  extremities  much  increased 
upon  intentional  movement,  excited  patellar  reflexes  and  retro])ulsion  in 
complex  movements  and  in  attempts  to  walk  backward  s]iontaneously. 
The  Romberg  sign  was  absent.  There  were  ptrriiesthesias  and  pains  in 
the  earlier  stages  but  no  other  sensory  symptoms.  Sometimes  there  was 
uncontrollable  laughter,  but  no  other  psychic  alterations  were  observed. 
The  condition  is  not  fully  recognized  as  manganese  poisoning  and  needs 
further  study, 


CHAPTER  VIII. 

CARBON.  MONOXIDE   POISONING.     ILLUMINATING   GAS 

POISONING.     COMBUSTION  PRODUCT  POISONING. 

CHRONIC  CARBON  BISULPHIDE  POISONING. 

By  DAVID  L.  EDSALL,  M.  D., 

Contrary  to  the  conditions  in  most  of  the  other  intoxications,  acute 
poisoning  of  the  variety  now  under  discussion  is  of  special  interest  to  the 
medical  chnician  and  neurologist,  because  it  not  infrequently  produces 
subacute  or  chronic  disorders.  Acute  carbon  monoxide  poisoning  is  some- 
what like  acute  arsenic  poisoning  in  this  respect,  since  it  may  be  followed 
immediately  or  after  a  considerable  interval  by  more  or  less  persistent 
conditions  that  are  impossible  of  correct  interpretation  unless  the  previous 
occurrence  of  poisoning  and  its  nature  are  known.  It  is  of  more  general 
and  more  complex  interest  than  arsenic  poisoning  because  of  its  much 
greater  frequency  and  because  its  sequelae  are  more  varied  in  nature  and 
often  less  characteristic.  At  the  present  time  also,  the  sources  of  poison- 
ing are  more  numerous  and  more  readily  encountered  by  accident  or 
design.  Considerable  technical  knowledge  too,  is  necessary  in  many 
instances  in  order  to  appreciate  the  fact  that  carbon  monoxide  is  the  toxic 
agent;  and  an  added  source  of  confusion  lies  in  the  fact  that  many  acute 
poisonings  are  suicidal,  and  unsuccessful  attempts  at  suicide  are  often 
subsequently  concealed. 

It  is  necessary,  therefore,  to  lay  emphasis  not  only  upon  those  sources 
of  poisoning  that  act  repeatedly  or  persistently  but  also  upon  those  that 
exert  their  effects  through  transitory  exposure.  The  acute  poisoning  with 
its  sequelae  has,  indeed,  been  far  better  studied  than  the  chronic.  The  im- 
portance of  the  latter  is  very  difficult  to  determine,  and  its  clinical  picture 
cannot  be  very  clearly  given :  this  is  partly  due  to  the  fact  that  it  occurs 
chiefly  in  persons  whose  hygienic  circumstances  are  bad  in  many  ways, 
and  it  is  hard  to  determine  how  large  a  part  carbon  monoxide  plays  in 
producing  any  resulting  symptoms,  partly  because  it  is  difficult  in  many 
instances  to  demonstrate  that  carbon  monoxide  was  present  and  active 
at  all;  partly  because  the  rather  small  number  of  investigators  who  have 
studied  the  question  clinically  have  often  made  partisan  statements  with- 
out due  proof,  while  most  of  the  profession  give  the  subject  only  casual 
thought  or  none. 

The  forms  of  poisonings  mentioned  under  this  heading  are  not  identical 
but  they  are  most  easily  considered  together,  for  the  s}Tnptoms  are  similar 
in  all,  and  carbon  monoxide  is  the  chief  toxic  agent  in  all.  While  various 
gases  other  than  carbon  monoxide  are  present  in  illuminating  ^as  and  in 
combustion  products,  and  while  it  has  been  shown  both  experimentally 
and  clinically  that  the  effects  produced  by  illuminating  gas  and  combus- 


■142  DISEASES  DUE  TO  CHEMICAL  AGENTS 

tion  products  arc  not  wholly  the  same  as  those  due  to  pure  carbon  mon- 
oxide, neither  the  clinical  nor  the  experimental  effects  of  the  other  gases 
that  are  ])resent  are  sufficiently  distinctive  to  permit  of  separate  descrip- 
tion of  the  three  conditions. 

Etiology. — Pure  carbon  monoxide  poisoning  has  been  excessively  rare 
because  o])p()rtunities  for  its  occurrence  have  been  most  unusual.  It  has 
been  seen  in  a  few  instances  in  laboratories,  and  a  number  of  distinguished 
investigators  have  had  very  grave  effects  as  a  result  of  accident  or  physio- 
logical experiment.  In  recent  years  a  new  cause  of  almost  pure  carbon 
monoxide  poisoning  has  been  coming  into  some  prominence.  Moissan, 
originator  of  the  electric  furnace  for  chemical  researches,  drew  attention 
to  the  danger  of  carbon  monoxide  poisoning  if  this  furnace  was  used 
carelessly,  and  a  certain  lunnber  of  cases  are  likely  to  a]:)pear  from  this 
source,  because  electric  fiu-naccs  are  now  so  exiensively  used  for  commer- 
cial purposes.  Large  numbers  of  these  furnaces  have  been  installed  in 
industries  such  as  those  at  Niagara  Falls,  and  Mr.  F.  J.  Tone,  general 
manager  of  one  of  the  companies,  states  that  the  furnaces  of  that  com- 
pany discharge  about  sixteen  tons  of  carbon  monoxide  daily,  which  is 
as  a  rule  oxidized  at  once  to  carbon  dioxide  and  carried  off  by  special 
ventilating  apparatus.  He  has  seen  no  chronic  effects,  but  states  that  oc- 
casionally the  oxidation  or  ventilation  becomes  temporarily  imperfect  and 
the  workmen  are  quickly  made  ill,  usually  with  headache,  nausea  and 
circulatory  failure.  The  experience  in  other  companies  is  much  the  same. 
Professor  Edgar  Smith  states  that  two  students  of  chemistry  at  the  Uni- 
versity of  Pennsylvania  had  poisoning  of  moderate  severity  from  this 
source,  which  left  mild  mental  symptoms  for  weeks  afterward. 

Intoxication  wdth  illuminating  gas  is  commonly  looked  upon  as  being 
practically  carbon  monoxide  poisoning,  but  Ferchland  and  Vahlen's 
experiments^  show  that  illuminating  gas  really  produces  a  more  severe 
poisoning  than  does  simple  carbon  monoxide;  nevertheless  carbon 
monoxide  is  certainly  the  chief  agent  in  the  poisoning.  Water  gas,  as  is  well 
known,  is  particularly  dangerous  because  of  the  large  amount  of  carbon 
monoxide  that  it  contains.  Acute  cases  of  gas  poisoning  are,  of  course, 
usually  due  to  leaving  the  gas  turned  on  in  sleeping  rooms,  either  by  ac- 
cident or  attempt  at  suicide;  in  the  last-mentioned  connection,  this  poison- 
ing has  a  profound  economic  importance  because  more  deaths  are  at 
present  due  to  this  cause  than  to  any  other  form  of  suicide  by  poisoning. 
Intoxication  with  illuminating  gas  sometimes  occurs  in  the  acute  or 
chronic  form  in  employees  of  gas  works;  and  protracted  poisonings  of 
slight  degree,  occasionally  acute  and  even  fatal  cases,  may  occur  in  the 
occupants  of  buildings  from  which  gas  escapes  from  leaks  in  the  pipes  or 
fixtures.  Pettenkofer  and  others  have  shown  that  the  leak  need  not  be 
in  the  building  itself;  the  gas  may  travel  through  the  ground  for  some  dis- 
tance, certainly  for  many  yards,  and  hence  while  escaping  from  the  mains 
may  reach  the  interior  of  houses  that  are  at  a  considerable  distance  from 
the  break.  This  is  especially  likely  to  occur  in  winter,  when  the  heating 
of  the  interior  of  buildings  causes  active  motion  of  the  atmosphere,  and 
thereby  draws  the  gas  into  houses  by  aspiration.  This  manner  of  poison- 
ing at  long  "range,  so  to  speak,  is  not  confined  to  illuminating  gas;  it  has 

^  Archiv.  fiir  ex-per.  Path,  und  Pharm.,  Bd.  xlviii,  Hefte  1  and  2. 


CARBON  MONOXIDE  POISONING  143 

occurred  from  mines  situated  near  dwelling  houses.  It  is  also  of  import- 
ance and  much  interest  that  under  these  circumstances  the  odor  of  the 
gas  is  usually  lost,  and  hence  its  presence  may  be  detected  only  through 
the  occurrence  of  poisoning.  Intoxication  from  this  source  is  probably 
quite  uncommon  now,  however. 

The  exact  frequency  and  importance  of  chronic  illuminating  gas  poison- 
ing is  not  well  known,  and  it  is  hard  to  determine  because  of  technical 
difficulties  in  the  study  of  the  question.  It  is  probably  of  somewhat 
greater  consequence  than  is  generally  recognized,  but  is  almost  certainly 
less  important  than  it  has  been  thought  to  be  by  many  who  have  written 
of  it  since  Pettenkofer's  studies  were  published. 

Combustion  products  cause  poisoning  chiefly  as  a  result  of  the  carbon 
monoxide  they  contain,  though  this  is  intensified  by  the  other  gases 
present,  more  particularly  carbon  dioxide.  The  amount  of  carbon  mon- 
oxide in  such  gases  naturally  varies  greatly,  but  it  may  be  exceedingly 
large.  In  iron  furnaces,  for  example,  the  escaping  gas  may  contain  as 
much  as  twenty-five  per  cent,  to  thirty  per  cent.  Mild  grades  of  combus- 
tion product  poisoning  very  frequently  occur  and  severe  cases  are  not  ex- 
tremely uncommon.  Nearly  every  one  has  experienced  transitory  effects 
from  gases  produced  by  heating  apparatus  with  poor  draughts,  and  such 
mild  effects  are  common  in  persons  who  are  closely  confined  in  rooms 
heated  by  badly  drawing  stoves  or  house  furnaces.  More  or  less  severe 
effects  also  occur  at  times  in  cooks,  and  in  persons  employed  in  charcoal 
furnaces,  iron  and  similar  furnaces,  in  coke  ovens,  in  gas  plants,  in  tar 
distilleries,  in  the  moulding  of  various  metals,  in  kilns  of  various  kinds 
(brick,  tile,  pottery,  etc.)  and  in  similar  occupations. 

The  "miner's  disease"  that  has  aroused  so  much  interest,  has  been 
shown  to  be  due  chiefly  to  carbon  monoxide  derived  principally  from  the 
explosive  used  in  blasting.  Carbon  monoxide  poisoning  also  occurs  at 
times  in  the  employees  of  chemical  factories.  In  the  various  occupations 
mentioned,  severe  and  even  fatal  acute  poisoning  is  sometimes  seen,  and 
chronic  ill  health  occurs  not  infrequently. 

The  cases  that  occur  accidentally  in  households  are  usually  mild  but 
are  sometimes  very  severe;  as  in  several  instances  in  which  one  or  more 
members  of  a  household  suffered  from  poisoning  that  was  so  pronounced 
as  to  produce  unconsciousness,  and  in  which  severe  after-effects  occurred, 
a  stove  or  house  furnace  being  the  cause.  Fatal  cases  have  occasionally 
occurred  even  from  modern  heating  appliances ;  in  some  European  places, 
this  is  considered  of  such  importance  that  the  use  of  dampers  in  stove  pipes 
is  not  permitted.  When  charcoal  braziers,  and  other  fires  without  chimney 
connections  were  much  used,  domestic  poisoning  of  all  grades  of  severity 
was  quite  common,  and  the  brazier,  as  is  well  known,  has  often  provided 
the  means  of  committing  suicide.  Cases  are  still  occasionally  reported 
from  the  use  of  such  heat  in  apparatus  for  drying  out  excavations,  etc.  A 
few  years  ago  a  number  of  severe  and  even  fatal  cases  were  caused  by  the 
cab  heaters  in  Paris,  Gautier  himself  having  suffered  severely.  Recently 
the  common  use  of  gas  or  oil  stoves  in  small  and  ill-ventilated  rooms, 
and  particularly  the  use  of  gas  water  heaters  in  bathrooms,  has  led  to  a 
noteworthy  number  of  poisonings,  some  of  which  have  been  very  severe; 
one  of  the  nurses  at  St.  Christopher's  Hospital,  Philadelphia,  had  pro- 
longed and  nearly  fatal  coma  from  this  cause. 


144  DISEASES  DUE  TO   CHEMICAL  AGENTS 

Pathology. — The  lesions  have  been  studied  with  reUable  results  almost 

solely  in  acute  cases  or  in  those  that  the  while  suffering  from  sequelje  of 
acute  poisoning.  The  striking  features  in  acute  eases  are  the  red  or  bluish- 
red  spots  on  the  surface  of  the  body,  chiefly  the  front  of  the  neck,  trunk 
and  thighs;  the  brilliant  cherry-red  color  of  the  blood  and  of  many  or  all 
the  organs;  the  marked  degenerative  changes  in  the  muscles;  the  scat- 
tered, small  hemorrhages  and  intense  hyperjemia  of  all  the  organs;  and 
in  many  cases  marked  cerebral  changes.  Among  the  immediate  or  more 
remote  sequehie  are  gastro-enteritis,  sometimes  pseudomembrane  forma- 
tion on  the  upper  digestive  and  respiratory  passages,  bronchitis,  bron- 
chopneumonia, or  at  times  lobar  pneumonia.  Nephritis  is  common, 
sometimes  with  very  severe  degenerative  changes  and  interstitial  reaction. 
Peripheral  neuritis  has  repeatedly  been  described,  and  poliomyelitis  and 
disseminated  encephalomyelitis  have  been  seen.  The  most  important 
nervous  lesions,  however,  are  those  in  the  brain:  they  are  chiefly  hyperse- 
mia;  scattered,  small  hemorrhages,  with  occasionally  more  extensive 
hemorrhage;  and  striking  foci  of  softening,  which  ])articularly  tend  to  be 
situated  in  the  lenticular  nucleus  and  the  internal  capsule,  but  may  in- 
volve various  parts  of  the  basal  ganglia.  Cysts  may  form  as  a  result  of 
the  softening.  The  areas  of  softening  have  a  striking  tendency  to  be 
symmetrical;  they  are  probably  the  result  of  primary  changes  in  the 
vessels,  though  there  is  some  evidence  that  both  the  softening  and  the 
diffuse  changes  in  the  cells  of  the  cortex  and  in  the  nerve  fibers,  that  are 
often  seen,  are  due  to  a  primary  encephalitis.  Sibelius  has  recently  dis- 
cussed the  literature  relating  to  cerebral  symptoms  and  lesions. 

In  chronic  poisoning  Koren  has  described  fatty  changes  in  the  vessels 
and  heart,  with  cardiac  dilatation,  anaemia,  splenic  enlargement,  and 
pleural  effusions. 

Mode  of  Entrance  and  Pathogenesis.— Carbon  monoxide  enters  the 
system  solely  by  inspiration,  unless  experimentally  introduced  otherwise. 
Its  chief  effect  is  in  displacing  the  oxygen  from  oxyhsemoglobin  and 
forming  carbon  monoxide  haemoglobin,  thus  rendering  the  affected  por- 
tion of  the  red  blood  corpuscles  incapable  of  performing  their  function  as 
oxygen  and  carbon  dioxide  carriers.  This  combination  is  commonly 
spoken  of  as  a  permanently  fixed  one ;  it  is  relatively  fixed,  but  not  abso- 
lutely so.  Oxygen  cannot  directly  displace  the  carbon  monoxide  from  its 
haemoglobin  combination  and  it  is  not  probable  even  that  any  noteworthy 
amount  of  the  carbon  monoxide  that  is  thus  combined,  is  oxidized  to  car- 
bon dioxide  and  excreted  in  this  way;  but  it  has  been  established  that 
dissociation  of  carbon  monoxide  haemoglobin  occurs,  and  also  that  carbon 
monoxide  is  excreted  as  such,  in  the  expired  air,  after  poisoning.  Detoxi- 
cation  is,  therefore,  always  carried  out  to  some  degree  and  small  repeated 
doses  are  probably  rapidly  excreted  in  this  way.  There  is  no  evidence 
that  it  is  gotten  rid  of  by  actual  destruction  of  the  affected  corpuscles. 
Fodor  has  claimed  that  carbon  monoxide  has  a  cumulative  action  when 
taken  in  small  doses,  but  there  is  no  good  proof  of  this. 

It  is  not  yet  fully  settled  whether  the  gas  has  any  direct  toxic  action 
upon  animal  tissues  or  whether  it  acts  solely  by  robbing  the  blood  of  its 
effective  haemoglobin,  but  it  is  highly  probable  that  both  occur.  The 
testimony  differs  as  to  whether  it  poisons  animals  whose  blood  contains 
no  haemoglobin,  bacteria,  and  the  higher  forms  of  plants;   but  a  number 


CARBON  MONOXIDE  POISONING  145 

of  experimenters  consider  with  much  reason  that  it  has  a  direct  toxic  effect, 
in  higher  animals  at  any  rate,  exerting  this  chiefly  upon  the  central  ner- 
vous system,  the  muscles,  the  nervous  mechanism  of  the  heart,  and  some 
other  organs,  and  also  upon  the  peripheral  nerves  and  the  parenchyma 
of  various  organs. 

An  atmosphere  becomes  dangerous  when  it  contains  0.05  per  cent,  of 
carbon  monoxide  (Gruber,  Haldane).  Severe  symptoms  may  be  caused 
by  0.02  per  cent.  (Haldane).  Fodor  has  shown  the  presence  of  carbon 
monoxide  in  the  blood  of  animals  that  had  breathed  an  atmosphere  con- 
taining only  one  part  in  25,000,  but  such  amounts  are  not  positively 
known  to  cause  any  ill  effects.  This  whole  subject  has  recently  been 
extensively  reviewed  by  W.  Sachs. ^ 

Symptoms. — ^The  main  symptoms  of  acute  poisoning  are  an  indefinite 
feeling  of  illness,  usually  accompanied  by  throbbing  of  the  vessels,  a 
burning  sensation  in  the  face,  and  soon  by  severe  headache,  vertigo,  and 
very  marked  muscular  weakness,  the  latter  being  a  somewhat  character- 
istic and  peculiar  symptom.  Nausea  and  vomiting  often  occur.  If  the 
dose  is  large,  severe  symptoms  develop;  the  subject  becomes  drowsy  and 
then  loses  consciousness,  and  with  this,  there  is  usually  loss  of  control 
over  the  sphincters.  Sometimes  unconsciousness  comes  rather  gradually, 
sometimes,  as  occasionally  with  miners,  for  example,  it  may  be  the  first 
symptom,  and  the  subject  may  drop  as  suddenly  as  if  he  had  been  shot. 
Muscular  twitching  is  common,  even  in  the  earlier  stages,  and  sometimes 
convulsions  occur  when  the  symptoms  have  become  more  marked.  Very 
commonly  the  patient  is  not  seen  until  he  is  unconscious,  when  he  shows 
heavy  and  unduly  rapid  breathing,  the  pulse  is  sometimes  fairly  full  and 
strong  but  generally  very  rapid,  and  it  is  weak  if  the  poisoning  is  severe  or 
advanced.  The  skin  and  mucous  membranes  are  usually  more  or  less 
cyanotic,  but  this  is  sometimes  made  obscure  by  a  peculiar  and  character- 
istic redness  of  the  skin.  There  are,  at  times,  the  red  patches  on  the  skin 
mentioned  under  pathology.  Drawn  blood  is  bright  cherry-red  in  color 
and  gives  the  characteristic  reactions  for  carbon  monoxide.  If  recovery 
occurs,  there  is  a  gradual  awakening,  and  for  some  hours,  often  much 
longer,  a  hazy  mental  state  persists.  Coma  may  last  many  days  and  then 
be  followed  by  recovery.  Gilman  Thompson,^  considers  it  a  bad  sign  if 
the  leukocytosis,  which  is  usually  present,  is  of  high  degree. 

The  sequelae  are  common  and  interesting.  There  may  be  nothing  but 
weakness  and  fever;  these  usually  occur  in  some  degree  and  last  for 
variable  periods,  it  may  be  for  only  a  day,  or  even  for  several  weeks 
particularly  when  pulmonary  sequelae  develop.  The  fever  is  frequently 
associated  with  bronchopneumonia,  much  less  commonly  with  lobar 
pneumonia,  but  sometimes  no  cause  for  it  is  evident.  This  fever  has 
caused  interesting  errors  in  diagnosis,  particularly  in  accidental  cases, 
and  especially  when  the  poisoning  has  been  prolonged,  but  not  severe 
enough  to  cause  violent  cerebral  manifestations  at  the  onset.  House 
epidemics  that  were  very  puzzling  and  in  which  the  cause  was  traced 
with  great  difficulty,  have  occurred  and  have  repeatedly  suggested  infec- 
tions; cases  have  been  considered  to  be  typhoid  fever,  for  example,  be- 
cause of  the  fever  and  "typhoid  state."    Pulmonary  sequelae  as  indicated 

^  Die  Kohlenoxydvergiftung,  etc. 
2  Medical  Record,  July  9,  1904. 
10 


146  DISEASES  DUE  TO  CHEMICAL  AGENTS 

are  very  common.  Bronchitis,  bronchoj)neumonia,  rarely  lobar  pneumo- 
nia, occur  and  are  of  extremely  variable  duration,  sometimes  causing 
death  weeks  after  the  poisoning.  Tlie  vascular  system  shows  marked 
involvement  during  the  acute  attacks,  and  localized  hyperemias,  cardiac 
palpitation,  and  irregularity  often  occur  for  indefinite  periods  alterw^ard. 
Gastro-intestinal  disturbance  is  not  uncommon  and  may  persist  for  a 
long  time;  gastric  irritability,  tenderness  and  pain  of  long  duration  have 
been  repeatedly  describeil.  Icterus  has  been  seen  in  rare  instances.  A 
striking  and  very  common  symptom  of  the  poisoning,  which  is  a  sequel 
also,  though  a  transitory  one,  is  glycosuria.  Skin  lesions  are  common; 
local  necroses  and  gangrene  in  areas  ex])osed  to  pressure  occur  frequently, 
and  heal  slowly,  and  vesicular,  herpetic,  and  bullous  lesions  have  often 
been  seen  and  they  also  heal  poorly.  Localized  oedema  (Klebs)  or 
gelatinous  infiltration  (Litten)  and  curious  areas  of  redness  and  swelling, 
that  may  closely  resemble  cellulitis,  have  occurred. 

The  most  important  sequelae  involve  the  nervous  system.  Neuritis, 
usually  localized,  with  paralysis  and  anaesthesia,  neuralgias,  choreiform 
movements,  intention  tremor,  scanning  or  stuttering  speech,  and  incon- 
tinence of  urine  have  been  seen  alone  or  associated  with  other  symptoms. 
Cases  with  symptoms  of  Landry's  paralysis  or  of  distinct  multiple  sclero- 
sis have  been  described.  Ocular  disorders  are  not  very  common  but  are 
extremely  interesting;  there  may  be  partial  or  complete  blindness  of  vary- 
ing duration,  with  or  without  ophthalmoscopic  changes,  xanthopsia, 
nystagmus,  and  paralyses  of  the  eye  muscles,  and  there  have  been  re- 
peated instances  of  complete  ophthalmoplegia  with  marked  protrusion  of 
the  eyeballs.  Occasionally,  deafness  or  roaring  noises  in  the  ears  develop. 
Persistent  headache  sometimes  follows.  The  most  common  and  the 
gravest  nervous  sequelae  are  those  due  to  cerebral  changes;  these  may  be 
local  or  diffuse  and  the  results  are  chiefly  paralyses  or  mental  disturbances. 
These  disorders  tend  to  occur  chiefly  in  those  well  advanced  in  life,  but 
have  been  seen  even  in  a  five  year  old  child;  they  may  develop  a  con- 
siderable time  after  the  poisoning.  The  paralyses  from  this  cause  are,  of 
course,  likely  to  persist;  they  may  be  monoplegic  or  hemiplegic.  The 
mental  disturbances  vary  much  in  type;  they  include  simple  hallucina- 
tions, simple  confusion  of  more  or  less  pronounced  degree,  very  remark- 
able instances  of  amnesia,  mania;  but  most  "commonly,  the  mental 
disturbances  are  confusional  states  or,  in  persistent  cases,  actual  dementia. 

It  is  of  very  great  importance  to  keep  in  mind  the  fact  that  sequelae  of 
all  kinds  may  appear  immediately  after  the  poisoning,  or  may  be  post- 
poned for  weeks;  blindness,  paralyses,  mental  disturbances  and  other 
sequelae  have  repeatedly  been  seen  days  or  weeks  after  the  poisoning,  and 
the  cerebral  changes  have  a  strong  tendency  to  be  delayed  in  their  appear- 
ance. It  is  of  equal  importance  to  UQte  that  sequelae  often  of  much  gravity 
may  be  caused  by  a  mild  attack  of  poisoning.  Cheneau,  in  his  investiga- 
tions, was  very  moderately  poisoned  but  had  distinct  mental  and  physical 
symptoms  for  months  afterward,  and  Professor  Smith's  students  had  in 
both  instances  weeks  of  disturbance,  which  in  the  one  case  was  a  "far 
away"  mental  feeling,  in  the  other  marked  depression. 

The  symptoms  of  chronic  poisoning  have  not  been  satisfactorily 
studied.  They  differ  qualitatively  as  well  as  quantitatively  from  those 
seen  in  acute  cases.     There  are  complaints  of  headache,  vertigo,  nausea 


CARBON  MONOXIDE  POISONING  147 

and  sometimes  vomiting.  Often  there  is  slow  pulse  and  usually,  there 
is  general  weakness,  languor,  and  anaemia;  very  recently,  however.  Rein- 
hold  has  described  two  interesting  cases  in  which  there  was  a  pronounced 
polycythsemia  with  over  11,000,000  red  cells.  With  the  above  mentioned 
symptoms,  there  is  usually  some  mental  disturbance,  lack  of  concentra- 
tion, sluggish  intellectual  action  or  poor  memory.  These  symptoms  tend 
to  increase,  and  may  be  associated  with  weak  or  absent  tendon  and  pupil- 
lary reflexes ;  Musso  described  a  series  of  5  patients,  2  of  whom  recovered 
after  nine  months,  while  the  other  3  became  demented  and  died  with  the 
typical  picture  of  paretic  dementia.  This  subject  is  one  that  deserves 
much  more  general  attention  and  study,  particularly  in  relation  to  poi- 
soning from  combustion  products. 

Diagnosis.— This  depends  upon  the  history,  a  knowledge  of  the  tech- 
nique of  the  patient's  occupation,  or  demonstration  of  the  presence  of 
carbon  monoxide  in  the  blood.  The  best  tests  for  the  latter  are  Hoppe- 
Seyler's  sodium  hydrate  test  or  his  spectroscopic  test;  Katagama's  reac- 
tion; or  the  Kunkel-Welzer  reaction  with  potassium  ferrocyanide  and 
acetic  acid.  The  sodium  hydrate  test  is  made  with  a  solution  of  about 
1.30  specific  gravity;  add  this  to  the  blood,  and  with  carbon  monoxide 
poisoning  the  result  is  a  clotted  mass  of  bright-red  color,  while  normal 
blood  gives  a  mucoid-like  mass  of  greenish-brown  color.  The  spectro- 
scopic test  depends  upon  the  fact  that  carbon  monoxide  haemoglobin  is 
not  reduced  by  such  substances  as  ammonium  sulphide.  Oxyhsemoglo- 
bin  and  carbon  monoxide  haemoglobin  produce  two  absorption  bands 
that  are  much  alike,  the  chief  difference  being  that  the  carbon  monoxide 
haemoglobin  bands  are  somewhat  nearer  the  violet  end  of  the  spectrum. 
If,  however,  ammonium  sulphide  is  added,  normal  blood  shows  the  single 
band  of  reduced  haemoglobin,  though  this  often  becomes  accompanied 
soon  after  by  the  haematin  band;  ammonium  sulphide,  on  the  contrary, 
does  not  affect  the  carbon  monoxide  haemoglobin  spectrum,  and  the  ab- 
sorption bands  therefore  remain  as  before.  With  some  care  they  can  be 
easily  distinguished  from  the  two  bands  due  to  reduced  haemoglobin  and 
haematin,  for  the  haematin  band  lies  in  the  red,  while  the  carbon  monoxide 
bands  are  both  in  the  yellow.  Katagama's  test  consists  in  adding  to  10 
c.  c.  of  blood  diluted  with  water  0.2  c.  c.  of  ammonium  sulphide  solution 
and  0.2  c.c.  of  30  per  cent,  acetic  acid.  Carbon  monoxide  blood  gives  a 
bright-red  precipitate,  normal  blood  a  greenish  precipitate.  In  the  Kun- 
kel-Welzer test,  undiluted  blood  is  used  and  an  equal  amount  of  20  per 
cent,  potassium  ferrocyanide  and  a  small  quantity  of  30  per  cent, 
acetic  acid  are  added;  carbon  monoxide  blood  gives  a  bright-red  color, 
normal  blood  blackish-brown;  the  difference  may  persist  for  weeks. 
Tests  may  be  made  with  copper  salts,  lead  acetate,  etc.;  the  precipitate 
that  they  produce  with  carbon  monoxide  blood  is  bright  red  while  with 
normal  blood  it  is  a  dirty  dark-brown  color. 

These  tests  in  doubtful  acute  attacks  will  occasionally  clear  up  tht> 
nature  of  subsequent  sequelae.  Two  years  ago,  for  example,  a  patient  in 
the  care  .of  the  author  had  for  over  six  weeks  insanity  of  confusional  type 
associated  with  marked  hallucinations,  and  ending  in  paralysis  and  death; 
the  nature  of  the  case  would  have  been  very  obscure  had  it  not  been  de- 
termined by  chemical  tests  when  he  was  admitted,  at  which  time  he  was 
comatose. 


148  DISEASES  DUE   TO   CHEMICAL  AGENTS 

The  poisoning  should  be  easily  recognized  if  tiie  history  is  clear,  but 
may  readily  be  niisinterj)reted  if  the  source  is  not  known.  Acute  attacks 
are  likely  to  be  mistaken  for  alcoholism  or  unemia.  Among  the  points 
distinguishing  them  from  the  former,  are  the  absence  of  odor  of  alcohol, 
the  marked  hyi)erannia  of  the  surface  and  the  chemical  tests.  Uraemia 
is  distinguished  chiefly  by  the  urinary  conditions  and  the  cardiovascular 
changes,  together  with  the  history  and  the  absence  of  carbon  monoxide, 
if  tested  for.  Chronic  cases  are  very  difficult  of  proj)er  interpretation. 
Pettenkofer  insists  upon  the  im])ortance  of  looking  for  this  cause  of 
poisoning,  if  various  persons  in  the  same  house  have  a  tendency  to  wake 
with  headache  or  nausea.  Proper  consideration  of  the  occuy)ation  will 
often  lead  to  a  correct  diagnosis  of  chronic  cases.  The  reliability  and 
delicacy  of  chemical  tests  of  either  the  blood  or  the  res})ired  atmosphere  in 
chronic  cases  are  not  very  certain  as  yet,  and  these  have  not  so  far  been 
made  very  valuable  to  clinicians. 

Prognosis. — In  acute  cases,  this  depends  largely  upon  the  dose,  but 
much  more  upon  the  rapidity  with  which  treatment  is  undertaken. 
Patients  usually  recover  if  they  are  promptly  and  energetically  treated; 
in  the  last  five  years,  there  have  been  received  in  the  EjMscopal  Hospital, 
Philadelphia,  39  cases;  of  these,  34  recovered;  and  of  the  fatal  cases 
several  were  due  to  sequelfe.  Even  with  recovery  from  acute  symptoms, 
the  prognosis  should  be  a  little  guarded  for  at  least  a  month  or  six  weeks, 
until  it  is  determined  that  sequelae  are  not  about  to  follow,  for  some  of 
the  most  serious  after-effects  have  ensued  upon  mild  poisoning.  If 
sequelae  occur,  their  prognosis  must  be  determined  by  the  individual 
circumstances;  naturally,  those  due  to  central  nervous  lesions  are  especially 
unfavorable.  Sequelae  are  more  likely  to  occur  in  persons  of  advanced 
years,  particularly  the  cerebral  ones.  The  chronic  poisonings  are  of 
good  prognosis  if  they  have  not  caused  distinct  mental  changes.  In  the 
latter  case  it  must  be  guarded. 

Treatment. — The  treatment  of  acute  poisoning  consists  in  immediate 
removal  from  the  poisoned  atmosphere,  free  use  of  oxygen  inhalations, 
venesection  followed  by  intravenous  or  hypodermic  administration  of 
normal  salt  solution,  artificial  respiration  if  necessary,  and  the  generous 
exhibition  of  stimulants  (caffeine,  digitalis,  strychnia)  if  they  are  required. 
Persistent  treatment  suffices  to  bring  most  cases  out  of  even  the  most  des- 
perate straits.  In  chronic  cases,  the  removal  of  the  cause  is  of  chief  im- 
portance, with  subsequent  treatment  of  the'  anaemia  or  other  features. 
This  condition  is  deserving  of  greater  attention  from  the  standpoint  of 
prophylaxis,  particularly  in  the  dwellings  and  workrooms  of  the  poor, 
who  often  have  ill-constructed  heating  apparatus,  and  who  husband 
warmth  at  the  expense  of  breathing  bad  air.  The  general  public  also 
needs  to  have  a  better  appreciation  of  the  occasional  danger  attendant 
upon  the  use  of  gas  and  kerosene  stoves  and  water  heaters.  The  pro- 
phylaxis of  chronic  occupational  poisoning  is  dependent  chiefly  upon 
hygienic  construction  and  management. 


'  .  CARBON  MONOXIDE  POISONING  149 

CHRONIC  CARBON  BISULPHIDE  POISONING. 

Chronic  intoxication  with  carbon  bisulphide  has  never  received  much 
attention  in  America,  and  the  number  of  cases  that  occur  is  also  much 
smaller  than  it  was,  both  because  oi  hygienic  improvements  and  because 
local  conditions  of  trade  in  this  country  have  led  to  a  great  reduction  in  its 
use  here  in  the  manufacture  of  rubber  goods.  Other  substances  have 
to  a  large  extent  replaced  it  in  the  manufacture  of  rubber  clothes  espe- 
cially. Carbon  bisulphide  is  to  a  certain  extent  still  used  in  making  the 
cheaper  grades  of  rubber  clothes  and  also  some  other  rubber  articles,  espe- 
cially those  that  are  not  intended  for  long  service;  for  example,  it  is  pretty 
generally  used  in  the  manufacture  of  surgeon's  rubber  gloves.  Hence, 
although  this  form  of  poisoning  is  rare,  it  occasionally  occurs;  and  it  is 
probable,  as  Laudenhoimer  states,  that  a  very  considerable  proportion  of 
the  cases  that  do  appear  are  misinterpreted.  There  are  several  reasons 
for  the  latter  statement.  In  the  first  place  the  cases  reported  have  come 
chiefly  from  a  relatively  small  number  of  specially  interested  observers, 
while  the  industries  that  may  cause  poisoning  are  much  more  widespread, 
and  hence  it  is  probable  that  there  is  but  a  limited  appreciation  of  the 
fact  that  carbon  bisulphide  is  freely  used  in  certain  industries  and  that  it 
produces  poisoning  in  those  employed.  A  second  important  reason  is 
that  the  clinical  picture  of  the  poisoning  is  extremely  varied  and  there  are 
no  symptoms  that  directly  indicate  the  nature  of  the  intoxication,  knowl- 
edge that  exposure  has  occurred  being  necessary  in  order  to  establish  a 
diagnosis,  and  usually  even  to  suggest  it. 

Etiology. — Intoxication  with  this  substance  occurs  almost  entirely  as 
an  occupational  condition.  Acute  poisoning  has  occasionally  occurred  from 
swallowing  large  amounts  for  suicidal  purposes  or  by  mistake,  and  acci- 
dental intoxication  through  inhalation  has  been  described,  but  in  most 
acute  and  practically  all  chronic  cases  occupation  is  the  source.  Carbon 
bisulphide  is  used  chiefly  as  a  solvent  for  sulphur  and  various  fatty  sub- 
stances. The  industry  in  which  most  of  the  reported  cases  of  poisoning 
have  occurred  is  the  making  of  various  forms  of  rubber  goods,  vulcaniz- 
ing having  for  more  than  half  a  century  been  done  with  a  solution  of 
sulphur  in  carbon  bisulphide.  In  the  beginning  of  the  latter  half  of  the 
last  century,  when  the  substance  came  into  use  for  this  purpose,  the  vats 
containing  it  were  freely  exposed  in  rooms  that  had  poor  natural  ventila- 
tion and  no  special  ventilating  apparatus;  and  at  that  time  Delpech, 
who  made  the  earliest  and  a  very  thorough  and  extensive  investigation 
of  this  form  of  poisoning,  found  the  health  of  the  workmen  so  frequently 
and  so  seriously  affected,  that  governmental  action  to  control  the  use  of 
carbon  bisulphide  was  soon  taken.  Since  then,  comparatively  few  cases 
have  been  reported  from  France.  In  more  recent  times  many  cases  have 
occurred  in  England  and  Germany,  Laudenheimer  having  reported  over 
aO  cases  in  Leipsic  within  thirteen  years.  The  gravity  of  the  danger 
when  these  industries  are  practically  uncontrolled  is  illustrated  by  the 
fact  that  vulcanizing  "had  increased  at  least  tenfold  in  fifteen  years"  in 
and  about  Leipsic,  and  yet  at  most  250  persons  were  employed  as  vul- 
canizers;  nevertheless  over  50  cases  of  severe  poisoning  had  occurred 
in  this  small  group  of  persons  within  thirteen  years,  and  from  one  factory 


150  DISEASES  DUE   TO  CHEMICAL  AGENTS 

where  only  10  persons  did  viilcanizino;,  6  eases  of  psyehosis  were  sent  to  the 
Leipsic  Psyehiatric  Clinic  in  the  period  1885-87.  Hebuilding  and  in- 
stituting hygienic  arrangements  in  this  factory  Avere  so  effectual  that  no 
cases  were  received  from  it  in  the  ensuing  four  years.  In  this  country 
carbon  bisulphide  is  probably  not  used  extensively  in  more  than  half  a 
dozen  rubber  factories.  In  one  of  these,  where  the  ventilating  apparatus 
is  excellent,  they  still  have  an  occasional  case  of  poisoning,  especially  of 
transitory  acute  intoxication  in  new  workmen;  in  some  others  they  state 
frankly  that  no  ])recautions  against  })oisoning  are  taken,  and  the  work- 
men employed  in  them  must  therefore  be  dangerously  exposed. 

Other  occupations  have  caused  intoxication  in  unusual  instances. 
Chemists,  for  example,  use  carbon  bisulphide  and  in  certain  lines  of  work 
employ  it  freely  and  frequently,  and  this  has  caused  even  grave  chronic 
poisoning;  but  the  exposure  of  chemists  is,  as  a  rule,  so  slight  and  so  brief 
that  serious  results  are  very  rare.  It  is  used  to  some  extent  in  extracting 
fats  from  wools,  in  purifying  paraffin  and  oils,  in  dissolving  asphalt,  in 
extracting  sul]>hur  from  some  ores  and  in  separating  crystalline  from 
amorphous  sulphur,  in  extracting  fats  from  seeds,  in  extracting  vegetable 
perfumes,  in  freeing  bones  from  fat,  in  making  collodion,  in  removing 
varnish,  and  in  various  other  ways,  even  in  exterminating  prairie  dogs  and 
rabbits.  In  most  of  these  the  manner  of  use  makes  the  danger  of  poisoning 
slight.  Serious  danger  may,  however,  occasionally  be  found  in  new  and 
unexpected  sources.  Recently  a  factory  producing  so-called  "artificial 
silk"  has  furnished  a  number  of  cases  at  the  University  Hospital  in 
Philadelphia. 

Pathology. — The  lesions  in  the  condition  have  been  little  studied  in 
human  beings.  Schwalbe,  Kiener  and  Engel,  and  Poincare  have  inves- 
tigated the  effects  on  animals,  and  Koster  has  recently  reported  the  most 
complete  and  suggestive  experimental  research  that  has  yet  been  made. 
Beyond  some  emaciation,  definite  and  constant  effects  do  not  seem  to  occur 
except  in  the  nervous  system.  Pigmentation  of  various  organs  was  noted 
by  Schwalbe  and  by  Kiener  and  Engel,  but  Koster  searched  for  it  with 
negative  results.  Changes  in  the  red  blood  corpuscles  have  also  been 
observed  but  are  not  constant.  The  same  is  true  of  meth;emoglobinuria 
(Westberg);  various  observers  have  found  it  absent.  In  human  cases 
any  noteworthy  blood  changes  are  not  usually  found.  The  cause  of 
death  in  acute  poisoning  seems  to  be  respiratory  paralysis  and  asphyxia 
(Lewin,  Koster),  and  any  blood  changes  seen  in  chronic  cases  are  prob- 
ably due  largely  to  mild  chronic  carbon  dioxide  poisoning.  The  nervous 
system  suffers  severely,  however,  and  Koster  considers  the  changes  he 
found  to  be  somewhat  specific.  He  observed  degenerative  changes  in  the 
medullary  sheaths  throughout  the  nervous  system,  but  less  marked  in  the 
nerve  roots  and  peripheral  nerves  than  in  the  central  nervous  system;  the 
myelin  was  fragmented  and  along  the  course  of  the  nerve  fibers  and  near 
them  were  large  round  or  oval  objects  and  also  numerous  granules,  both 
of  which  took  fat  stains;  the  nerves  also  showed  swelling  and  irregularity 
of  outline  and  oedema;  and  the  ganglion  cells  showed  several  striking 
forms  of  change.  In  the  ganglion  cells  fatty  degeneration  was  common, 
and  it  frequently  began  in  the  dendrites  or  in  localized  portions  of  the  cell 
body;  the  nucleus  frequently  became  involved,  though  later  than  the 
cell  body;    the  pericellular  spaces  were  frequently  widened;    the  end 


CARBON  MONOXIDE  POISONING  151 

branches  were  often  broken  oft".  Quensel  has  recently  reported  a  fatal 
human  case  in  which  there  were  extensive  clianges  in  the  central  nervous 
system  but  none  that  are  not  often  found  in  other  conditions. 

Mode  of  Entrance  and  Pathogenesis. — As  stated,  inhalation  is  the 
usual  mode  of  entrance,  but  there  is  some  distinct  clinical  and  experimental 
evidence  that  purely  local  changes  (anaesthesia,  para'sthesia,  neuritis) 
may  be  produced  by  frequently  dipping  an  extremity  into  carbon  bisul- 
phide. The  way  in  which  the  poison  acts  is  not  wholly  clear  but  it  seems 
certainly  to  have  a  special  affinity  for  the  central  nervous  tissue,  and  from 
what  is  generally  known  about  it  one  would  suspect  a  solvent  action  upon 
ihe lipoid  elements  of  this  tissue.  Acute  human  or  experimental  poisoning, 
except  that  convulsions  often  occur,  resembles  that  due  to  alcohol  or  to  the 
anaesthetics  in  that  it  produces  excitement  followed  by  narcosis,  and  in 
chronic  cases  the  effects  may  resemble  chronic  alcoholism;  but  the 
actual  chemical  action  has  not  been  determined. 

The  amount  of  poisoning  necessary  to  produce  symptoms  has  been 
studied  by  Rosenblatt  and  Hertel.  They  find  an  hour's  exposure  to  2.07 
mg.  per  liter  of  air  (Rosenblatt),  or  even  to  1.1  mg.  per  liter  (Hertel), 
sufficient  to  cause  symptoms;  when  seven  or  eight  hours'  work  must  be 
done,  an  atmosphere  containing  0.5  to  0.8  mg.  (Rosenblatt),  or  (accord- 
ing to  Hertel)  0.8  to  0.9  mg.,  per  liter  may  cause  poisoning.  Carbon  bisul- 
phide is  soon  eliminated,  a  day  or  two  usually  sufficing  for  the  excretion 
of  even  large  doses. 

Symptoms. — Some  emaciation  is  common;  nausea  or  vomiting  and 
constipation  may  occur  early;  eczema  is  sometimes  observed;  strangury 
has  been  noted;  and  disturbance  of  the  sexual  function  is  a  very  com- 
mon feature,  particularly  in  more  advanced  cases  with  marked  psychic 
or  spinal  symptoms,  but  sometimes  even  when  other  severe  nervous 
symptoms  are  absent.  The  earlier  stages  of  poisoning  are  often  asso- 
ciated with  sexual  excitement,  while  in  the  late  stages,  especially  when 
severe  nervous  symptoms  of  other  form  have  developed,  sexual  power 
is  usually  reduced  or  lost.  Nocturnal  emissions  or  involuntary  seminal 
discharges  also  appear  to  occur  frequently.  Women  show  menstrual 
anomalies,  and  if  they  become  pregnant  abortion  or  miscarriage  is  likely 
to  occur. 

Headache,  which  may  be  very  severe,  vertigo,  palpitation,  frightful 
dreams,  insomnia,  mental  depression,  and  apprehension  without  distinct 
psychosis,  may  be  present  in  the  earlier  stages,  and  the  English  Com- 
mittee that  investigated  this  poisoning  especially  insisted  upon  the  fre- 
quency of  visual  disturbances  even  in  very  early  stages. 

When  clearly  recognizable  intoxication  occurs,  however,  it  presents 
the  picture  of  organic  disease  of  the  nervous  system  with  or  without 
psychosis,  or  it  resembles  hysteria  more  or  less  closely,  or  organic  and 
"hysterical"  symptoms  are  combined.  The  grouping  of  symptoms  ap- 
pears to  be  of  almost  endless  variety.  The  common  presence  of  so-called 
hysterical  symptoms,  especially  of  anaesthesias  of  the  hysterical  type, 
usually  combined  with  symptoms  of  actual  organic  lesions,  is  one  of  the 
most  striking  characteristics.  A  much  graver  and  hence  more  important 
feature  is  the  tendency  to  pronounced  and  sometimes  incurable  psychoses. 
The  symptoms  of  a  spinal  lesion,  particularly  symptoms  of  tabetic  type  are 
also  often  present. 


152  DISEASES  DUE  TO  CHEMICAL  AGEXTS 

The  important  details  are  tlie  followino-.  Anivsthesia  is  extremely  com- 
mon. It  may  be  limited  to  the  area  of  distribution  of  one  or  more  nerves 
and  may  be  associated  with  other  signs  of  mononeiu'itis  or  polyneuritis, 
though  actual  eyidences  of  neuritis  are  apparently  yery  uncommon,  in 
spite  of  the  earlier  statements  of  the  French  School.  Much  more  fre- 
quently the  an.vstliesia  is  glove-like,  affecting  the  hands  or  feet  or  both, 
and  having  no  relation  to  nerve  distribution;  Delpech  thought  the  hands 
were  more  frequently  aniesthetic  or  paretic  in  those  whose  occupation 
caused  the  hands  to  be  much  exposed  to  the  vapor  or  fluid,  and  some 
other  authors  have  agreed  with  him,  while  still  others  have  questioned 
this.  Not  infrequently  there  is  hemianifsthesia,  diffuse  antiesthesia,  or 
local  areas  of  distinctly  hysterical  type.  Delayed  sensation  may  be  seen. 
Parresthesias  of  various  kinds  and  of  varied  distribution  also  occur;  a 
common  complaint  is  a  feeling  of  coldness,  especially  of  the  hands,  and 
the  extremities  may  actually  be  very  cold,  perhaps  as  a  result  of  local  ac- 
tion of  the  poison.  Hyperesthesia  occurs,  particularly  in  the  feet,  or 
more  commonly  in  the  ovarian  region,  in  cases  with  hysterical  symptoms. 
The  nerve  trunks  have  occasionally  been  found  tender,  Delpech  having 
repeatedly  noted  this,  and  Laudenheimer  having  seen  it  in  cases  in  which 
there  was  also  paralysis  of  the  peronei  and  therefore,  perhaps,  neuritis. 
Spontaneous  pain,  especially  along  the  course  of  nerves,  is  sometimes  quite 
marked  (Delpech,  Rosenblatt,  Hertel). 

The  special  senses  are  frequently  affected,  particularly  vision  and  taste. 
Ring  vision,  macropsia,  micropsia,  obscuration  of  vision,  chromatopsia, 
muscfe  volitantes,  and  other  disturbances  may  be  present  with  or  with- 
out signs  of  organic  lesion.  Ambyopia  is  extremely  common  even  early 
in  the  poisoning.  A  persistent  taste  of  carbon  bisulphide  long  after 
the  poison  must  have  been  completely  excreted  is  a  common  com- 
plaint, or  everything  may  taste  sweet  or  bitter.  In  their  experiments 
Rosenblatt  and  Hertel  noted  first  a  salty  and  then  a  bitter  taste.  Dis- 
turbances of  smell,  especially  a  constant  odor  of  carbon  bisulphide,  have 
been  repeatedly  observed.  Delpech  and  others  have  noted  more  or 
less  pronounced  unilateral  or  bilateral  deafness  or  roaring  noises  in  the 
ears. 

The  reflexes,  both  superficial  and  deep,  may  be  normal,  excited,  re- 
duced, or  lost.  The  cremasteric  reflex  is  often  absent,  particularly  when 
sexual  power  is  lost.  The  knee-jerk  shows  various  changes;  the  fact  that 
it  may  be  absent  is  a  point  of  much  importance  in  the  pseudotabetic 
cases,  as  is  also  the  fact  that  the  pupillary  reflex  may  show  any  variety  of 
change.  There  may  be  also  disturbance  of  the  sphincters  of  the  bladder, 
and  loss  of  sexual  power.  If  ataxia  is  joined  to  some  or  all  of  these  symp- 
toms, tabes  dorsalis  is  extremely  closely  simulated. 

Motor  symptoms  are  very  common.  Tremor  is  occasionally  observed; 
Laudenheimer  states  that  it  is  almost  constant  in  the  maniacal  form  of 
psychosis,  and  in  other  cases  it  is  at  times  associated  with  symptoms  that 
produce  a  resemblance  to  general  paresis  or  to  chronic  alcoholism.  Tre- 
mor has  been  seen  in  such  violent  form  that  it  greatly  or  completely  inter- 
fered with  the  patient's  work.  Ataxia  is  often  present ;  Koster  holds  that 
the  ataxia  and  the  common  weakness  of  the  peroneal  muscles  produce  a 
peculiar  and  characteristic  gait  with  a  combination  of  steppage,  ataxia, 
and  shuffling. 


CARBON  MONOXIDE  POISONING  153 

The  most  important  motor  symptom  is  paresis  or  paralysis,  paresis 
being  the  much  more  common.  In  severe  form  it  is  most  frequent  in  the 
peroneal  muscles,  and  the  especially  common  involvement  of  the  lovv^er 
extremities  has  led  many  to  the  view  that  the  poison  acts  upon  them 
locally,  since  the  vapor  is  heavy  and  tends  to  sink  to  the  lower  levels  of 
the  workrooms.  This  idea  is,  however,  pretty  well  disproved  by  the  fact 
that  in  animal  experiment  the  hind  legs  are  especially  affected,  even 
though  all  the  extremities  are  equally  exposed.  The  paresis  also  fre- 
quently involves  the  hands  and  arms,  and  a  feeling  of  general  weakness 
is  a  common,  indeed  an  almost  constant  complaint,  even  in  the  early 
stages  of  poisoning.  This  weakness  may  be  of  the  most  extreme  severity 
so  that  the  patient  may  become  unable  even  to  feed  himself.  Paresis  may 
be  of  one  extremity  alone,  or  of  both  legs  or  arms  or  of  half  of  the  body; 
and  the  actual  paralysis  that  occasionally  appears  may  have  asimilardistri- 
bution,  producing  monoplegia,  hemiplegia,  or,  more  commonly,  paraplegia. 

Muscular  irritability  is  often  increased  in  early  stages,  and  there  may 
be  cramps  and  local  spasms  of  the  facial,  the  orbicularis,  and  other  mus- 
cles. A  pseudotetanic  condition  has  been  described  by  Rendu.  General 
convulsions  are  a  peculiar  feature  of  acute  poisoning  as  contrasted  with 
other  narcotic  intoxications,  and  they  may  occur  in  severe  chronic  poison- 
ing and  may  even  become  persistent  (Laudenheimer).  Contractures 
may  follow  paralyses.  Atrophy  is  not  infrequent  in  the  cases  w^ith 
paresis  of  the  extremities;  it  involves  chiefly  the  interossei  and  the 
peroneal  muscles.  It  is  likely  to  be  associated  with  loss  of  faradic  ir- 
ritability and  degeneration  reaction;  and  a  point  of  much  interest  in 
relation  to  the  more  or  less  profound  weakness  of  the  extremities,  so  com- 
mon both  early  and  late,  is  that  poisoned  animals  showed  pronounced 
fatigue  reaction  (Koster). 

Psychic  disturbances  are  common  and  very  important.  Their  character 
varies  greatly.  Transitory  attacks  often  occur  in  which  there  are  hilarity 
and  general  exaltation  resembling  acute  alcoholism;  less  commonly  there 
is  depression.  If  the  exposure  continues,  these  attacks  occur  repeatedly 
and  more  readily,  and  a  more  or  less  prolonged  psychosis  may  develop. 
Symptoms  of  a  definite  psychosis  usually  appear  rather  suddenly,  and 
most  commonly  in  persons  who  have  a  hereditary  predisposition.  As  a 
rule  they  develop  after  but  a  few  weeks'  exposure,  while  other  severe 
nervous  symptoms  (spinal  or  hysterical)  are  not  likely  to  occur  unless  the 
exposure  has  been  prolonged.  Laudenheimer  divides  the  psychoses  into 
three  general  groups;  while  the  psychic  symptoms  are  so  variable  that  it 
is  doubtful  whether  any  classification  can  be  well  adhered  to,  this  group- 
ing serves  to  make  somewhat  clearer  a  description  of  the  characters  that 
the  cases  are  likely  to  present.  He  describes  a  maniacal,  a  depressive,  and 
a  stuporous  form.  The  first  is  important  in  that  the  prognosis  is  almost 
always  good;  it  usually  occurs  in  persons  with  a  good  family  history;  it 
develops  suddenly;  and  the  chief  feature  is  motor  and  intellectual  excite- 
ment, usually  hilarity.  Erotism  is  common;  hallucinations  rarely  occur. 
Hypochondriacal  complaints  constitute  an  odd  but  frequent  feature, 
and  tremor  is  almost  constant.  The  pupils  are  usually  unequal  or  react 
slowly.    The  duration  is  rather  short,  usually  one  to  four  months. 

The  depressive  form  is  of  much  worse  prognosis;  four  of  Lauden- 
heimer's  ten  cases  persisted.    This  form  exhibits  marked  hallucinatory 


154  DISEASES  DUE  TO  CHEMICAL  AGENTS 

delusions  and  excitement,  with  profound  apprehension  and  severe  hypo- 
chondriasis. The  favorable  cases  average  three  and  three-quarters 
months'  duration.  Sinijile  melancholia,  Laudenheinier  has  never  seen. 
The  stuporous  form  may  be  acute  and  raj)idly  ini]:)rove,  or  may  persist. 
This  form  shows  no  motor  excitement.  The  pupils  are  dilated  and  react 
slowly.  Other  varied  psychic  disturbances  also  occur,  and  the  indi- 
vidual cases  do  not  readily  come  within  distinctive  groups. 

The  symptoms  of  hysterical  character  in  this  poisoning  are  of  great 
interest  in  themselves,  and  also  of  special  interest  because  they  have 
been  used  by  some  authors,  particularly  of  the  French  School,  in  favor 
of  the  view  that  hysteria  is  due  to  some  essential  anomaly  in  the  indi- 
vidual and  is  merely  brought  out  by  any  "provocative  agent"  such  as 
carbon  bisulphide,  and  is  not  due  to  any  direct  efiects  of  such  agents. 
It  has  even  been  claimed  by  jMarie  and  others  that  carbon  bisulphide 
poisoning  is  essentially  hysteria.  Koster,  however,  has  shown  that  anaes- 
thesia of  characteristically  hysterical  distribution  was  produced  in  a  large 
proportion  of  the  animals  poisoned  with  carbon  bisulphide,  a  sufficient 
evidence  that  the  anaesthesia  need  not  be  "hysterical,"  even  though  its 
distribution  is  of  this  type.  As  has  been  noted,  hysterical  signs  are  often 
combined  with  those  of  chronic  disease.  The  latter  signs  may  be  of  the 
most  mixed  and  illogical  character,  but  in  such  cases  organic  disease  is 
usually  present,  and  the  anaesthesias  even,  though  of  hysterical  type,  are 
probably  due  to  organic  lesions.  In  other  cases  careful  search  for  dis- 
tinct signs  of  organic  disease  has  apparently  shown  their  absence,  and 
there  are  only  functional  symptoms,  such  as  profound  weakness,  visual 
and  gastric  disturbance,  and  hypochondriasis,  together  with  stigmatic 
anaesthesia.  The  interpretation  of  these  cases  is  difficult,  but  it  seems 
to  me  that  Koster  makes  good  his  contention  that  there  is  no  definite 
place  to  draw  a  dividing  line,  and  these  should  be  provisionally  consid- 
ered to  be  actual  organic  carbon  bisulphide  poisoning  rather  than  essential 
hysteria  in  which  carbon  bisulphide  is  a  mere  collateral  provocative 
agent. 

Diagnosis. — This  depends  upon  a  knowledge  of  exposure  to  carbon 
bisulphide.  The  only  characteristic  features  of  the  symptoms  are  their 
extremely  varied  character  and  the  apparently  illogical  manner  in  which 
they  are  often  combined,  and  these  are  manifestly  insufficient  for  a  diag- 
nosis if  there  is  not  a  good  suspicion  at  least  of.  exposure.  The  dis- 
tinction from  psychic,  spinal,  ocular,  and  hysterical  disorders  of  other 
source  will  depend  upon  demonstration  of  exposure;  the  exclusion  of 
tabes  dorsalis,  for  example,  may  depend  almost  absolutely  upon  this,  so 
closely  may  it  be  simulated.  Occasionally  other  central  nervous  lesions 
will  be  extremely  closely  simulated;  sometimes  neuritis  is  present,  in 
which  case  the  cause  may  easily  be  overlooked;  more  often  neuritis  will  be 
simulated  by  central  lesions. 

The  determination  of  the  character  of  the  lesion  present  demands  care- 
ful study  of  the  symptoms.  Peripheral  neuritis  was  accepted  as  present  in 
many  cases  by  the  French  School,  particularly  in  the  pseudotabetic 
cases,  but  more  accurate  observation  almost  always  demonstrates  signs 
of  central  disease  in  such  cases.  Hysteria  is  very  likely  to  be  diagnosed 
in  a  considerable  proportion  of  cases,  but  more  careful  study  will  fre- 
quently show  evidences  of  organic  lesion ;    and  even  when  these  evidences 


CARBON  MONOXIDE  POISONING  155 

are  absent  it  is  not  justifiable,  in  this  poisoning  at  any  rate,  to  consider 
hysterical  symptoms  entirely  functional. 

Prognosis. — Mild  transitory  attacks  of  psychic  or  other  disturbances 
are  not  likely  to  be  followed  by  any  permanent  results  unless  exposure 
continues;  when  the  exposuredoes  continue  and  repeated  transitory  attacks 
of  intoxication  occur  there  is  serious  danger  of  a  grave  psychosis.  The 
outlook  in  these  cases  has  been  already  indicated.  The  cases  with  spinal 
symptoms  and  those  with  peripheral  symptoms  usually  recover  slowly, 
but  if  they  have  lasted  for  a  long  time  and  the  symptoms  are  very  severe 
there  may  be  little  or  no  improvement.  The  general  depression  of  health 
and  the  hysterical  symptoms,  muscular  weakness,  etc.,  appear  to  last  for 
a  long  time.  The  eye  symptoms  are  of  much  importance.  They  often 
recover  but  the  English  Ophthalmological  Society  found  that  about 
20  per  cent,  showed  no  improvement  and  about  25  per  cent,  more 
showed  imperfect  recovery.  Recurrence  of  any  symptoms  from  which 
the  patient  has  recovered  or  the  development  of  new  symptoms  is 
extremely  probable  if  he  returns  to  worl^  in  which  he  is  exposed. 

Prophylaxis  and  Treatment.— Prophylaxis  should  be  of  very  specific 
character.  Treatment  is  almost  entirely  symptomatic.  Workmen 
should  wear  gloves  and  use  instruments  for  dipping  the  material  into  the 
carbon  bisulphide  mixture  instead  of  exposing  their  hands,  and  they 
should  also  be  taught  extreme  care  about  exposing  themselves  to  inhala- 
tion of  the  vapor.  All  these  will  be  of  relatively  little  avail,  however, 
unless  proper  ventilation  is  secured  by  means  of  special  apparatus  and 
the  rooms  are  so  constructed  that  proper  ventilation  can  be  carried  out. 
If  these  things  are  done  most  of  the  cases  can  be  avoided.  When  the 
poisoning  has  developed,  treatment  is  largely  a  question  of  absolute 
removal  from  exposure,  symptomatic  drug  treatment  when  necessary,  and 
the  use  of  the  general  eliminative  measures  indicated  in  any  intoxication. 
Phosphorus  was  at  one  time  used  freely  by  the  French  School,  they 
believed  with  good  results ;  but  apparently  it  is  no  longer  used,  and  there 
is  no  drug  that  has  any  peculiar  value.  Oxygen  inhalations  have  been 
recommended  but  are  probably  of  little  use.  The  most  important  points 
are,  unquestionably,  fresh  air;  passive  or,  if  possible,  moderately  active 
exercise;  and  seeing  to  it  that  the  excretion  from  the  intestines  and  kidneys 
is  satisfactory.  Alcohol  should  be  rigidly  excluded,  as  should  sexual  and 
other  excesses. 


PART  IV. 
DISEASES  CAUSED  BY  OE&Al^IC  AGENTS. 


CHAPTER  IX. 

AI.COHOL. 
By  ALEXANDER  LAMBERT,  M.D. 

Historical. — ^From  time  immemorial  man  has  used  some  substances 
to  help  increase  the  joys  of  life  or  deaden  the  keen  edge  of  sorrow. 
Alcohol  in  some  form  has  probably  been  most  extensively  employed  for 
these  purposes  and,  whenever  used,  it  has  been  to  excess.  The  monu- 
ments of  the  Egyptians  show  the  use  and  abuse  of  wine;  the  oldest 
Chinese  manuscripts  contain  records  of  drunkenness;  and  in  the  Vedas 
there  are  prayers  to  the  Deity  beseeching  Him  to  condescend  to  come 
and  get  drunk  with  his  worshippers,  that  he  might  grant  their  requests 
and  bestow  favors  upon  them  which,  when  sober,  he  would  refuse.  The 
Old  Testament  contains  records  of  its  widespread  use,  of  consequent 
drunkenness,  and  warnings  against  the  evils  which  follow  alcoholic 
excess.  As  civilization  developed,  man  learned  to  make  liquids  contain- 
ing a  higher  content  of  alcohol  and  the  civilized  races  have  taught  the 
uncivilized  to  substitute  the  distilled  for  the  weaker  fermented  liquids. 
Acute  and  chronic  alcoholism  have  been  present  from  the  unknowable 
past  to  the  present  day,  and  their  occurrence  has  always  been  bound 
up  in  the  routine  of  man's  daily  toil,  in  the  expression  of  his  emotions, 
and  in  the  performance  of  his  religious  rites. 

Etiology. — An  unstable  nervous  system  is  the  fundamental  basis  on 

which  habitual  alcoholic  excesses  develop.     There  is  the  weakness  of 

will,  the  tendency  to  over-indulgence,  the  lack  of  self-control,  and  when 

once  the  narcotic  effect  of  alcohol  is  felt,  the  inevitable  craving  for  more 

cannot  be  resisted.     In  these  weak  individuals  there  is  often  the  marked 

self-conceit  which  deludes  them  into  the  belief  that  they  can  resist  when 

they  wish  and  that  further  indulgence  will  make  no  difference.     Among 

the  very  poor  the  grinding  weariness  of  overwork  and  insufficient  food 

drives  them  to  seek  temporary  relief  in  alcohol,  and  before  long  what 

was  first  only  a  luxury  becomes  a  dominating  necessity.     The  false  idea 

that  alcohol  is  a  tonic  and  strength-producer  causes  many  of  the  poor 

to  give  alcohol  to  their  children  and  thus  lay  the  foundation  for  early 

157 


158  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

excess.  In  Bellevue  Hospital,  New  York,  in  259  young  male  alcoholics 
in  whom  there  was  no  mental  degeneration  from  chronic  alcoholism 
and  whose  statements  therefore  may  be  deemed  fairly  accurate,  4  be- 
gan before  six  years  of  age,  13  between  six  and  twelve,  60  between 
twelve  and  sixteen,  102  between  sixteen  and  twenty-one,  71  between 
twenty-one  and  thirty,  and  8  after  thirty  years  of  age.  Almost  all 
gave  a  history  of  intemperance  in  other  members  of  their  families. 
The  force  of  example  is  therefore  often  a  potent  cause  of  alcoholism; 
the  fear  of  ridicule  from  their  comrades  and  what  is  thought  to  be 
social  necessity  or  a  vain  desire  to  be  thought  manly,  arc  also  factors 
in  certain  individuals.  In  the  struggle  to  improve  their  position,  in- 
dividuals are  often  placed  in  new  environments  for  which  they  are  un- 
])repared,  or  over-education  for  the  position  in  life  which  by  force  of 
circumstances  they  must  occupy,  produces  a  mental  dissatisfaction,  with 
a  consequent  strain  on  their  nervous  systems,  and,  turning  to  alcohol  for 
relief,  they  soon  become  addicted  to  its  excessive  use.  Lives  of  idle- 
ness and  pleasure-seeking,  among  the  wealthy,  not  infrequently  lead 
to  alcoholism.  In  this  country  there  is  a  little  appreciated  but  not 
uncommon  cause  of  alcoholism  in  the  use  of  patent  medicines  and 
nostrums  as  tonics  and  cure-alls.  A  large  number  of  these  nostrums 
contain  from  6  to  47^  per  cent,  of  alcohol  and  they  seem  to  be  popular 
in  ratio  to  their  alcoholic  content.  Chronic  alcoholism  has  thus  been 
unwittingly  acquired.  Many  acquire  alcoholic  habits  in  their  endeavors 
to  alleviate  the  pains  of  disease  or  disordered  functions.  The  worries 
of  life,  business  or  domestic,  and  the  desire  for  relief  from  sorrow,  fre- 
quently cause  men  and  women  to  seek  oblivion  in  alcoholic  narcosis. 

While  the  environment  of  certain  occupations  is  a  factor  in  producing 
alcoholism,  it  is  equally  true  that  in  other  situations  it  produces  tem- 
perance and  sobriety.  The  demands  of  modern  machinery  and  elec- 
trical devices  require  a  clear  mind  and  steady  hands,  both  for  the 
production  of  good  work  and  also  as  a  matter  of  self-protection,  so  that 
employers  are  more  and  more  demanding  sobriety  among  their  em- 
ployees. In  the  large  centres  of  population  these  have  been  potent 
factors  in  the  diminution  of  alcoholism  among  the  younger  working 
men.  Judging  from  some  10,636  male  alcoholics  admitted  to  Bellevue 
Hospital,  New  York,  the  professions  in  which  mental  strain  with 
worry,  excitement  and  especially  irregular  hours,  are  a  predominating 
factor,  show  a  larger  proportion  of  alcoholics  than  those  in  which  such 
conditions  are  less  pronounced.  Journalists,  actors,  and  physicians  are 
thus  more  prone  to  alcoholism  than  lawyers,  engineers  and  other  profes- 
sional men.  Bookkeepers,  clerks,  accountants,  and  stenographers,  seem 
as  a  class  to  show  a  high  proportion  of  those  who  drink  to  excess. 
A  craving  for  excitement  as  a  reaction  to  what  seems  a  monotonous 
existence,  may  account  for  the  large  numbers  in  this  class  of  occupation. 
Those  demanding  physical  exertion  near  fires,  such  as  stokers,  firemen, 
black-smiths,  iron  and  brass  moulders,  have  long  been  recognized  as 
producing  a  craving  for  alcohol  to  relieve  the  physical  exhaustion.  Stable 
men,  hostlers,  hackmen,  and  teamsters  of  all  kinds,  men  whose  occupa- 
tions vary  with  periods  of  hard  work  and  rest  and  idleness,  together 
with  exposure  to  varying  weather,  form  a  large  class  in  cities,  who  unfor- 
tunately acquire  their  habits  of  intemperance  in  the  early  and  most  pro- 


ALCOHOL  150 

ductive  years  of  life.  The  age  of  more  than  half  of  the  admissions  in 
the  large  numbers  belonging  to  these  occupations  was  from  five  to  fifteen 
years  less  than  the  age  at  which  the  greatest  number  of  alcoholics  was 
admitted  to  the  hospital.  Among  the  large  number  of  men  employed  in 
the  building  trades  in  New  York,  alcoholism  predominated  in  the  following 
order:  stone-cutters,  plasterers,  painters,  masons,  roofers  and  copper- 
smiths, plumbers  and  carpenters.  From  the  opportunities  and  tempta- 
tions of  their  occupation,  saloon-keepers,  bartenders  and  waiters  show  a 
high  ratio  of  alcoholism.  Among  some  2,700  female  alcoholics  admitted 
to  Bellevue  Hospital,  house  work  and  domestic  service  was  given  as  the 
occupation  in  more  than  half,  but  this,  in  a  large  but  unknown  number, 
really  hid  prostitution.  Laundresses  and  cooks  predominated  among 
those  whose  definite  domestic  service  was  given.  Seamstresses,  dress- 
makers, and  miUiners  comprised  about  six  per  cent,  of  the  admissions 
and  were  more  numerous  than  women  working  in  factories  and  shops. 

The  influence  of  heredity  is  believed  by  sorne  authors  to  be  more 
potent  than  environment.  Plutarch's  saying  that  "drunkards  beget 
drunkards"  has  been  long  recognized.  Many  descendants  of  alcoholic 
parents  inherit  a  weakened  and  unstable  nervous  system.  How  large 
this  proportion  is  to  the  total  of  such  descendants  it  is  impossible  to 
calculate,  but  that  it  is  large  is  undoubtedly  true.  The  statistics  of 
many  institutions  show  that  from  20  to  75  per  cent,  of  these 
alcoholics  have  had  either  an  alcoholic  father  or  mother,  or  both 
parents  given  to  such  excesses.  The  compelling  craving  for  alcohol  in 
the  parent  is  not  inherited  but  a  weak  and  unstable  nervous  system  which 
renders  the  individual  liable  to  excess  in  all  things,  and  slighter 
indulgences  lead  quicker  to  the  formation  of  the  alcoholic  habit. 

It  is  of  interest  to  note  the  relation  of  age  to  the  admissions  for  var- 
ious forms  of  alcoholism  in  Bellevue  Hospital.  For  comparison,  the 
ages  of  10,636  male  and  8,132  female  admissions  were  taken.  The 
largest  number  of  admissions  for  males  occurred  in  the  period  33-37, 
and  the  largest  number  of  females  in  the  period  28-32.  Up  to  the 
ag3  of  thirty-two  there  was  a  greater  percentage  of  women  than  men. 
Between  thirty-three  and  fifty-seven  there  was  a  greater  percentage  of 
men;  at  58-62  and  older,  there  was  a  slightly  larger  percentage  of  women. 
Of  the  women  20.8  per  cent,  were  in  the  period  of  28-32  and  19.9  per 
cent,  of  the  men  in  the  period  33-37.  Of  the  women  17.2  per  cent.,  and 
of  the  men  9.7  per  cent.,  were  younger  than  twenty-eight  years;  37.9  per 
cent,  of  the  women  and  27.5  per  cent,  of  the  men  were  younger  than 
thirty-three  years;  and  54.5  per  cent,  of  the  women  and  47.5  per  cent, 
of  the  men  were  younger  than  thirty-eight  years.  Through  the  three 
periods  of  twenty-eight  to  forty-two  years  there  were  53  per  cent,  of  the 
women  and  57  per  cent,  of  the  men;  through  the  five  periods  of  thirty- 
three  to  fifty-seven  years  there  were  66  per  cent,  of  the  men  and  53.8 
per  cent,  of  the  women.  In  the  old  age  periods,  after  fifty-seven  years 
of  age,  there  were  7.6  per  cent,  of  the  women  and  6.4  per  cent,  of  the 
men.  The  greater  relative  number  of  young  women  is  due  to  the 
facts  that  alcohol  usually  poisons  women  quicker  than  men  and,  among 
the  working  classes,  the  men,  by  a  larger  amount  of  muscular  work, 
burn  up  more  alcohol  and  thus  escape  some  of  its  toxic  action.  These 
statistics  are  also  influenced  by  the  number  of  young  prostitutes  who 


160  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

are  necessarily  included  in  tlie  stutistics  from  any  large  city.  Alco- 
holism, as  is  well  known,  i,'^  more  prevalent  among  men  than  women;  dur- 
ing the  ten  years,  1S95  to  1905,  there  were  two  and  a  half  times  more 
men  than  women  admitted  to  Bellevue  Hospital  suffering  from  alco- 
holism. 

The  effect  of  season  and  other  external  influences  is  well  shown  by 
the  admissions  for  alcoholism  for  the  ten  years,  1895-1905,  in  Bellevue 
Hospital.  The  total  admissions  in  the  alcoholic  wards  in  that  time 
were  43,916  males  and  1(),07()  females.  Considering  the  male  and  female 
curves  for  each  of  the  ten  years,  there  are  some  variations  which  are  not 
shown  in  the  average  curve  for  the  ten  years.  Periods  of  great  heat 
cause  a  marked  rise  in  the  male  curves  but  only  a  slight  corres})onding 
rise  in  the  female  curves.  In  some  630  cases  of  insolation  collected  in 
August,  1896,  in  New  York,  there  was  a  history  of  alcoholism  in  nearly 
90  per  cent,  and  the  men  greatly  predominated,  there  being  589  men, 
40  women  and  1  child. 

Sociological  conditions,  such  as  labor  strikes,  cause  a  great  increase 
of  alcoholism  among  both  men  and  women,  as  occurred  in  New  York, 
in  1903.  The  variations  in  the  Bellevue  records  show  more  varied  and 
wider  excursions  in  the  male  than  in  the  female  curves,  and  t^ie  rises 
and  falls  of  the  two  curves  in  the  same  years  do  not  always  run  parallel. 
Taking  the  average  curves  for  the  ten  years  by  monthly  admissions, 
the  point  of  the  January  curves  in  both  sexes  is  lower  than  the  previous 
December;  in  February  there  is  a  distinct  fall,  reaching  the  lowest  period 
of  the  year.  There  is  a  spring  rise  in  March  and  April,  a  May  fall,  a 
June  rise,  a  fall  in  July  and  iVugust,  a  marked  September  rise  and  here 
the  two  curves  separate,  there  being  an  October  fall  in  the  male  and  an 
October  rise  in  the  female  curve,  the  point  of  the  October  rise  being  the 
highest  point  for  the  year  in  the  female  curve,  a  November  rise  in  the 
male,  the  highest  point  for  the  year,  and  a  November  fall  in  the  female 
and  a  December  fall  in  the  male  and  December  rise  in  the  female  curve. 
Both  agree  in  having  the  greatest  number  and  highest  daily  average 
during  the  last  four  months  of  the  year.  Comparing  the  curve  of  the 
alcoholic  with  those  of  the  general  medical  and  surgical  admissions,  a 
striking  difference  is  evident.  The  two  curves  are  practically  reversed 
for  both  men  and  women,  as  the  greatest  number  of  admissions  for 
general  diseases  occurs  in  the  first  four  months  of  the  year.  The  curves 
for  alcoholism  here  described  are  not  those  of  the  delirious  cases  alone, 
but  are  for  all  forms  of  alcoholism,  the  acute  cases  forming  a  minority. 

Pathology. — There  is  no  drug  used  in  medicine  about  which  more 
erroneous  ideas  have  been  transmitted  than  concerning  alcohol,  and  the 
knowledge  of  the  results  of  experiments  on  which  is  based  our  realiza- 
tion of  its  true  action  in  the  body,  is  not  widespread  among  the  medical 
profession.  Ethyl  alcohol  is  the  one  chiefly  to  be  considered,  but 
in  the  distillation  of  whiskies  there  occur  other  bodies  as  aldehydes, 
and  some  of  the  higher  alcohols  which  are  usually  grouped  together  under 
the  name  of  "fusel  oil,"  and  their  action  deserves  consideration.  In  the 
compounding  of  cheap  whiskies,  and  in  their  adulteration  and  manu- 
facture, methyl  alcohol  must  be  considered  by  itself.  In  the  ageing  of 
wines,  the  ethers  giving  the  various  bouquets  are  not  without  their 
separate  action. 


ALCOHOL  161 

Methyl  Alcohol. — This  is  also  called  wood  alcohol  and  is  sold  in  the 
United  States  as  Columbian,  colonial,  union,  or  eagle  spirits.  In  Canada, 
it  is  sold  as  greenwood  or  standard  wood  spirits.  This  is  used  instead 
of  ethyl  alcohol  to  adulterate  the  various  essences  or  colognes  and  often 
to  adulterate  cheap  whiskies.  In  experiments  on  the  toxicity  of  the 
different  alcohols,  considering  that  of  ethyl  alcohol  as  1,  methyl  alcohol 
is  from  .46  to  .8,  but  this  gives  a  false  idea  of  its  true  toxicity  when  taken 
by  man,  although  idiosyncrasies  of  resistance  to  methyl  alcohol  vary 
greatly,  as  the  ingestion  of  two  teaspoonsful  of  it  has  been  followed  by 
bhndness;  in  other  individuals  many  ounces  have  been  taken,  followed 
only  by  intoxication.  Another  peculiarity  of  methyl  alcohol  is  that, 
except  in  very  large  doses,  the  serious  toxic  symptoms  may  be  delayed 
for  twenty-four  hours  or  even  several  days.  Even  in  animal  experimen- 
tation, while  more  methyl  than  ethyl  alcohol  may  be  required  per  gram 
of  body  weight  to  cause  death  in  one  or  two  days,  several  observers 
have  noted  that  methyl  alcohol,  administered  to  animals  over  long 
periods,  causes  serious  nervous  symptoms  and  produces  pathological 
lesions  in  doses  in  which  ethyl  alcohol  has  little  effect.  The  intolerance 
for  methyl  alcohol  for  long  periods  is  due  to  the  fact  that  a  considerable 
portion  of  it  is  turned  into  formic  acid  in  its  passage  through  the  body. 
The  single  constant  pathological  change  found  in  animals  after  poison- 
ing by  methyl  alcohol  is  fatty  degeneration  of  the  liver,  the  amount  of 
fat  extracted  from  the  dried  liver  of  dogs,  thus  poisoned,  being  over 
double  the  normal  amount. 

Recently  Wood  and  BuUer  published  275  cases  of  methyl  alcohol 
poisoning,  among  which  there  were  122  deaths  and  ]53  instances  of 
blindness.  In  New  York  City,  in  the  winter  of  1904r-1905,  there  were 
25  deaths  from  methyl  alcohol  poisoning,  after  drinking  whisky  adul- 
terated with  it.  These  authors  emphasize  the  great  idiosyncrasies  to 
the  toxic  effect  of  methyl  alcohol  and  give  three  degrees  of  intoxica- 
tion. The  first  shows  the  ordinary  marked  symptoms  of  intoxication 
with  dizziness,  nausea  and  marked  gastro-intestinal  disturbances,  termi- 
nating in  perfect  recovery  in  a  few  days,  sometimes  followed  by  more 
or  less  serious  damage  to  vision.  In  the  second  degree,  the  dizziness, 
nausea,  vomiting  and  gastro-intestinal  disturbances  are  much  more  pro- 
nounced; there  is  marked  cardiac  depression,  w^eak  pulse,  sweating 
and  slow  respiration;  there  may  be  delirium  or  unconsciousness  which 
often  deepens  into  coma  and  death.  If  coma  once  supervenes,  recovery 
seldom  takes  place,  for  even  if  the  patients  recover  consciousness,  they 
usually  relapse  into  coma  and  die.  There  is  very  often  a  sudden  develop- 
ment of  widely  dilated,  reactionless  pupils,  with  complete  or  nearly  com- 
plete blindness.  After  recovery,  dimness  of  vision,  often  increasing  to 
total  blindness,  is  characteristic  of  this  degree  of  poisoning.  The  third 
degree  is  that  in  which  an  overwhelming  prostration  comes  on,  which 
terminates  in  coma  and  death.  Nearly  all  the  severe  cases  which  are 
not  fatal,  show  characteristic  bilateral,  total  blindness,  coming  on  in  a 
few  hours  or  perhaps  not  for  several  days;  this  is  followed  by  partial 
restoration  of  vision,  which  again,  after  days  or  weeks,  gives  place  to  a 
more  or  less  complete  and  permanent  blindness  and  atrophy  of  the 
optic  nerve.  In  the  majority  of  fatal  cases,  death  seems  to  occur  in 
less  than  twenty-four  hours,  though  methyl  alcohol  may  kill  within  an 


l62  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

hour  or  death  may  be  delayed  for  one  or  two  days  or  even  longer.  Con- 
sidering the  visual  disturbances,  in  41  instances  there  were  16  cases  of 
total  blindness,  3  total  in  one  eye,  15  partial  recoveries  and  7  recoveries. 
In  35  patients,  the  sight  became  dim  in  G,  in  from  three  to  twelve  hours;  in 
20,  in  twenty-four  hours;  in  5,  in  forty-eight  hours;  in  2,  in  seventy-two 
hours;  in  1,  in  six  days.  The  sight  was  lost  in  2,  in  twelve  hours;  in  10, 
in  twenty-four  hours;  in  5,  in  from  thirty  to  forty-eight  hours;  in  12,  from 
the  third  to  the  eighth  day;  in  1,  in  seventeen  days.  The  ophthalmoscopic 
(examination  shows  the  visual  field  contracted,  absolute  central  scoto- 
mata,  the  nerve  head  first  congested,  followed  by  gray  or  white  atrophy 
and  contracted  vessels.  Pathological  examination  shows  a  retrobulbar 
neuritis,  papillitis,  other  inflammatory  symptoms  and  atrophy  of  the 
optic  nerve. 

In  those  dead  from  methyl  alcohol  poisoning,  at  autopsy,  intense  con- 
gestion of  the  stomach  and  intestines,  with  a  characteristic  odor  of 
methylated  spirits,  is  noticeable.  For  the  sake  of  conciseness,  we  will 
consider  here  the  treatment  of  methyl  alcohol  poisoning.  The  treat- 
ment of  the  optic  nerve  atrophy  is  not  very  satisfactory  in  severe  cases, 
although  pilocarpine,  sweat  baths  and  potassium  iodide  as  soon  as  the 
patient's  condition  permits,  in  the  early  stages  of  neuritis,  followed  by 
strychnine,  hypodermically,  seem  to  limit  the  extension  of  the  secondary 
atrophy.  The  general  treatment  consists  in  washing  out  the  stomach, 
and  vigorous  stimulation  by  strychnine,  caffeine  and  digitalis,  hypo- 
dermically. It  seems  useless  to  give  these  drugs  by  the  mouth.  Ergot, 
hypodermically,  will  also  be  found  useful.  High  enemata,  of  warm 
saline  solution  or  of  glycerine  and  castor  oil,  should  be  given. 

Higher  Alcohols. — These,  such  as  propyl,  butyl,  and  amyl  alcohol, 
are  undoubtedly  more  toxic  than  ethyl  alcohol  and  their  toxicity  in- 
creases as  they  mount  in  the  chemical  scale.  This  group,  with  sub- 
stances such  as  furfurol,  compose  what  is  generally  called  fusel  oil.  It 
has  often  been  claimed  that  these  alcohols  cause  many  of  the  symptoms 
of  chronic  alcoholism,  but  recent  work  shows  that  they  practically  play 
no  role  in  the  acute  or  chronic  poisoning.  It  is  however  claimed  that 
the  so-called  moonshine  whisky,  produced  in  the  mountains  of  some 
of  the  Southern  states,  is  very  deleterious  if  drunk  when  freshly  dis- 
tilled. The  fresh  rye  or  corn  whisky  would  contain  the  greatest  amount 
of  fusel  oil,  for  these  higher  alcohols  are  oxidized  and  changed  into 
other  substances,  which  give  to  old  whiskies  the  various  ffavors,  and 
the  older  they  are,  the  less  they  contain  of  these  substances.  Huss 
has  shown  that  amyl  alcohol,  in  human  beings,  taken  in  doses  of  J  to 
^  grain,  caused  no  toxic  symptoms;  doses  of  1  to  2  grains  were 
followed  by  sensations  of  oppression  in  the  chest,  with  temporary  feel- 
ings of  dizziness;  doses  of  from  3  to  4  grains  acted  as  a  gastro- 
intestinal irritant,  causing  a  burning  sensation  in  the  epigastrium,  colic, 
vomiting  and  diarrhoea.  He  estimates  that  the  total  amount  of  amyl  alco- 
hol contained  in  twelve  to  fifteen  glasses  of  brandy  is  only  1  to  1^  grains, 
and  the  effect  produced  by  this  in  ordinary  drunkenness  would  prac- 
tically be  nil.  Baer  studied  the  effect  of  adding  a  definite  percentage 
of  these  higher  alcohols  to  ethyl  alcohol,  and  found  that  the  addition 
of  2  per  cent,  of  amyl  alcohol  caused  an  appreciable  increase  in  toxicity, 
and  the  addition  of  4  per  cent.,  a  very  considerable  increase,  so  that  a 


ALCOHOL  163 

severe  type  of  poisoning  resulted  in  animals.  It  is  evident  therefore, 
that  larger  percentages  of  these  higher  alcohols  than  are  found  in  even 
the  worst  alcoholic  beverages  must  be  added  to  ethyl  alcohol,  bei'ore 
we  can  attribute  to  them  any  great  share  in  the  fatal  outcome  of  an 
acute  poisoning.  Chittenden  has  shown  that  these  higher  alcohols, 
when  present  in  amounts  in  which  they  are  likely  to  occur  in  the  alco- 
holic beverages,  tend  rather  to  increase,  than  to  decrease,  the  rate  of 
digestive  action.  Furfurol,  or  pyromucic  aldehyde,  is  also  present  in 
fusel  oil.  Joffroy  has  found  that  the  toxic  equivalent  of  this  substance 
is  0.14  for  rabbits  and  0.20  for  dogs  as  against  8.20  to  8.60,  the  true 
toxic  equivalent  of  ethyl  alcohol  for  these  animals.  But  as  a  liter  of 
rum  contains  only  0.015  to  0.040  grams,  a  liter  of  cognac  0.005  to  0.015 
grams,  if  we  assume  that  man  is  as  sensitive  as  rabbits  to  furfurol,  it 
would  require  from  300  to  700  liters  of  rum  or  brandy  to  furnish  the 
fatal  dose.  We  must  therefore  leave  out  the  consideration  of  this 
aldehyde  in  the  conditions  produced  by  ordinary  alcoholic  beverages. 

Ethyl  Alcohol. — This  is  the  main  constituent  of  most  alcoholic  bever- 
ages and  to  its  action  alone  are  due  the  symptoms  of  alcoholism  as  seen 
in  man.  The  spirituous  liquors  contain  from  47  to  56  per  cent,  alcohol; 
fortified  wines,  such  as  sherry,  madeira  and  port  contain  about  18  to 
22  per  cent.  The  Sicilian  wines,  such  as  malaga  and  marsella,  contain 
from  16  to  20  per  cent.,  champagne  about  9.2  per  cent.,  the  Rhine  wines 
about  10  to  12  per  cent,  and  the  clarets  9  per  cent. ;  of  malt  liquors,  ale 
5  to  8  per  cent,  and  beer  2J  to  5  per  cent,  of  alcohol.  Spirituous 
liquors  may  be  considered  as  acting  in  ratio  to  their  alcoholic  content; 
the  wines,  however,  vary  in  their  action,  either  from  the  ethers  which 
they  contain  or,  in  some  instances,  as  far  as  digestion  is  concerned,  in 
proportion  to  the  contained  solid  matters,  rather  than  to  their  alcoholic 
content. 

After  the  ingestion  of  ethyl  alcohol,  the  first  action  produced,  aside 
from  that  on  the  mucous  membrane  of  the  mouth  and  stomach,  is  the 
flushing  of  the  face  and  skin.  This  often  follows  small  doses,  which 
show  no  other  effect  upon  the  circulation.  Sometimes  a  slight  sweating 
of  the  hands  and  face  accompanies  this  flushing.  This  may  be  due  to 
a  beginning  paralysis  of  the  vasoconstrictors,  or  as  Meltzer  believes, 
to  a  stimulation  of  the  vasodilators  or  of  some  inhibitory  function 
acting  on  the  vasomotor  centre  and  inhibiting  its  tonus.  In  either  of 
these  last  two  cases,  it  would  be  a  stimulation,  and  not  a  paralysis,  of 
a  normal  function.  Most  observers  find  that  moderate  doses  dilate  the 
peripheral  capillaries  without  altering  the  blood  pressure,  and  without 
any  stimulation  or  depression  of  the  heart  action.  The  pulse  rate  is 
not  altered  after  moderate  doses,  and  an  increase  does  not  occur  until 
doses  sufficiently  large  to  cause  a  fall  in  the  blood  pressure  have  been 
given.  It  has  been  long  noticed,  however,  that  a  change  in  the  char- 
acter of  the  pulse  does  occur  and  it  feels  as  if  fuller  and  stronger  after 
moderate  doses  of  alcohol. 

Some  experiments  of  Kochmann  give  results  opposed  to  some  of  the 
above  conclusions,  but  furnish  experimental  proof  for  others.  He  found 
that  in  human  beings,  doses  of  40  to  60  Cc.  of  a  10  per  cent,  or  40  to  50 
Cc.  of  a  15  per  cent,  alcoholic  solution,  caused  a  rise  in  blood  pressure. 
This  reached  its  maximum  20  to  30  minutes  after  the  ingestion  of  the 


164  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

alcohol,  and  then  gradually  diiniiiishcd  until,  after  60  to  75  minutes,  it  had 
entirely  di.sapj)eared.  This  rise  amounts  usually  to  15  mm.  Hg.  In  some 
individuals,  however,  it  was  as  much  as  30  mm.,  but  in  others  it  amounted 
to  only  5  mm.  and  in  still  other  ])atients  did  not  occur  at  all.  Doses  of 
60  to  SO  Cc.  of  a  20  per  cent,  solution  or  50  to  60  Cc.  of  a  30  per  cent,  so- 
lution of  alcohol  caused  at  first  a  slight  rise  followed  by  a  fall  of  blood 
pressure.  A  dose  of  50  Cc.  of  a  50  per  cent,  solution  of  alcohol  produced 
from  the  beginning  a  fall  of  arterial  pressure,  but  this  was  not  more  than 
10  mm.  Hg.  and  60  minutes  after  the  pressure  had  risen  to  the  ordinary 
height.  These  results  could  only  be  obtained  in  individuals  who  were 
complete  abstainers  or  practically  so.  It  was  also  noted  that,  after  the 
rising  blood  pressure  had  reached  its  maximum,  it  was  ])ossible  to  keep 
it  at  this  level  by  the  administration  of  a  second  similar  dose  of  alcohol. 
It  was  further  found  that  the  pressure  could  be  kept  up  for  four  hours  at 
the  given  height  by  administering  alcohol  at  thirty-minute  intervals  and 
the  blood  pressure  did  not  fall  to  its  ordinary  level  until  an  hour  after  the 
last  dose.  During  these  experiments  the  frequency  of  the  pulse  remained 
practically  constant,  increasing  only  after  large  dosage  with  a  fall  of  blood 
pressure.  The  size  of  the  pulse  was  noticeably  increased  both  to  the 
palpating  finger  and  in  sphygmographic  tracing;  in  the  latter,  the  pulse 
excursion  became  greater  and  the  dicrotic  notch  more  noticeable. 
The  rise  of  blood  pressure  seems  dua  to  stimulation  of  the  vasomotor 
centre  followed  by  contraction  of  the  vessels  of  the  splanchnic  area, 
which  overcompensates  the  peripheral  dilatation.  Large  toxic  doses 
of  alcohol  gradually  lower  the  reflex  excitability  of  the  vasocon- 
strictor centres,  dilating  the  arteries  and  capillaries  of  the  splanchnic 
and  peripheral  areas,  lowering  the  blood  pressure,  and  acting  directly  on 
the  heart  muscle  as  a  powerful  depressant,  weakening  first  the  auricular 
and  then  the  ventricular  systole,  causing  more  or  less  distension  of  both 
cavities  and  gradual  diminution  in  the  output  of  blood.  The  action 
of  alcohol,  therefore,  on  the  circulation,  after  moderate  doses,  is  a 
change  in  the  distribution  of  the  blood  and  perhaps  an  increase  in 
the  power  of  the  heart's  action  without  increasing  the  pulse  frequency. 
In  large  doses,  it  paralyzes  both  the  control  of  the  vessels  and  the  heart 
muscle. 

Dilatation  of  the  skin  capillaries  gives  a  sensation  of  warmth  and  there 
is  increased  radiation  of  heat  from  the  body,  but  the  temperature  is  seldom 
reduced  more  than  1°  or  2°  F.  That  very  large  doses  of  alcohol  may 
cause  a  fall  of  5°  to  9°  F.  or  even  more,  was  exemplified  in  a  patient  whose 
temy)erature  on  admission  was  90°  and  remained  between  90°  and  92°  for 
fifteen  hours;  it  then  rose  slowly  to  normal,  reaching  this  point  thirty-six 
hours  after  admission.  The  lowest  temperature  Avhich  has  come  under 
the  writer's  observation,  was  in  a  woman  found  comatose  from  alcohol, 
when  the  temperature  of  the  air  was  about  6°  above  zero.  After  she 
had  been  in  the  hospital  for  three  hours,  wrapped  in  blankets,  her  rectal 
temperature  was  80°  F.  The  temperature  reached  normal  twelve  hours 
after  admission.  Such  temperatures  as  these,  in  drunkards  exposed  to 
cold,  are  unusual,  but  by  no  means  unique.  Shafer  gives  records  of 
temperatures  in  drunkards  after  such  exposure,  of  79.5°,  86.6°  and 
83.1°  F.,  the  patients  dying,  while  others,  with  temperatures  of  72.2°, 
76.4°,  82.2°  and  86°  F.,  recovered  after  a  few  days. 


ALCOHOL  165 

The  respiration  is  directly  stimulated  by  moderate  doses — according 
to  Binz — more  in  fasting  and  fatigued  individuals,  than  after  a  meal 
or  in  non-fatigued  persons.  This  direct  stimulating  action  on  respir- 
ation is  not  accepted  by  all,  alcohol  being  often  classed  as  an  indirect 
respiratory  stimulant.  In  large  toxic  doses  there  is  a  paralyzing  efi'ect 
on  the  respiratory  centres,  and  the  breathing  becomes  stertorous  and 
slow. 

In  studying  the  effects  of  alcohol  on  the  digestion,  we  find  that  it  stimu- 
lates the  flow  of  saliva  and  also  the  concentration  and  amylolytic  power 
of  human  mixed  saliva.  This  is  purely  a  local  reaction  of  short  duration, 
ceasing  when  the  alcohol  is  swallowed.  Alcoholic  fluids,  when  intro- 
duced directly  into  the  stomach,  do  not  stimulate  the  salivary  flow.  Upon 
gastric  secretions,  alcohol  has  a  marked  effect,  increasing  very  greatly  the 
flow  of  gastric  juice  and  its  content  of  acid  and  total  solids,  giving  a  juice 
of  strong  proteolytic  action.  Furthermore,  this  action  is  exerted,  not  only 
by  the  presence  of  alcohol  in  the  stomach,  but  also  indirectly  through  the 
influence  of  alcohol  absorbed  from  the  intestines.  Any  direct  influence  of 
alcohol  on  the  pancreatic  or  intestinal  secretions  must  be  small,  because 
of  its  rapid  disappearance  from  the  stomach  by  absorption.  On  the 
chemical  processes  of  digestion,  Chittenden  has  found  that  pure  absolute 
alcohol  has  no  very  marked  influence  on  the  digestion  of  farinaceous  foods 
by  the  saliva.  The  presence  of  5  per  cent,  of  absolute  alcohol  may  lead  to 
a  slight  increase  in  the  digestive  power  of  active  saliva.  Large  quantities 
cause  retardation  of  amylolytic  action,  but  even  10  per  cent,  of  absolute 
alcohol  produces  only  slight  retardation,  hardly  recognizable  in  the  solvent 
action,  but  showing  in  the  amount  of  reduced  sugar  formed.  Whisky, 
brandy,  wine,  and  malt  liquors  show  a  powerful  inhibitory  influence  upon 
salivary  digestion,  out  of  proportion  to  their  alcoholic  content  and  due 
almost  entirely  to  their  acid  properties.  The  influence  of  alcohol  on  the 
chemical  action  of  gastric  juice  is  nil  when  present  from  1  to  2  per  cent., 
and  not  until  the  digestive  mixture  contains  from  5  to  10  per  cent,  of 
absolute  alcohol  is  the  action  of  the  gastric  juice  materially  interfered 
with.  The  malt  liquors  in  small  amounts  are  without  inhibitory  influence 
on  the  gastric  juice,  showing  a  tendency  to  slightly  increase  the  rate  of 
digestion.  In  larger  amounts,  they  give  rise  to  an  inhibition  of  proteolysis, 
which  is  entirely  unconnected  with  the  small  amounts  of  alcohol  present, 
but  directly  traceable  to  the  comparatively  larger  amount  of  extractives 
they  contain. 

There  seems  but  little  chance  that  alcohol,  when  consumed  in  moderate 
amounts,  influences  digestion  in  the  small  intestine,  it  being  too  rapidly 
absorbed  to  have  much  effect.  Pancreatic  juice,  how^ever,  in  its  proteoly- 
tic action,  is  more  sensitive  to  pure  alcohol  than  gastric  juice,  2  or  3  per 
cent,  of  absolute  alcohol  being  sufficient  to  produce  a  distinct  retardation 
of  proteolysis.  The  acid  substances  contained  in  the  spirituous  liquors 
and  wines  have  a  more  detrimental  action  on  the  proteid  digestion  of  the 
pancreatic  juice  than  the  alcohol  in  these  beverages.  The  extractives  in 
the  malt  liquors  likewise  exert  an  inhibitory  action  upon  the  pancreatic 
proteolysis.  The  amylolytic  ferment  of  the  pancreatic  juice,  being  similar 
to  the  salivary  enzyme,  is  affected  the  same  as  in  salivary  digestion. 
Moderate  doses  of  alcohol,  taken  not  too  frequently,  would  seem,  as  a 
sum  total  of  their  action,  to  favor  an  increase  in  the  digestive  processes, 


166  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

but  after  repeated  consumption,  the  digestive  processes  are  perverted 
and  diminished. 

We  know  from  the  experiments  of  Atwater  and  Benedict,  that  after  the 
absorption  of  alcohol,  98  per  cent,  of  moderate  doses  is  consumed  in  the 
body,  the  residue  being  excreted  by  the  lungs  and  kidneys.  It  is  used  by 
the  body  for  the  needs  of  heat  and  muscular  work,  and  in  this  way  protects 
the  body  fats  from  consumjjtion.  It  can,  and  sometimes  does,  protect  the 
protein  of  food  or  body  tissue  from  consumption,  but  at  other  times,  in 
small  doses,  especially  in  persons  not  accustomed  to  its  use,  it  fails  to  do 
this,  even  increasing  the  protein  disintegration.  In  large  quantities  it  is 
positively  toxic;  retarding  or  even  preventing  metabolism,  and  protein 
metabolism  in  particular.  It  is  evident  that  alcohol,  up  to  a  certain 
amount,  in  healthy  persons  furnishes  the  equivalent  of  energy  of  the  iso- 
dynamic  amount  of  fats  and  carbohydrates,  and  the  total  amount  of 
nitrogen  under  these  circumstances  must  remain  the  same.  The  form  in 
which  nitrogen  is  excreted  in  the  urine  is  often  materially  changed  under 
the  influence  of  moderate  doses  of  alcohol.  From  the  experiments  of 
Beebe,  in  healthy  young  men  on  a  given  diet  and  in  a  state  of  nitroge- 
nous equilibrium,  when  alcohol  is  given,  the  percentage  of  urea  to  the 
total  nitrogen  is  diminished  and  the  percentage  of  ammonia  and  uric 
acid  are  noticeably  increased.  The  men  used  in  these  experiments 
were  unaccustomed  to  alcohol  and  showed  under  its  influence  a  slight 
increase  in  the  total  amount  of  nitrogen  excreted.  From  the  recent 
work  of  Folin,  experiments  on  persons  of  low  nitrogenous  diet  and  on 
persons  of  high  nitrogenous  diet,  show  that  the  distribution  of  the  nitro- 
gen in  the  urine  among  urea  and  the  other  nitrogenous  constituents,  de- 
pends on  the  absolute  amount  of  total  nitrogen  excreted  per  diem,  but 
after  taking  this  into  account,  the  experiments  of  Beebe  show  that 
the  uric  acid  and  ammonia  are  increased  and  the  urea  diminished  under 
the  influence  of  only  moderate  doses  of  alcohol.  From  some  yet  unpub- 
lished work,  kindly  furnished  to  me  by  F-wing  and  Wolf  of  Cornell  Uni- 
versity, in  the  urine  obtained  from  patients  suffering  from  various  degrees 
of  alcoholism  in  Bellevue  Hospital,  New  York,  excreting  from  10.3  to  17.4 
grams  of  nitrogen  in  twenty-four  hours,  the  urea  nitrogen  ranged  from  64.7 
to  84.1  per  cent,  of  the  total  nitrogen.  The  percentage  of  the  ammonia 
nitrogen  to  the  total  nitrogen  ranged  from  2.2  to  7.4  per  cent,  and  the 
relative  percentage  of  the  amino  acids  to  the  total  nitrogen  from  4.8 
to  14.4  per  cent.  Comparing  this  with  the  results  given  in  Folin's  work 
for  normal  individuals  excreting  over  10  grams  of  nitrogen,  it  is  seen  that 
in  normal  persons  excreting  from  14.8  to  18.2  grams,  the  percentage 
of  urea  was  from  86.2  to  89.4  per  cent,  of  the  total  nitrogen,  the  ammonia 
from  3.3  to  5  per  cent,  and  the  amino  acids  from  2.7  to  5.3  per  cent. 
Comparing  the  above  results,  it  seems  fair  to  conclude  that  in  some  indi- 
viduals suffering  from  chronic  alcoholism,  the  percentage  distribution  of 
the  substances  forming  the  total  nitrogen  in  the  urine  is  materially  altered 
in  the  ratio  of  urea,  ammonia  and  amino  acids  to  the  total  nitrogen.  In 
three  patients  suffering  from  alcoholism,  who  excreted  less  than  10 
grams  of  nitrogen  in  twenty-four  hours,  the  ratios  of  urea,  ammonia  and 
amino  acids  to  the  total  nitrogen  did  not  vary  to  any  greater  extent 
than  was  seen  in  Folin's  experiments  with  five  healthy  individuals  excret- 
ing an  equally  low  total  nitrogen.     In  some  of  the  patients  in  whom  the 


ALCOHOL  167 

ratios  mentioned  deviated  most  from  normal,  postmortem  examination 
showed  the  livers  extensively  diseased;  whether  this  was  a  coincidence  or 
not  is  uncertain.  It  is  evident,  however,  that,  although  alcohol  may  be 
used  by  the  body  for  energy,  the  metabolic  changes  are  not  similar,  and 
it  must  be  a  question  of  some  moment  from  whence  the  body  draws  its 
energy,  whether  it  be  [alcohol,  fats  or  carbohydrates.  It  is  evidently 
possible  for  the  body  to  use  alcohol  as  a  food  material  but  the  changes  in 
metabolic  results  show  that  while  being  consumed  as  a  food,  alcohol 
may  simultaneously  exert  its  drug  or  toxic  action. 

As  to  whether  alcohol  is  a  source  of  heat  when  oxidized,  Atwater  found 
in  his  rest  experiments,  the  heat  given  off  from  the  body  was  equivalent  to 
the  total  potential  energy  of  the  material  oxidized.  This  was  as  true  in 
the  experiments  in  which  alcohol  made  part  of  the  diet  as  in  those  with 
ordinary  food  exclusively.  Hence  alcohol  must  have  contributed  its  full 
quota  of  heat  as  did  the  starch  or  fat,  and  all  its  potential  energy  was 
converted  into  heat.  The  same  principles  apply  in  the  work  experi- 
ments and  unless  all  the  potential  energy  in  the  alcohol  was  converted 
into  the  energy  of  internal  work  in  the  rest  experiments  and  into 
that  of  internal  and  external  work  in  the  work  experiments,  certainly 
an  improbable  hypothesis,  part  must  have  been  transformed  directly  into 
heat  in  the  body.  The  question  whether  the  energy  of  alcohol  is  used  for 
muscular  work  is  not  definitely  settled.  There  is  no  evidence  that  there  is 
a  difference  in  the  energy  or  heat  derived  from  alcohol  and  from  other 
nutrients,  but  there  is  no  proof  that  such  difference  does  not  exist.  It 
certainly  seems,  from  these  experiments,  that  probably  such  energy  for 
muscular  work  is  derived  from  the  alcohol.  It  is  Atwater's  opinion  that 
the  utilizations  of  the  energy  of  the  whole  ration  are  slightly  less  economi- 
cal with  alcohol  than  with  ordinary  diet,  especially  when  the  subjects  were 
at  hard,  muscular  work.  For  it  was  noticed  that  there  were  indications 
that  the  subjects  worked  to  a  slightly  better  advantage  with  ordinary 
rations  than  with  alcohol.  The  possibility  here  shown  of  alcohol  in 
moderate  doses  furnishing  energy  for  muscular  work  is  a  far  different 
question  from  the  possibility  of  alcohol  as  a  part  of  the  diet  for  muscular 
labor.  General  observations,  and  the  results  of  practical  tests  on  a  large 
scale,  show  such  beverages  to  be  of  doubtful  value  or  even  harmful. 
Alcohol  apparently  increases  the  power  of  fatigued  muscles,  although  it 
does  not  restore  to  them  the  same  amount  of  power  as  they  possessed 
before  they  were  fatigued,  and  this  restoration  of  power  is  only  temporary 
and  of  short  duration.  It  also  lessens  the  sensation  of  fatigue,  acting  in 
some  measure  through  the  nervous  system.  To  non-fatigued  muscles  it 
gives  only  a  temporary  increase  in  the  work  done.  Alcohol  will  thus 
enable  a  brief  spurt  to  be  made,  but  it  will  not  give  sustained  muscular 
power  and  is  followed  by  a  depression  of  energy  to  below  the  normal. 

The  action  of  alcohol  on  the  brain  is  still  a  subject  of  dispute.  Binz 
holds  that  alcohol  first  stimulates  and  then  depresses;  Schmiedeberg, 
Bunge,  and  others  that  the  apparent  stimulation  of  alcohol  is  a  paralysis 
of  the  higher  functions  and  that  alcohol  depresses  from  the  beginning. 
Kraepelin  claims  to  have  proven  from  his  experiments,  that,  in  the  early 
stages  of  its  action,  alcohol  truly  stimulates  the  motor  functions  of  the 
brain,  but  that  all  reactions  requiring  nicety  of  judgment  are  dulled  by 
even  small  doses.    Kraeplin  has  also  shown  that  small  doses  diminish  the 


168  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

accuracy  and  ability  to  add  numbers  or  to  learn  numbers  by  heart  Smith 
has  shown  that  this  is  especially  noticeable  when  small  doses  of  alcohol 
are  taken  daily,  and  that,  when  the  alcohol  is  cut  off,  the  ability  to  add  and 
to  memorize  immediately  returns.  It  is  also  noticeable  that  the  tendency 
to  erroneous  judgments  is  increased,  the  subjects  experimented  upon 
believing  that  they  had  performed  their  reactions  better  under  alcohol, 
when,  as  a  matter  of  fact,  the  reactions  were  diminishetl  in  accuracy  and 
rapidity.  Alcohol  in  moderate  doses  does  not  increase  the  quantity  or 
vigor  of  mental  processes,  and  the  flow  of  ideas  with  the  feeling  of  mental 
richness  is  due  to  the  removal  of  normal  inhibitions.  Alcohol  clearly 
tends  to  lessen  the  power  of  clear  and  consecutive  reasoning  and  decidedly 
lowers  the  acuteness  of  the  senses.  After  large  doses  the  judgment  is  lost, 
the  powers  of  self-control  and  will  are  in  abeyance,  all  idea  of  ])roportion 
is  gone,  the  sense  of  responsibility  and  restraining  impulse  is  destroyed, 
and  finally,  the  motor  power  for  speech  and  motion  disappears  and  torpor 
and  coma  supervene.  The  result  of  the  continued  action  of  large  doses  is 
the  permanent  loss  of  these  mental  functions  and  the  chronic  alcoholic 
becomes  an  irresponsible  animal. 

Pathological  Effects. — Since  Anstie  classified  alcoholism  as  a  nervous 
disease,  it  has  been  generally  so  considered.  As  concerns  the  relation- 
ship of  man  to  his  environment,  the  effect  of  alcohol  on  the  brain  is  a 
predominant  manifestation,  but  for  the  individual,  the  effect  of  alcohol 
on  the  heart  and  circulation  in  acute  poisoning,  and  on  the  heart  and 
abdominal  viscera  in  chronic  poisoning,  is  often  more  important. 
All  the  viscera  are  aft'ected  by  chronic  alcoholism,  the  cerebral  symptoms 
dominating  only  because  of  the  special  function  of  the  brain.  Death 
from  acute  poisoning  by  alcohol  is  rare,  and  usually  follows  large  doses 
in  those  unaccustomed  to  its  use,  or  sometimes  in  children,  who  have 
accidentally  swallowed  a  large  amount  of  some  concentrated  alcoholic 
beverage.  The  lesions  found  at  autopsy  do  not  correspond  to  the  severity 
of  the  symptoms  There  is  an  intense  overwhelming  of  the  functions  of 
the  various  organs,  which  occurs  so  quickly  that  it  leaves  no  corresponding 
anatomical  change.  Thus  a  young,  healthy  man  who  had  been  drinking 
heavily  all  day,  after  sitting  quietly,  attempted  to  walk  across  the  ward 
and  dropped  dead;  the  autopsy  showed  no  cause  for  death.  Death 
may  occur  suddenly,  as  in  this  case,  after  several  hours  of  drinking,  or 
within  half  an  hour,  or  coma  may  suddenly  come  on  after  several  hours 
and  be  fatal.  In  such  acute  poisoning,  if  death  follows  soon,  the  body 
may  resist  decomposition  for  an  unusual  length  of  time.  The  stomach 
and  tissues  may  even  have  a  more  or  less  well  marked  alcoholic  odor. 
The  stomach,  oesophagus,  and  duodenum  may  be  of  a  deep  red  color, 
with,  at  times,  punctiform  ecchymosis  in  the  gastric  mucous  membrane. 
There  is  at  times,  but  not  constantly,  a  venous  congestion  in  some  of  the 
viscera  and  the  bladder  is  often  greatly  distended.  There  is  frequently 
congestion  and  sometimes  extravasation  of  blood  or  oedema  in  the  brain 
and  its  membranes.  There  may  be  a  serous  effusion  in  the  ventricles. 
In  one  young  woman,  thirty-two  years  of  age,  previously  a  total  abstainer, 
who  took  enormous  amounts  of  alcohol,  dying  after  four  days'  poisoning, 
the  brain  showed  acute  encephalitis  with  marked  cellular  degeneration; 
the  spinal  cord  showed  degeneration  in  the  posterior  tracts  and  in  the 
cells  of  the  anterior  horns.    The  peripheral  nerves  were  normal 


ALCOHOL  \m 

Microscopically,  the  nerve  cells  show  two  different  lesions.  One,  as 
shown  by  the  Goigi  method,  is  the  so-called  moiiiliforni  change,  character- 
ized by  the  appearance  of  irregular  swelling  from  varicosities  in  the  course 
of  the  protoplasmic  processes  of  some  of  the  nerve  cells,  associated  with 
partial  loss  of  the  delicate  bud-like  or  spinous  projections  normally  pres- 
ent in  these  processes.  The  second  change  is  that  of  chromatolysis,  and 
is  shown  by  the  disintegration  of  the  small  chromatin  granules,  known 
as  the  Nissl  bodies,  as  brought  out  by  the  stain  of  that  name.  These 
changes  are  not  in  ratio  to  the  severity  of  the  symptoms  and  as  Welch 
says,  they  do  not  represent  any  serious  permanent  damage  to  the  nerve 
cells,  but  are  rapidly  recovered  from  after  the  disappearance  of  the  causa- 
tive factor.  They  seem  to  be  the  only  significant  anatomical  change 
produced  by  acute  alcoholic  intoxication.  These  changes  are  not  general 
and  occur  only  in  a  minority  of  the  cells,  but  they  have  been  found  in  the 
cells  of  the  cerebral  hemispheres,  the  cerebellum,  medulla,  the  spinal 
cord  and  the  sympathetic  ganglia. 

In  studying  the  lesions  of  chronic  alcoholism,  one  is  forcibly  struck  by 
the  great  variations  in  their  intensity  in  the  various  organs  of  different 
individuals.  Personal  idiosyncrasy  is  as  marked  in  the  lesions  produced 
by  alcohol  as  it  is  in  the  susceptibiUty  of  different  individuals  to  the  same 
dose.  In  1  person,  the  brain  may  show  the  greatest  change,  and  in 
another,  the  heart  and  arteries  seem  chiefly  affected;  in  others,  in  may  be 
the  liver,  or  the  kidneys,  which  seem  to  have  borne  the  brunt  of  the  toxic 
action.  In  studying  the  age  at  which  death  occurs  from  various  forms  of 
chronic  alcoholims,  there  is  a  noticeable  difference  between  the  sexes. 
Taking  541  deaths  from  alcoholism  in  Bellevue  Hospital,  New  York, 
318  men  and  223  women,  it  is  noticeable  that  the  highest  per- 
centage of  the  men  died  in  the  same  quinquennial  period  in  which 
there  were  the  greatest  admissions,  while  the  greatest  percentage 
of  female  deaths  was  ten  years  later  than  the  period  of  greatest  admissions; 
thus  20  per  cent,  occur  in  men  between  thirty-three  and  thirty-seven  years 
of  age,  and  19  per  cent,  of  the  deaths  in  woman  occur  between  thirty-eight 
and  forty- two  years  of  age.  This  is  undoubtedly  due  to  the  prevalence  of 
pneumonia  at  these  ages.  Between  thirty-three  and  forty-two  years  of 
age,  both  sexes  show  practically  the  same  percentage  (men,  34.4, 
women  38.2).  But  there  is  a  very  great  difference  in  the  number 
of  deaths  before  thirty-two  years  of  age,  the  percentage  in  men  being  17.2 
and  in  women  31.4;  that  is,  nearly  twice  as  many  young  women  die  of 
alcoholism  as  young  men.  The  fact  that  a  large  number  of  young  pros- 
titutes are  necessarily  included,  accounts  for  the  larger  number  of  young 
women  dying  from  alcoholism.  From  the  same  causes,  there  are,  both 
relatively  and  actually,  more  fat  alcoholic  women  than  men  and  the  bodies 
of  the  great  majority  of  both  sexes  are  well  nourished,  and  this  is  striking, 
when  we  consider  for  what  long  periods  these  patients  subsist  on  alcohol 
alone,  without  other  food;  it  also  shows  well  the  possible  food  action 
of  alcohol.  The  fine,  white,  smooth  skin  of  most  chronic  alcohoHcs 
is  noticeable,  due  partly  to  accumulation  of  fat  beneath  the  skin  and 
partly  to  atrophy  of  the  skin  itself.  To  obtain  an  idea  of  the  lesions  in 
chronic  alcoholism,  the  records  of  125  cases  are  taken  from  the  post- 
mortem reports  of  Bellevue  Hospital,  90  of  which  were  men  and  35 
women.    These  were  not  chosen  because  they  showed  certain  lesions,  but 


170  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

because  the  patients  had  given  a  definite  history  of  alcohohc  excesses. 
Many  histories  with  pneumonia  have  purposely  been  rejected. 

In  the  heart,  we  find  lesions  resulting  from  direct  poisoning  and  from 
associated  conditions.  Fatty  degeneration  of  the  muscle  is  the  most  com- 
mon lesion,  brown,  atro])hy  combined  with  fatty  degeneration  is  the  second 
most  common,  brown  atrophy  alone  the  third,  and  fibroid  myocarditis  the 
fourth.  There  are  often  various  combinations  of  the  above  lesions,  and 
while  fatty  infiltration  is  said  by  most  observers  to  be  more  common  than 
fatty  degeneration,  the  reverse  held  true,  in  my  experience.  That  brown 
atrophy  of  the  cardiac  muscle  is  caused  by  alcohol  seems  to  be  true,  for 
after  excluding  all  cases  in  which  carcinoma  was  present  and  in  which 
there  were  any  signs  of  healed  or  active  tuberculosis,  in  the  125  cases, 
there  remained  23  hearts  from  individuals  under  fifty-five  years  of  age 
in  which  this  degeneration  was  present.  The  secondary  effect  on  the 
heart  is  shown  through  the  circulatory  system,  and  from  disease  of 
the  coronary  arteries  we  obtain  fibroid  myocarditis;  and  the  enormous 
hy])ertrophied  hearts  of  beer-drinkers  are  produced  by  the  large  amount 
of  fluid  passing  through  the  bloodvessels.  The  arteriosclerosis  produced 
by  alcohol  or  secondary  to  the  kidney  lesions  produced  by  it, 
is  also  a  cause  of  the  cardiac  hypertrophy  and  later  of  the 
fibroid  myocarditis.  Sudden  death  not  infrequently  occurs  in  young 
alcoholics,  who,  possessing  a  heart  with  fatty  degeneration,  further  poison 
it  with  alcohol,  and  when  some  sudden  muscular  action  causes  a  sudden 
strain  on  the  cardiac  muscle,  it  fails,  and  death  results.  Alcoholic  poison- 
ing is  usually  considered  as  a  cause  of  arteriosclerosis  and  atheromatous 
degenerations.  Lance reaux  states  that  atheroma  of  the  aorta  and  vessels 
is  so  rare  in  alcoholism  that  its  presence  almost  excludes  alcoholism. 
Certainly  the  experience  in  this  country  is  widely  different;  it  is  charac- 
teristic of  arteriosclerosis  that  lesions  are  unevenly  distributed  in  the  body, 
and  the  peripheral  arteries  may  remain  unaffected,  while  the  aorta  or 
central  arteries  may  be  extensively  degenerated.  Atheromatous  degenera- 
tion is  a  frequent  cause,  in  alcoholics,  of  aneurism,  apoplexy,  and 
embolism.  Cabot,  in  studying  the  frequency  with  which  arteriosclerosis 
may  be  made  out  in  the  radial  arteries  in  alcoholics,  comes  to  the  con- 
clusion that  it  is  not  noticeably  present  in  more  than  6  per  cent.,  but  the 
atheromatous  degeneration  from  alcohol  is  more  commonly  present  in  the 
aorta  and  large  vessels  of  the  neck  and  in  the  cerebral  and  viscereal 
arteries  than  in  the  peripheral.  It  is  usually  uniformly  extensive  in  the 
aorta  and  vessels,  although  it  is  sometimes  extensive  in  the  aorta  and  but 
slight  in  the  vessels  of  the  neck,  and  in  other  cases,  the  reverse  is  true. 
The  aorta  and  vessels  may  show  very  slight  atheromatous  changes  and 
yet  the  coronary  arteries  be  extensively  calcified.  In  53  men  dying  under 
fifty  years  of  age,  atheroma  was  extensive  in  9,  moderate  in  26,  slight  in  14 
and  absent  in  4.  In  19  women  atheroma  was  extensive  in  6,  moderate 
in  6,  slight  in  6  and  absent  in  1. 

The  most  common  conditions  found  in  the  lungs  are  oedema,  congestion, 
and  the  various  forms  of  pneumonia,  such  as  lobar,  broncho-  septic;  and 
aspiration  pneumonia  is  not  infrequent,  especially  in  those  who  have 
serous  meningitis  and  inhale  particles  of  food.  It  is  also  very  common  to 
find  tuberculosis  in  various  stages;  the  old'idea  that  alcohol  is  preventive 
of  tuberculosis  is  proven  to  be  unfounded  and  it  is  unquestionably  true 


ALCOHOL  ■  171 

that  alcoholism  reduces  the  resistance  of  the  bofly  and  distinctly  predis- 
poses to  tuberculous  infection.  Puhnonary  emboli  from  cardiac  throm- 
bosis and  embolism  of  the  pulmonary  arteries  were  also  found  in  this 
series. 

The  liver  has  always  been  considered  as  especially  prone  to  show 
changes  from  chronic  alcoholic  poisoning  with  fatty  degeneration  and 
cirrhosis  as  the  two  special  forms  of  degeneration.  Rosenfeld  has  found 
that  a  fatty  liver  can  be  produced  in  dogs,  if  they  be  starved  for  six  days 
and  then  fed  on  alcohol,  and  by  this  method,  after  more  than  four  doses  of 
3J  to  4  Cc.  of  96  per  cent,  alcohol,  the  fatty  content  of  the  liver  increases 
over  the  normal  10  per  cent,  in  starving  dogs  to  an  average  of  22.6  per 
cent.  If  sugar  be  given  with  the  alcohol,  fatty  degeneration  does  not  take 
place.  This  seems  to  indicate  that  the  frequency  of  fatty  degeneration  in 
man  may  depend  in  some  measure  on  the  common  abstinence  from  food 
among  alcoholics.  It  is  very  noticeable  clinically,  that  those  who  par- 
take of  large  amounts  of  malt  liquors  are  especially  prone  to  fatty  degener- 
ation of  the  liver.  In  the  90  livers  of  men  examined,  fatty  degeneration 
occurred  in  37  per  cent.,  and,  of  the  35  women  examined,  it  occurred 
in  40  per  cent.  In  combination  with  cirrhosis,  brown  atrophy  and  paren- 
chymatous degeneration,  fatty  degeneration  was  present  in  43  per  cent,  of 
the  men,  and  34  per  cent,  of  the  women.  That  is,  it  was  present  in  80  per 
cent,  of  the  livers  examined  of  the  men  and  74  per  cent,  of  the  women. 
Fatty  degeneration  combined  with  cirrhosis  was  the  second  most  common 
lesion,  being  seen  in  31  per  cent,  of  the  men  and  17  per  cent,  of  the  women. 
Animal  experimentation  has  not  yet  proven  that  progressive  cirrhosis  of 
the  liver  is  produced  by  alcohol,  but  clinically  we  find  a  well  defined  history 
of  excessive  alcoholic  indulgence  in  the  great  majority  of  patients  suffering 
from  cirrhosis.  The  fact  that  it  occurred  in  almost  one-half  of  the  men 
and  over  one-third  of  the  women  examined  in  the  necropsies  under  con- 
sideration, would  certainly  indicate  its  alcoholic  origin.  The  term  cir- 
rhosis, here  used,  is  meant  to  designate  an  increase  in  the  connective  tissue, 
whether  the  liver  was  larger  or  smaller  than  normal  or  of  normal  size  and 
weight. 

The  enlarged  cirrhotic  liver  seems  to  be  the  most  frequent,  and  the  true 
biliary  cirrhosis,  the  least  frequent.  Clinical  experience  in  Bellevue  Hos- 
pital, New  York,  suggests  that  the  extreme  degrees  of  cirrhosis  do  not  occur 
so  commonly  as  they  did  fifteen  or  twenty  years  ago.  This  is  probably  due 
to  the  greater  use  of  malt  liquors.  Lancereaux  believes  that,  in  Paris, 
those  who  drink  wine  in  excess  are  the  most  prone  to  suffer  from  cirrhosis 
of  the  liver.  Whisky,  gin,  and  rum  are  more  likely  to  produce  the  atrophic 
form  of  cirrhosis  and  the  contracted  hob-nail  liver.  The  exact  process  by 
which  cirrhosis  is  produced  is  still  a  disputed  point.  Alcohol  is  a  cellular 
poison,  causing  degeneration  and  death  of  cells,  which  may  be  followed  by 
an  increase  in  connective  tissue  and  thus  be  the  chief  cause  of  cirrhosis,  or 
since  acute  and  chronic  congestions  are  at  times  followed  by  an  increased 
growth  of  the  fibrous  tissue,  the  cirrhosis  may  result  from  the  chronic 
hyperaemia  produced  by  the  dilatation  of  the  vessels  and  congestion  result- 
ing from  the  incessant  doses  of  alcohol.  Rosenfeld  expresses  the  view 
with  considerable  reserve,  that  cirrhosis  of  the  liver  is  the  result  of  very 
long  continued  alcoholic  poisoning  with  doses  which  cause  most  men  to 
succumb;    this  he  believes  would  explain  the  infrequency  of  cirrhosis 


172  DISEASES  CAUSED  BY  ORGAXIC  AGEXTS 

relative  to  the  large  numbers  of  alcoholics.  In  the  reported  cases  of 
children  sufferino;  from  cirrhosis  of  undoubted  alcoholic  origin,  it  is 
noticeable  that  the  disease  seems  to  follow  more  (]uickly  and  from  smaller 
doses  than  in  adults.  In  the  Bellevuc  Hospital  necropsies  it  was 
present  in  some  ilegr^ee  in  48. S  per  cent,  of  the  men  and  34  per  cent,  of 
the  women.  It  is  a  very  striking  fact  that  in  not  a  single  individual  of  the 
125  examined  was  the  liver  reported  normal. 

In  the  spleen,  chronic  congestion  and  fibrosis  are  the  two  most  common 
pathological  conditions.  Chronic  congestion  was  found  in  30  per  cent,  of 
the  men  and  66  per  cent,  of  the  women,  fibrosis  in  25  per  cent,  of  the  men 
and  18  per  cent,  of  the  women.  Acute  congestion  occurred  next  in  fre- 
quency; other  conditions  found  were  brown  atrophy,  amyloid  degener- 
ation, Inemachromatosis  and  brown  atrophy.  Perisplenitis  is  recorded 
in  4  patients.    In  4  men  and  1  w^oman  the  spleen  was  normal. 

In  the  ])ancreas,  the  great  frequency  with  which  chronic  fibrosis  occurs 
is  very  noticeable.  In  the  seventy-four  times  in  which  the  pancreas  is 
mentioned  in  the  men,  chronic  fibrosis  occurred  in  52  per  cent,  and 
in  29  women  it  occurred  in  50  per  cent.  Fatty  infiltration  occurred  in 
16  per  cent,  of  the  men  and  in  14  per  cent,  of  the  women.  The  pancreas 
was  mentioned  as  normal  in  23  per  cent,  of  the  men  and  in  25  per  cent,  of 
the  women.  It  was  atrophic  in  3  patients  and  hemorrhagic  in  1  man 
and  1  woman.  The  adrenal  bodies,  in  70  men,  showed  fatty  degenera- 
tion of  the  cortex  in  34  per  cent.,  and  in  21  women  this  lesion  was  present 
in  57.5  per  cent.  These  bodies  were  mentioned  as  normal  in  58  per 
cent,  of  the  men  and  in  38  per  cent,  of  the  women. 

There  has  been  much  discussion  as  to  the  effect  of  alcohol  upon  the 
kidneys.  It  has  been  frequently  demonstrated,  as  Welch  points  out,  that 
the  urine,  even  after  a  single  alcoholic  excess,  often  contains  abnormal 
elements,  indicative  of  transient  irritation  or  of  slight  inflammation.  In 
animal  experiments,  von  Kahlden  has  shown  that  in  dogs  there  occurs  a 
fatty  degeneration  and  necrosis  of  the  renal  epithelium,  hypereemia  of  the 
veins  and  capillaries  with  hemorrhages,  and  he  considers  that  with  longer 
duration  of  the  experiments,  chronic  interstitial  nephritis  would  appear  as 
a  result.  Formad  found  in  alcoholics,  who  died  suddenly,  a  marked  hyper- 
semia  of  the  kidneys  with  noticeable  enlargement  in  beer-drinkers.  The 
enormous  amount  of  fluid  taken  produces  a  functional  hypertrophy. 
When  arteriosclerosis  has  developed,  the  chronic  forms  of  kidney  disease 
necessarily  follow.  It  has  been  very  noticeable  in  the  autopsy  experience 
of  the  author  that  there  are  no  records  of  normal  kidneys;  all  examina- 
tions showed  some  lesions,  chronic  ones  greatly  predominating.  Acute 
nephritis  was  mentioned  in  only  2  men  and  1  woman.  Acute  inflammation 
grafted  on  chronic  nephritis  was  present  in  7  men  and  in  1  woman. 
Chronic  parenchymatous  nephritis,  often  with  congestion,  was  the  most 
common  lesion,  being  present  in  60  per  cent,  of  the  men  and  in  63  per 
cent,  of  the  women.  Chronic  interstitial  nephritis,  at  times  with  conges- 
tion, occurred  in  39  per  cent,  of  the  men  and  29  per  cent,  of  the  women. 
As  these  examinations  were  made  on  patients  from  twenty  to  over  seventy 
years  of  age  who  had  died  from  chronic  alcoholism,  it  would  seem  to 
show  that  while  the  kidneys  for  years  may  escape,  and  personal  idiosyn- 
crasies vary  greatly  the  intensity  of  the  lesions  in  various  organs,  sooner 
or  later  the  kidneys  are  certain  to  become  diseased. 


ALCOHOL  173 

The  stomach  shows  various  forms  of  gastritis;  chronic  gastritis  is  one 
of  the  commonest  lesions.  An  inflamed  gastric  mucosa,  covered  with  ropy 
mucus,  is  common  from  acute  alcoholism,  and  the  acute  sooner  or  later 
goes  on  into  the  chronic  form.  Chronic  atrophic  gastritis  was  present  in 
50  per  cent,  both  of  the  men  and  the  women  examined.  Hemorrhagic 
gastritis  was  present  in  24  per  cent,  of  the  men  and  in  16  per  cent,  of  the 
women.  These  two  conditions  were  not  infrequently  combined.  The 
mucosa  of  the  intestines  does  not  suffer  so  much  as  the  gastric  mucosa. 
The  most  common  condition  found  is  congestion,  sometimes  with  oedema. 
In  about  50  per  cent,  of  the  patients  examined  the  intestinal  mucosa  was 
normal. 

The  bladder  is  very  apt  to  be  over-distended  in  patients  who  have  died 
suddenly  or  had  unconsciousness  before  death.  It  may  even  be  ruptured 
as  was  the  case  in  two  men  in  the  service  of  the  author.  In  about  25  per 
cent,  of  both  sexes  we  found  the  lesions  of  either  acute  or  chronic 
cystitis . 

That  alcohol  tends  to  produce  sterility  has  long  been  known.  In  5 
among  12  women  between  twenty  and  thirty  years  of  age,  the  ovaries 
were  markedly  atrophic,  appearing  like  those  a  number  of  years  after  the 
menopause,  and,  in  women  between  thirty-one  and  forty,  they  were 
atrophic  in  5  among  8.  Thus  in  half  of  20  women  under  forty  years*  of 
age,  they  showed  extensive  atrophy.  In  the  men,  the  testicles  did  not 
show  gross  evidences  of  atrophy,  JDut,  in  the  few  examined  microscop- 
ically, there  was  sclerosis.  Lancereaux  has  proved  this  and  Simonds 
observed  that  in  60  per  cent,  of  chronic  alcoholics  on  postmortem  exam- 
ination, azoospermia  was  found.  Broun  and  Garnier  have  confirmed  by 
animal  experimentation  this  atrophy  of  the  testicles  following  alcoholic 
ingestion. 

It  has  long  been  recognized  that  alcohol  has  a  special  affinity  for  the 
higher  nervous  centres,  and  especially  on  those  coming  more  into  the 
clinical  aspect  of  the  disease.  Inherited  or  acquired  constitutional  defects 
cause  great  variations  in  the  effects  of  alcohol  upon  individual  nervous 
systems  and  it  is  difficult  to  estimate  the  difference  between  the  lesions 
caused  by  alcohol  in  previovisly  normal  persons  and  in  those  inheriting 
various  defects.  That  a  previously  weakened  nervous  system  will  show 
earlier  and  more  extensive  lesions  seems  logical  and  is  probably  true,  but 
the  idiosyncrasies  of  normal  persons  to  alcohol  present  wide  variations. 
There  seems  no  question  that  serious  nervous  diseases  in  persons  of  pre- 
viously normal  constitutions  are  produced  by  alcohol.  Some  individuals 
will  die  of  various  somatic  degenerations  and  still  retain  apparently  nor- 
mal cerebral  tissues,  while,  in  others,  the  brain  and  spinal  cord  seem  to 
suffer  early,  and  disproportionately,  compared  with  the  heart  and  ab- 
dominal viscera.  The  lesions  in  the  central  nervous  system  seem  to  be 
brought  about  either  from  the  degeneration  of  the  cerebral  arteries  or  from 
the  direct  action  of  alcohol  on  the  nerve  cells.  In  examinations  of  given 
brains,  it  is  difficult,  or  often  impossible,  to  differentiate  how  much  the 
changes  are  due  to  one  or  other  of  these  causes.  Qi)dema  and  congestion 
of  the  membranes  are  usually  present,  especially  the  former,  and  this  ordi- 
narily extends  into  the  cerebral  tissue  itself  and  was  mentioned  as  present 
in  72  per  cent,  of  the  76  brains  of  the  men  and  in  51  per  cent,  of  the  29 
brains  of  the  women  examined  by  us.     Congestion  of  the  cerebral  tissue 


174  DISEASES  CAUSED  BY  ORGAXIC  AGEXTS 

was  found  in  54  per  cent,  of  thr  men  and  in  14  per  cent,  of  the  women. 
Adhesions  of  the  dura  to  the  skull,  with  increase  in  the  Pacchionian 
bodies,  are  common,  and  very  frequently  there  is  thickening,  o])acity, 
and  adhesions  of  the  pia.  Chronic  meningitis  was  observed  in  65  per 
cent,  of  the  men  and  in  41  per  cent,  of  the  women  and,  combined  with 
this,  atrophy  of  the  ccnvoiutions  was  found  in  31  per  cent,  of  the  men  and 
in  41  per  cent,  of  th?  women.  Cerebral  degeneration  seems  to  be  more 
common  among  women  and  corresponds  with  the  clinical  experience  that 
women  degenerate  mentally  from  alcoholic  excesses  more  quickly  and 
more  completely  than  men.  Pachymeningitis  is  not  uncommon  and 
pachymeningitis  hemorrhagica  is  not  infrequently  seen  in  alcoholics, 
probably  from  trauma  acting  on  the  diseased  vessels.  All  inflammations 
in  alcoholics  seem  to  be  prone  to  the  hemorrhagic  type  and  hemorrhagic 
meningitis  was  present  in  three  men.  The  degeneration  of  the  vessels 
produced  miliary  aneurysms  and  it  is  not  uncommon  to  find  recent  cere- 
bral hemorrhages  or  encysted  old  hemorrhages  or  areas  of  cerebral  soften- 
ing from  cerebral  embolism. 

Microscopical  examination  of  the  cerebral  tissues  shows  an  intense 
degree  of  atheromatous  degeneration  of  the  minute  vessels  which  are 
enlarged,  often  tortuous,  unevenly  distended,  usually  by  fusiform  dilata- 
tions, and  their  tissues  covered  with  nuclear  proliferations.  About  these 
vessels  the  spider  or  glia  cells  are  crowded  in  great  abundance.  These  so- 
called  scavenger  cells  form,  with  their  branching  processes,  a  thick  con- 
nective tissue  felting,  densest  just  underneath  the  pia,  converting  the 
outer  fourth  of  the  cortex  into  a  closely  matted  layer,  much  diminished 
from  the  normal  thickness  and  often  clearly  mapped  off  from  the  layers 
beneath.  Sometimes  the  cellular  elements  of  the  glia  predominate,  but 
in  later  cases  many  of  the  protoplasmic  masses  have  disappeared,  leaving 
a  dense  connective-tissue  structure  in  which  the  remaining  nuclei  are 
thickly  sprinkled.  The  perivascular  spaces  are  often  filled  with  lymphoid 
cells.  The  second  and  third  layers  of  the  cortex  show  but  little  change, 
but  according  to  Bevan  Lewis,  a  few  of  the  low,  pyramidal  cells  may  be 
degenerated;  the  fifth  layer  of  motor  cells  shows  extensive  fatty  degener- 
ation and,  with  the  spider  cells  beneath,  is  undergoing  disintegration  and 
absorption.  The  cells  show  a  marked  degeneration  of  their  apical  pro- 
cesses and,  in  many,  these  have  disappeared.  The  axis  cylinder  shows  a 
loss  of  medullary  investment  and  is  itself  greatly  swollen  and  often  irregu- 
larly fusiform.  The  bodies  of  the  motor  cells  are  swollen,  rounded,  and 
constantly  show  an  abnormal,  coarsely  defined  boundary  wall  with  pig- 
ment crowding  against  the  cell  body,  wliich  also  shows  vacuolization  and 
often  extensive  chromatolysis.  The  white  matter  of  the  cortex  shows 
equally  extensive  atheromatous  changes  in  its  vessels  and  in  the  fusiform 
and  sacculated  dilatations  are  seen  deposits  of  htematoidin  granules. 
Not  infrequently  the  vessels  are  plugged  and  the  diseased  wall  found 
ruptured  with  extra vasated  blood  and  haematoidin  crystals  in  the  surround- 
ing areas.  The  changes  found  in  the  spinal  cord  are  similar  to  those  of 
the  cerebral  cortex.  The  vessels  of  the  posterior  and  lateral  columns  are 
more  involved  than  those  of  the  anterior  columns.  The  characteristic 
change  is  an  obliterating  endarteritis,  the  lumen  of  the  vessel  being  en- 
croached upon  to  mch  a  degree  that  the  intima  is  folded  into  ridges.  At 
times  the  vessels  are  even  occluded  by  this  process.    The  pia  of  the  cord 


ALCOHOL  175 

often  shows  thickening  and  evidences  of  inflammation,  an  extension 
downward  of  chronic  meningitis  of  the  cerebral  pia  or  a  coincident 
chronic  inflammation.  The  connective-tissue  processes  from  the  pia  into 
the  cord  are  thickened,  the  median  raphe  of  the  posterior  columns  and  the 
peripheral  zone  of  the  cord  being  the  areas  of  election  for  the  sclerotic 
processes.  The  anterior  and  posterior  nerve  roots  are  sometimes  involved. 
The  degenerative  processes  may  be  unilateral  or  bilateral  and  the  various 
segments  of  the  cord  show  varying  and  irregular  degrees  of  involvement. 

The  paralysis  produced  by  the  peripheral  neuritis  was  described  by 
older  writers,  such  as  Magnus  Huss,  as  due  to  lesions  in  the  central 
nervous  system.  When  the  peripheral  lesions  were  fully  studied  the  local 
changes  were  deemed  sufficient  to  account  for  all  symptoms  and  the 
central  nervous  system  was  not  considered  as  involved.  The  changes  in 
the  nerves  were  described  as  of  two  types:  the  first  in  which  the  degener- 
ation of  the  axis  cylinder  was  primary,  the  second  the  interstitial  type,  in 
which  hyperplasia  of  the  endoneurium  and  perineurium  were  primary, 
pressure  atrophy  following  in  the  axis  cylinder  process.  The  acceptation 
of  the  neuron  theory  has  caused  us  to  revert  to  the  ideas  of  the  older 
writers  and  realize  that,  in  the  vast  majority,  the  neuritis  of  alcoholics  is  of 
central  origin.  In  a  series  of  cases  of  alcoholic  neuritis  occurring  in 
Bellevue  Hospital,  Dr.  Harlow  Brooks,  with  whom  the  work  of  the  author 
in  the  pathology  of  alcoholism  has  been  done,  has  studied  the  central  ner- 
vous systems  and  peripheral  nerves.  In  one  patient  the  peripheral  nerves 
alone  showed  the  degenerative  changes ;  the  most  diligent  search  with 
the  Marchi  method  failed  to  show  any  corresponding  changes  in  the 
cord.  It  is  possible  therefore  that  alcoholic  neuritis  may  be  due  to  involve- 
ment of  the  peripheral  nerves  alone,  but  we  are  led  to  believe  that  such 
are  very  exceptional.  In  some  of  the  other  cases  there  was  marked  degen- 
eration in  the  cortical  cells  of  the  cerebrum,  especially  in  the  motor  areas, 
accompanied  by  degeneration  of  descending  fibers  in  the  internal  capsule 
and  in  the  descending  columns  of  the  spinal  cord;  not  a  true  tract  degener- 
ation but  one  of  isolated  and  often  widely  separated  fibers.  In  the  spinal 
cord,  extensive  cytoplasmic  degeneration  was  present  in  the  ganglion  cells 
of  the  anterior  horn,  the  ventrolateral  group  being  especially  studied,  and 
there  were  invariably  isolated  degenerated  fibers  in  the  anterior  nerve 
roots.  Degenerated  fibers  were  found  in  the  ascending  tracts  of  the  spinal 
cord,  particularly  in  the  severe  cases,  this  being  accounted  for  by  alter- 
ations, at  times  very  marked,  in  the  ganglion  cells  of  the  posterior  roots. 
In  some  cases  ascending  and  descending  degenerations  were  present  in 
the  same  spinal  cord.  Similar  results  have  been  found  by  numerous 
other  investigators. 

The  special  staining  of  nervous  tissues  by  the  Nissl  and  Marchi  methods 
at  first  raised  hopes  that,  in  delirium  tremens,  some  lesions  would  be  found 
in  the  brain  and  spinal  cord  which  would  correspond  to  the  clinical 
symptoms.  But  so  far  these  hopes  have  not  been  entirely  fulfilled.  Al- 
though the  Nissl  cell  changes  were  found  in  all  cases  of  delirium  and  in 
chronic  alcoholism,  Marchi's  degeneration  change  was  not  found  in 
pathological  amounts  in  all  cases  of  delirium  nor  in  the  chronic  alcoholism 
without  delirium.  The  changes  in  the  bloodvessels  and  connective  tissue 
in  delirium  tremens  seem  to  run  parallel  to  the  intensity  of  the  chronic 
alcoholic  processes.     Apart  from  the  tendency  of  the   chronic   arterio- 


176  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

sclerosis  to  cause  hein()rrlia<2:cs,  there  is  in  (lelirium  tremens  a  distinct 
tendency  to  minute,  acute  liemorrhages  which  are  (Htt'usely  scattereil  and 
numerous  in  the  cerebral  cortex  in  the  central  and  frontal  convolutions, 
less  frequent  in  the  cerebellum  and  still  less  common  in  the  sjjinal  cord. 
They  lie  in  the  tissues,  at  times  unaccompanied  by  a  bloodvessel,  and 
often  there  is  a  thin  layer  of  red  cells  along  a  vessel.  The  place  of  predi- 
lection for  these  hemorrhages  is  the  region  of  gray  matter  around  the  third 
ventricle  and  the  aqueduct  of  Sylvius.  They  vary  in  size  from  minute 
areas  to  the  size  of  a  bean;  a  concomitant  acute  inflammatory  process  does 
not  occur.  These  hemorrhages  are  very  commonly  observed  in  the 
regions  of  the  nuclei  of  the  oculomotorius  and  abducens  nerves.  Taking 
all  the  pathological  changes  into  consideration,  it  cannot  be  said  that 
delirium  tremens  presents  a  specific  ])atho]ogy. 

The  pathology  of  Korsakow's  ])sychosis  is  a  combination  of  what  has 
already  been  described.  This  has  the  dura  adherent  to  the  skull,  the 
thickened  pia  with  its  gray  striations  along  the  course  of  its  vessels,  the 
diffuse  cerebral  atrophy  and  increase  of  the  connective  tissue,  the  cellular 
degenerations  shown  by  Nissl's  staining  and  other  changes  produced  by 
chronic  alcoholism.  There  is  the  same  tendency  as  in  delirium  tremens  to 
small  hemorrhages  in  the  cortex,  spinal  cord,  jieripheral  nerves  and 
especially  in  the  regions  of  the  nuclei  of  the  third  and  fourth  nerves.  These 
may  extend  down  into  the  fourth  ventricle  and  involve  the  nuclei  of  the 
vagi.  They  occur  only  in  jiatients  succumbing  in  the  early  stages  but  in 
those  who  die  later  there  is  still  evidence  of  previous  hemorrhages.  The 
spinal  cord  shows  degenerations  in  the  various  tracts,  and  of  the  spinal 
neurons.  The  peripheral  nerves  show  the  various  lesions  of  neuritis  or 
stages  of  reconstruction. 

That  alcoholism  reduces  the  resistance  to  infectious  diseases  has  long 
been  known  and  is  generally  recognized.  This  increased  liability  to 
disease  is  undoubtedly  true  in  the  temperate  and  northern  climates.  In 
the  tropics,  however,  while  the  statistics  from  the  British  army  seem  to 
prove  the  same  for  India,  a  recent  article  by  Major  Woodruff  gives  statis- 
tics for  the  American  troops  in  the  Philippines  which  go  to  show  that  the 
moderate  and  even  excessive  drinkers,  after  two  years  residence,  were  in 
far  better  health,  and  much  more  able  to  throw  off  disease  than  the  total 
abstainers.  In  the  temperate  zones  an  attack  of  an  infectious  disease  in 
a  chronic  alcoholic  is  exceedingly  prone  to  cause  delirium  tremens  and  the 
prognosis  under  these  circumstances  is  always  grave.  Barthelemy  em- 
phasizes the  fact  that  waiters  and  workers  around  saloons  acquire  an 
especially  severe  form  of  syphilis.  Biirs  clearly  shows  that  in  epidemics  of 
cholera,  the  disease  claims  the  majority  of  its  victims  among  the  alcoholics 
and,  when  they  are  attacked,  the  chances  for  recovery  are  relatively  small. 
In  pneumonia,  the  mortality  among  the  alcoholics  greatly  exceeds  the 
average.  In  Bellevue  Hospital,  New  York,  in  1904,  there  were  1,001 
patients  with  lobar  pneumonia;  of  these  667  gave  a  history  of  alcoholism. 
Among  these  the  mortality  was  50  per  cent,  and  among  the  non-alcoholics 
23.9  per  cent. 

The  moderate  use  of  alcohol  is  a  relative  term;  moderation  for  one  is 
excess  for  another.  Duclaux  defines  excess  as  any  amount  of  alcohol,  any 
effects  from  which,  one  remains  conscious  of,  an  hour  after  its  ingestion. 
Many  moderate  drinkers  use  alcohol  throughout  a  long  life  and  show  no  ill 


ALCOHOL  177 

effects  from  its  use,  while  others  find  after  a  longer  or  shorter  period  that  it 
has  insidiously  produced  nephritis,  gout,  degeneration  of  the  liver,  or 
arteriosclerosis  and  that  their  viscera  are  permanently  damaged. 

The  results  of  chronic  alcoholism  unfortunately  do  not  end  with  the 
individual;  the  children  of  alcoholics  often  come  into  the  world  as  idiots 
or  weak  minded.  Howe,  in  Massachusetts,  found  that  145  of  .300  idiots 
were  descendants  of  drunkards,  and  that  among  the  poorest  classes 
of  the  population,  not  one-quarter  of  the  parents  who  had  idiotic  chil- 
dren could  be  considered  as  abstinent.  Beech,  in  England,  found  in  430 
idiots  that  31.6  per  cent,  were  children  of  alcoholics.  Bourneville,  in 
Paris,  found  that  of  1,000  idiotic  epileptics  and  weak  minded  children, 
471  had  a  father  who  was  alcoholic,  84  an  alcoholic  mother,  and  in  65 
both  parents  were  drunkards.  Only  in  209  of  these  cases  were  the 
parents  not  alcoholic.  In  Normandy,  Dahl  found  from  50  to  60  per 
cent,  of  the  idiot  children  had  either  an  alcoholic  father  or  mother.  In 
Sweden,  Lovens  ascribes  drunkenness  in  the  parents  as  the  cause  of 
25  per  cent,  of  the  idiots.  It  was  noted  that,  in  Norway,  from  1825- 
1835,  following  the  free  distillation  of  brandy,  drunkenness  enormously 
increased  and  simultaneously  the  number  of  idiots  increased  150  per 
cent.;  afterward,  in  the  ten  years  from  1855-1865,  when  the  consumption 
of  brandy  had  greatly  diminished,  the  number  of  idiots  diminished  16 
per  cent,  simultaneously  with  an  increase  in  the  population  of  14  per 
cent.  Bezzola,  in  Switzerland,  studied  70  cases  of  pronounced  idiocy 
and  found  that  half  of  these  idiots  were  generated  during  the  wine 
harvest.  New  Year's  week  and  the  Carnival;  that  is,  in  the  fourteen  weeks 
in  which  the  Swiss  chiefly  carouse,  while  the  rest  wei'e  divided  evenly 
over  the  remaining  thirty-eight  weeks  in  the  year.  The  normal  genera- 
tion curve  of  Switzerland  showed  on  the  other  hand  that  during  these 
same  periods  of  feasting  there  was  a  noticeable  diminution  in  the  num- 
ber of  children  generated. 

Epilepsy  in  children  frequently  follows  alcoholism  in  the  parents. 
Spratling  mentions  that  while  alcoholism  is  not  usually  a  direct  cause 
of  epilepsy  in  women,  it  is  frequently  an  indirect  cause  through  its  pres- 
ence in  the  parents,  nearly  always  in  the  father.  Fere  found,  in  France, 
that  among  308  male  epileptics,  118  were  descendants  of  alcoholics 
and  of  286  females,  130  were  descendants  of  alcoholics.  Kawalewsky, 
in  Krakow,  could  prove  drunkenness  in  60  per  cent,  of  the  epileptics. 
Wartman  found,  in  Germany,  the  same  history  in  130  of  452  epileptics. 
Blueler,  in  Switzerland,  could  prove  drunkenness  in  the  progenitors  of 
70  per  cent,  of  his  epileptics.  Congenital  deafness  and  dumbness  do 
not  seem  to  be  produced  by  alcoholism  in  the  parents  in  any  large  num- 
ber of  the  children  showing  these  afflictions.  Chronic  hydrocephalus 
seems  to  be  more  frequently  the  consequence  of  alcoholism  in  the  parents, 
for,  in  Berne,  23  of  38  children  suffering  from  this  disease  had  alcoholic 
parents;   in  Paris,  18  out  of  23  had  drunken  parents. 

That  alcoholism  tends  to  the  degeneration  of  the  race,  and  after  a 
few  generations  to  extinction,  has  been  abundantly  shown.  Legrain 
observed  215  alcoholic  famiUes,  in  three  generations  of  which  814  mem- 
bers were  hereditarily  tainted;  197  of  these  were  alcoholic,  322  were 
weak  minded  or  idiots,  161  stillborn,  37  prematurely  born,  121  died 
shortly  after  birth,  so  that  496  were  either  mentally  or  physically  degen- 

12 


178  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

erated.  That  174,  or  21  per  cent.,  were  stillborn  or  died  so  shortly  after 
birth  that  they  showed  inability  to  continue  their  existence,  is  a  striking 
example  of  the  effect  of  alcohol  on  the  unborn  child.  Demme  observed 
ten  alcoholic  families  and  comjjared  them  with  ten  non-alcoholic  families; 
in  the  alcoholic  families,  among  57  children,  25  were  stillborn  or  died  in 
the  first  month  of  life,  22  were  designated  as  sick,  and  10  as  healthy, 
while  in  the  non-alcoholic  families,  5  were  stillborn  or  died  early,  6  were 
sick,  and  50  were  healthy.  Only  17.5  per  cent,  in  the  alcoholic  families 
were  healthy,  while  practically  only  18  per  cent,  in  the  non-alcoholic 
families  were  not  healthy.  Of  the  37  children  in  the  |seven  families  in 
which  either  the  grandparents  or  the  mothers  were  alcoholic,  only  2 
children  were  normal.  Sullivan  found  that  from  120  female  alcoholics 
there  were  600  children,  and  of  these  335  died  under  two  years  of  age  or 
were  stillborn;  in  more  than  60  per  cent,  of  these  cases  the  children 
died  from  convulsions.  He  found  that  21  of  these  alcoholic  women 
had  sisters  or  daughters  who  were  abstinent  and  who  had  children 
from  temperate  men;  these  21  alcoholics  had  125  children,  of  whom 
55.2  per  cent,  died  before  the  second  year  of  life  and  the  28  non-alcoholic 
women  had  138  children  of  whom  23.9  per  cent,  died  before  the  second 
year  of  life.  The  mortality  of  children  from  alcoholic  mothers  is  thus  2.5 
times  greater  than  from  non-alcoholic  mothers  in  these  statistics.  Ani- 
mal experiments  shows  the  same  relative  mortality  between  alcoholic 
and  non-alcoholic  animals. 

INIorel  draws  attention  to  the  fact  that  individuals  who  are  given  to 
alcoholism  in  their  youth  as  well  as  the  descendants  of  drunkards,  are 
noticeable  for  their  small  stature  and  feeble,  muscular  development, 
presenting  a  type  of  infantilism.  Lancereaux  compares  this  condition 
Avith  the  descendants  of  the  tuberculous  and  considers  that  infantilism 
is  especially  marked  in  the  descendants  of  the  tuberculous  alcoholic; 
thus  he  believes  that,  pushed  to  its  extreme  limits,  alcoholism  creates  a 
special  race  as  it  were,  which  can  continue  itself  for  a  certain  period 
with  its  physical  infirmities  and  vicious  tendencies,  but  happily  it  lacks 
the  elements  sufficient  to  reproduce  itself  for  any  length  of  time;  with 
its  descendants  cursed  with  impotence  and  sterility,  it  is  not  slow  to 
disappear. 

DELIRIUM  TREMENS. 

Etiology. — Delirium  tremens  develops  on  the  foundation  of  chronic 
alcoholism.  Its  occurrence  does  not  run  parallel  to  the  amount  of  alco- 
hol taken,  for  idiosyncrasy  is  usually  as  strongly  marked  here  as  in 
all  conditions  in  which  alcohol  comes  in  question.  Many  men  who 
have  never  been  intoxicated,  but  who  have  for  years  steadily  taken 
alcohol  will,  after  some  severe  accident,  develop  delirium  tremens.  Its 
occurrence  as  far  as  climate,  age  and  sex  are  concerned,  is  the  same  as 
for  chronic  alcoholism,  but  it  differs  essentially  in  its  seasons  of  greatest 
frequency  and  is  dependent  for  its  development  on  other  causes,  which 
are  engrafted  on  the  chronic  alcoholism.  It  occurs  more  frequently  in 
northern  regions  and  in  the  great  industrial  centres.  Where  beer  and 
wine  are  the  predominating  drinks,  delirium  tremens  is  less  frequent 
than  in  the  countries  in  which  men  drink  spirits  chiefly.     It  has  been 


ALCOHOL  179 

claimed  that  since  the  distilled  liquors  contain  less  fusel  oil  there  are 
fewer  numbers  of  delirious  cases,  but  it  is  doubtful  whether  any  such 
deduction  is  justifiable.  The  writer  has  often  noticed  that  delirium  tre- 
mens patients  who  had  consumed  only  high  grade  whisky,  seem  to  clear 
up  quicker  than  those  who  had  consumed  a  cheaper  grade,  but  even  in 
these  cases  the  doubt  always  remains  whether  or  not  less  ethyl  alcohol  has 
been  consumed.  When  one  realizes  that  a  pint  of  cheap  whisky  may 
be  purchased  for  ten  cents,  and  that  not  infrequently,  at  least  among  the 
Bellevue  Hospital  patients,  a  pint  is  reckoned  as  a  single  drink,  even 
careful  calculations  on  the  amount  consumed  may  go  astray. 

The  time  of  year  shows  a  distinct  influence  on  the  number  of  delirious 
cases.  Bonhoeffer,  in  Breslau,  says  that  the  winter  months,  January, 
February,  and  March,  show  the  lowest  numbers ;  from  April  on  there  is 
an  increased  frequency  which  reaches  its  highest  point  in  July  and 
August.  The  curve  maintains  almost  the  same  rise  through  September, 
and  falls  rapidly  in  November  and  December.  He  quotes  Nacke  as 
having  noticed  essentially  the  same  differences  in  Konigsberg.  The 
occurrence  of  delirium  tremens  in  Bellevue  Hospital  corresponds  with 
the  above  statements  in  so  far  that  sudden  heat  always  shows  an  in- 
crease as  seen  in  July,  but  there  are  more  patients  suffering  from  de- 
lirium tremens  during  the  winter  months  than  in  the  spring  and  fall, 
and  the  number  during  the  cold  months  is  equal  to  or  even  greater 
than  during  the  hot  months.  This  is  due  undoubtedly  to  the  large 
number  of  pneumonia  patients  and  to  the  greater  number  of  accidents, 
such  as  fractures,  in  the  cold  months,  but  even  after  deducting  these, 
the  total  remaining  is  as  high  among  some  of  the  cold  months  as  during 
any  of  the  hot  months.  These  statements  are  based  on  the  statistics 
of  1,066  cases  of  delirium  tremens  occurring  between  January,  1904,  and 
July,  1905.  It  would  seem  therefore  that  the  varying  occurrence  of 
delirium  during  various  seasons  of  the  year  is  largely  affected  by  other 
well  known  accidental  causes  which  do  not  seem  to  act  in  different 
places  with  even  intensity.  The  previous  duration  of  chronic  alcoholism 
seems  to  have  more  influence,  and  it  is  said  that  the  average  is  from  six 
to  ten  years,  although  according  to  Jacobsohn  it  is  never  less  than  seven 
years.  The  age  at  which  delirium  tremens  develops  is  the  same  as 
that  in  which  chronic  alcoholism  is  most  common,  that  is,  between 
thirty  and  fifty  years.  In  children  it  is  rare.  Bonhoeffer  quotes  one 
of  sixteen  years  of  age,  and  the  writer  saw  one  boy  of  fifteen  years. 
It  occurs  most  frequently  in  men,  doubtless  because  they  are  more  ex- 
posed to  various  accidents,  which  tend  to  bring  about  an  outbreak. 
By  some  it  is  claimed  that  the  delirium  in  women  is  shorter  and  less 
severe  than  in  men ;  this  does  not  correspond  with  the  opinions  of  others, 
although  in  my  experience  the  delirium  in  women  is  usually  of  a  less 
violent  type.  It  is  impossible  to  say  to  what  extent  inherited  or  acquired 
mental  degeneration  influences  the  occurrence  of  delirium  tremens  in 
chronic  alcoholics  but  that  such  defect  of  mental  vigor  is  present  in 
the  majority,  is  beyond  question.  It  seems  certain,  however,  that  suc- 
ceeding attacks  of  delirium  tremens  are  more  easily  brought  about  than 
the  primary  one. 

Accidental  causative  factors  producing  delirium  tremens  in  chronic 
alcoholics  have  long  been  recognized,  such  as  acute  infections^  trauma, 


ISO  DISEASES  CAUSED  BY  ORGAXIC  AGEXTS 

hemorrhage,  epileptic  attacks,  the  sudden  withch'awal  of  alcohol,  sudden 
intensity  of  alcoholic  excesses  or  mental  shock.  Bonhoefl'er,  in  250 
cases  of  delirium  tremens,  could  prove  in  70  per  cent,  a  recent  acute 
illness  or  delirium  occurring  as  a  complication  of  it.  Undoubtedly  the 
most  common  acute  infection  which  brings  about  delirium  tremens  is 
pneumonia.  Kriickenberg  and  Bonhoeffer  found  j)neumonia  in  every 
seventh  delirious  patient.  Jacobsohn  in  2S1  delirious  patients,  found 
pneumonia  in  the  ratio  of  one  to  eight;  in  1,0GG  patients  in  Bellevue 
Hospital,  pneumonia  occurred  in  every  fifth  patient.  Traumatism  such 
as  fracture  of  the  ribs,  legs,  arras,  and  skull,  very  frequently  caused  an 
outbreak  of  delirium  tremens,  although  the  percentage  in  which  these 
occurred  is  much  less  than  the  acute  infections.  In  our  experience  it 
is  a  noticeable  fact  that  severe  dislocation  at  the  shoulder  or  elbow 
is  not  so  frequently  followed  by  delirium  tremens  as  fractures  of  the 
long  bones.  Bonhoeffer  believes  that  injuries  to  the  breathing  appa- 
ratus are  especially  likely  to  be  followed  by  an  outbreak  of  delirium. 
Many  others  lay  great  stress  on  epilepsy  as  a  causative  factor  in  the 
outbreak  of  delirium  tremens,  but  it  is  a  question  whether  the  epileptic 
seizure  is  not  an  expression  of  the  same  causative  factor  which  later 
produces  the  delirium.  An  epileptic  attack  is  given  as  the  direct  cause 
of  the  outbreak  of  the  delirium  in  from  2.5  to  16  per  cent.  Among 
chronic  alcoholics,  epileptic  attacks  are  very  common  and  in  the  majority 
are  not  followed  by  an  outbreak  of  delirium.  It  is  difficult,  therefore, 
to  accept  the  view  that  these  are  the  cause  of  delirium  tremens,  although 
one  cannot  deny  that  it  is  reasonable  to  suppose  that  the  mental  shock 
produced  by  them  may  at  times  be  sufficient  to  accelerate  the  outbreak 
of  an  already  developing  dehrium.  The  sudden  withdrawal  of  alcohol 
in  uncared  for  patients,  in  whom  no  attempt  is  made  to  replace  it  by 
proper  treatment,  is  undoubtedly  at  times  the  cause  of  an  outbreak 
of  delirium  tremens.  This  is  due  to  the  sudden  change  of  the  condi- 
tions of  life,  for  when  individuals  are  properly  treated,  the  sudden  with- 
drawal of  alcohol  does  not  produce  delirium.  That  delirium  tremens  is 
caused  by  some  factor  outside  of  chronic  alcoholism  seems  undoubtedly 
true  but  the  definite  specific  cause  is  unknown. 

Symptoms. — The  outbreak  of  delirium  tremens  is  never  sudden; 
there  are  always  premonitions.  The  patient  becomes  peevish,  excitable 
and  restless,  loses  sleep,  and  when  he  falls  into  slumber,  is  disturbed  by 
dreams  from  which  he  starts  in  anxious  fear.  Beginning  hallucinations 
appear  which  he  recognizes  as  dreams,  but  although  he  knows  they  are 
unreal,  they  still  disturb  him.  He  often  feels  oppression  around  his 
heart  which  may  increase  to  precordial  pain;  there  is  singing  in  his 
ears,  which  may  develop  into  voices  scolding,  abusing  or  even  threat- 
ening him;  the  dizziness  increases;  and  tremor  becomes  more  marked 
especially  in  the  hands  and  tongue.  This  incubation  period  may 
extend  over  several  days  or,  according  to  Kraft-Ebing,  as  long  as  twelve 
days.  Where  the  delirium  occurs  in  the  course  of  pneumonia  it  appears 
generally  on  the  third  or  fourth  day,  and,  following  an  accident  or  fracture, 
usually  on  the  second  or  third  or  may  be  delayed  until  the  fifth  or  sixth 
day.  The  writer  has  seen  it  appear  in  twenty-four  hours,  following  a 
severe  stab  wound  in  the  abdomen.  Many  patients  on  the  verge  of  an 
outbreak  of  delirium  tremens  will  deny  positively  and  firmly  that  they 


ALCOHOL  181 

have  drunk  any  alcohol;  when  this  is  in  marked  contrast  to  the  phy- 
sical evidences  of  alcoholic  indulgence  it  should  always  warn  one  of  the 
imminence  of  a  severe  outbreak. 

Many  patients,  when  they  begin  to  have  insomnia  and  disturbed 
dreams  at  night,  realize  their  condition  and  come  to  the  hospital  for 
treatment.  They  still  know  that  the  hallucinations  of  sight  or  hearing 
are  dreams  and  explain  this  carefully.  Some  are  still  able  to  focus 
their  attention  on  other  matters  and  avoid  the  hallucinations  that  appear 
when  dropping  to  sleep.  One  patient  explained  to  me  that  he  would 
read  most  of  the  night  in  order  to  avoid  the  family  of  skunks  that  came 
and  played  about  his  legs.  They  are  often  free  from  hallucinations 
during  the  day  time  and,  after  a  few  nights  of  disturbed  slumber,  im- 
prove, and  this  abortive  form  of  delirium  tremens  passes  over.  In  other 
patients,  after  the  premonitory  symptoms,  the  intensity  suddenly  in- 
creases and  they  are  brought  to  the  hospital  in  a  furious  and  active 
delirium.  This  is  usually  connected  with  their  daily  occupation  and 
they  show  no  fear  of  what  they  see  but  are  furiously  belligerent;  their 
attention  can  easily  be  obtained  and  they  will  explain  minutely  what 
they  see,  and  demand  to  have  their  orders  executed  and  explain  logically 
why  they  wish  to  have  this  done.  These  patients,  after  a  hypnotic  and 
a  night's  rest,  will  clear  up  absolutely  and  by  next  morning  remember 
shamefacedly  what  they  had  done.    The  delirium  usually  does  not  return. 

The  majority  of  patients,  when  the  delirium  is  fully  developed,  appear 
severely  ill  with  a  disturbed  and  anxious  countenance  or  their  ex- 
pression may  be  one  of  indifference;  the  face  is  congested,  often  slightly 
cyanotic  and  covered  with  sweat;  they  are  restless,  wandering  about, 
busily  twisting  and  turning,  listening  to  imaginary  voices  and  sounds. 
If  in  bed,  they  frequently  attempt  to  leave  it,  pull  and  pick  at  the  bed 
clothes,  jump  up,  attempt  to  rush  from  the  room  and  frequently  hurl 
themselves  against  the  walls  to  escape  imaginary  objects  or  push 
against  the  walls  to  prevent  their  falling  in  and  crushing  them.  They 
fail  to  notice  objects  in  their  way  and  are  indifferent  to  severe  injuries. 
The  gait  is  uncertain  from  the  muscular  tremor,  which  is  noticeable 
in  their  hands  with  every  movement,  and  often  extends  into  the 
tongue  and  the  muscles  of  the  face.  Their  speech  is  trembling 
and  stammering,  or  they  blurt  out  expressions  in  short,  sharp 
sentences.  Some  hardly  speak  at  all;  others  shriek  out  questions 
and  answer  them,  angrily  discussing  something  and  frequently  scolding 
and  cursing  imaginary  bystanders.  The  pulse  is  full,  bounding  and 
increased  in  frequency  in  the  young  and  vigorous  individuals  and  in 
the  elderly  or  weak  it  often  increases  in  frequency  but  is  soft  and  weak. 
The  respirations  are  increased,  the  tongue  is  usually  coated,  depending 
however  on  the  condition  of  the  stomach,  for  when  the  digestion  remains 
good  it  is  often  clean,  bright  red  and  glazed;  the  temperature  as  a  rule 
is  near  normal.  By  speaking  sharply  to  the  patient,  his  attention  may 
be  arrested  for  a  moment  and  he  may  answer  correctly  the  question 
put  to  him.  It  is  evident  that  ordinarily  the  ideas  of  his  personality 
and  past  remain  clear;  it  is  equally  true  that  he  has  false  ideas  regard- 
ing his  environment,  the  purpose  for  which  he  is  in  the  hospital,  the 
length  of  time  that  he  has  been  there,  and  the  individuals  who  are  around 
him. 


182  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

Hallucinations  of  sight  predominate  and  it  is  usually  an  occupation 
delirium;  for  example,  one  market  man  had  the  entire  field  of  vision 
filled  with  blue  potatoes  wiiieh  rained  incessantly  down  upon  him;  an 
hostler  saw  innumerable  niunbers  of  wagon-wheels  rolling  at  him;  the 
deck  hand  on  a  steam-boat  begged  me  that  he  might  go  to  bed  as  the 
room  was  rapidly  filling  with  steam-boats  that  were  bearing  down 
upon  him;  the  circus  man  saw  elephants  jutting  out  into  the  room,  which 
crowded  him,  although  they  did  not  terrify  him;  the  teamster  usually 
drives  horses  and  it  is  often  a  noticeable  fact  that  as  long  as  the  horses 
obey  his  orders,  he  is  not  terrified,  but  if  the  horses  back  against  his 
orders  and  he  is  unable  to  control  them,  there  is  instant  terror  inspired 
and  the  intensity  of  this  is  often  a  fair  criterion  of  the  severity  of  the 
delirium.  The  animal  or  menagerie  dehrium  is  common  and  the  pa- 
tients may  see  well  known  animals,  or  fantastic  beasts  and  various 
horrid  forms  of  monsters,  or  there  may  be  disgusting  insects,  crabs 
and  snakes  of  various  forms  or  the  animals  they  see  may  be  of  various 
abnormal  colors,  red  and  blue  predominating,  such  as  "pink  giraffes 
that  crossed  a  purple  bridge  and  nibbled  at  his  feet."  These  animals 
or  imaginary  monsters  are  not  seen  singly  but  usually  in  vast  numbers. 
At  times  the  hallucinations  are  pleasant  and  the  room  is  filled  with 
beautiful  pictures;  angels  are  seen  talking  to  them,  or  God  appears, 
talks  to  them,  and  commands  them  to  go  forth  as  his  messenger.  Some- 
times the  visions  take  on  a  sexual  type.  Various  paresthesias  of  the 
skin  cause  hallucinations  of  worms  or  spiders  crawling  on  them.  Specks 
on  the  walls  or  on  the  bedclothes,  may  be  mistaken  for  various  animals 
or  vermin.  Scratches,  furuncles  or  injuries  and  the  like  may  be  mis- 
taken for  the  bites  of  animals  or  for  Avounds  given  in  attempts  to  murder 
them.  The  hallucinations  of  hearing  consist  of  various  noises,  as  the 
ringing  of  bells,  crying  of  children,  shrieks  of  people  in  distress,  and 
volleys  of  musketry,  or  they  are  cursed  and  jeered  at  as  traitors,  mur- 
derers and  thieves,  or  they  hear  their  family  outside  the  door  conspiring 
to  kill  them  or  whispering  and  making  plans  to  come  in  and  mutilate 
them,  often  the  mutilations  taking  the  sexual  characteristics.  Rarely 
there  are  hallucinations  of  smell,  and  they  imagine  that  the  house  is 
on  fire,  that  smoke  is  coming  up  around  their  bed,  or  that  sulphur  fumes 
or  other  ill-smelling  gases  are  being  injected  through  the  key-hole.  The 
hallucinations  of  taste  are  also  rare,  but  they  may  imagine  that  their 
food  is  covered  with  disgusting  substances  or  that  poison  is  being  placed 
in  it.  The  imperative  monotone  hallucinations  are  absent,  although 
there  is  often  rhythmical  character  to  the  aural  hallucinations  given  by 
the  ticking  of  a  clock  or  dripping  of  water  from  the  faucet,  producing 
reflex  ideas  of  speech  hallucinations,  usually  of  a  scolding  nature.  Hypo- 
chondriacal illusions  from  sensations  in  the  intestines,  stomach,  bladder, 
etc.,  do  not  occur;  when  these  are  present  they  give  good  cause  for  the 
suspicion  of  other  mental  diseases.  Muscle  and  temperature  sense  are 
also  normal. 

The  mental  processes  in  delirium  tremens  are  of  a  peculiar  nature; 
there  is  no  diminution  in  general  in  the  sharpness  of  perception  of  the 
sense  organs;  the  ability  to  recognize  objects  seems  intact.  Some  authors 
however  believe  that  these  patients  are  unable  to  obtain  any  sharp, 
clear  impressions  and  explain  the  misinterpretation  of  noises,  etc.,  as  due 


ALCOHOL  183 

to  disturbances  of  apprehension;  these  b(;come  very  apparent  when  the 
patients  attempt  to  read,  when  instead  of  correct  sentences  there  is  a 
senseless  series  of  words  and  sound  associations  which  is  especially 
noticeable  when  the  type  is  small  and  indistinct;  sometimes  there  is 
no  relation  between  the  reading  and  the  subject  matter.  Bonhoeffer's 
explanation  that  the  inability  to  read  accurately  is  due  to  disturbances 
of  attention  seems  nearer  the  truth.  He  believes  that  the  paraphasia 
and  paralexia  are  closely  related  to  the  processes  of  physiological  in- 
attention. The  power  of  attention  under  special  conditions  in  delirium 
tremens  can  for  a  short  space  of  time  attain  the  sharpness  of  that  in 
healthy  persons,  but  the  ability  to  hold  the  attention  is  quite  different. 
The  more  complicated  the  mental  work,  the  greater  necessarily  are  the 
demands  on  the  attention  and  the  greater  the  tendency  to  paralexia. 
With  a  sharp  strain  on  the  attention  for  the  purpose  of  holding  fast 
this  maximum  accuracy  of  any  sensory  region,  a  transitory  normal  value 
is  attained  but  there  appears  an  increased  tendency  to  hallucinations 
in  the  sensory  regions.  If  the  attention  is  held  at  a  middle  level  but 
still  so  strongly  taxed  that  the  patient  must  talk  with,  and  give  answers 
to  the  examiner,  the  hallucinations  become  rarer  as  with  all  hallucina- 
tory mental  diseases.  The  disturbance  then  records  itself  in  a  tendency 
to  mix  up  words  and  ideas  similar  to  the  physiological  inattention. 
There  exists  in  delirium  tremens  a  persistent  tendency  to  sink  to  a 
still  lower  level  of  attention. 

Closely  allied  to  changes  in  the  ability  of  fixing  the  attention,  is  the 
train  of  thought  by  which  stimuli  through  the  various  sense  organs 
bring  about  the  final  conception  of  the  object.  Simple  pictures  pre- 
sented to  a  delirious  patient,  or  familiar  sounds,  may  be  often  correctly 
recognized  and  designated,  but  in  severe  cases  often  these  are  mis- 
understood and  cause  hallucinations.  At  times  the  misinterpretation  of 
pictures  would  lead  one  to  believe  that  lack  of  color  perception  played 
a  certain  role.  It  is  very  characteristic  for  the  misinterpretations  to 
influence  and  lead  to  illusions  through  internal  rather  than  through 
external  similarity,  as,  for  instance,  the  patient,  looking  at  a  picture 
of  a  bird,  declares  that  it  is  a  bird's  nest.  The  final  conception  of  the 
object  lacks  intensity  and  the  ideas  which  come  into  consciousness  are 
those  which  belong  to  associated  related  ideas.  These  patients  are 
particularly  susceptible  to  suggestion;  this,  however,  extends  only  to 
the  regions  of  sense  from  which  the  hallucinations  come  and  it  is  there- 
fore strongest  in  the  optic  and  in  the  auditory  senses  but  often  fails 
with  touch,  and  seems  to  completely  fail  in  the  regions  of  smell  and 
taste.  Suggestion  can  also  affect  the  hallucinations  concerning  their 
external  environment,  especially  as  to  occurrences  in  the  recent  past, 
but  has  no  effect  whatever  upon  the  events  of  their  early  life.  These 
patients  have  no  idea  of  the  passage  of  time  and  the  duration  of  their 
illness  is  usually  wrongly  given;  the  day,  the  week,  the  year,  are  ordi- 
narily misstated.  The  power  of  retention  is  much  diminished  and  memory 
of  objects  seen  is  defective,  this  being  strongest  at  the  height  of  the 
delirium  but  also  clearly  apparent  when  the  delirium  has  nearly  ceased. 
The  power  to  combine  thoughts  is  distinctly  in  abeyance;  this  is  clearly 
seen  when  one  permits  a  patient  to  read,  for  he  Avill  read  spontaneously 
the  greatest  nonsense  without  exerting  the  slightest  critical  faculty. 


184  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

One  cf  the  most  marked  ])eciilianties  is  the  misconception  of  place 
and  environment  and,  uj)  to  a  certain  degree,  of  time;  they  have  entirely 
lost  their  orientation.  They  are  able  to  remember  and  (lescribe  clearly 
the  contents  of  their  own  room;  one  can  sometimes  make  them  clearly 
appreciate  the  objects  which  compose  their  ]:)resent  environment,  and 
yet  they  will  be  absolutely  unable  to  a})preciate  that  they  are  not  in 
their  own  room  and  in  a  hospital.  Their  occupation,  former  life,  and 
all  ideas  that  relate  to  their  ])ersonality,  are  unaffected.  Ideas  of  gran- 
deur do  not  occur  in  true  delirium  tremens;  if  they  appear,  it  is  the 
complication  of  some  other  psychosis.  The  emotional  attitude  of  the 
patient  depends  largely  upon  the  character  of  the  hallucinations  and 
illusions;  they  may  be  happy  or  fearful,  they  are  more  often  anxious 
and  fearful,  and  these  may  rajiidly  replace  each  other  from  time  to 
time.  The  feeling  of  anxiety  is  almost  never  absent  from  the  beginning 
of  delirium  tremens;  it  is  first  seen  as  an  oppression  in  the  eldest  or  as 
an  external  restlessness;  this  feeling  of  anxiety  or  terror  seems  to  be 
particularly  prominent  in  patients  with  dyspnoea.  During  the  height 
of  the  delirium  the  anxiety  often  diminishes  and  gives  place  to  a  eu- 
phoria, so  that  the  patient  becomes  indifferent  even  to  the  hallucina- 
tions which  previously  terrified  him,  and  he  may  even  be  amused  at 
the  external  phantasies  that  are  being  worked  out  and  played  before 
him.  The  motor  impulses  are  in  most  patients  very  pronounced.  As 
many  patients  show  occupation  hallucinations  in  some  degree,  so  their 
movements  usually  correspond  with  these.  The  impulse  to  speak  often 
corresponds  with  these  movements,  but  frequently  patients  will  be  busily 
moving  about  for  hours,  or  lying  in  bed  actively  busy  in  many  ways, 
without  saying  a  word. 

The  tremor  from  which  the  disease  really  takes  its  name  is  apart 
from  the  motor  impulse  just  described  and  differs  from  the  ordinary 
tremor  in  chronic  alcoholism  only  in  its  intensity  and  in  the  greater 
distribution.  It  may  be  so  marked  in  delirium  tremens  that  the  pa- 
tients totter  and  are  unable  to  hold  themselves  erect,  or,  when  lying  in 
bed  and  suddenly  spoken  to,  it  may  assume  such  convulsive  intensity 
as  to  throw  them  off  the  bed.  It  persists  even  when  the  patients  are 
at  rest,  although  by  movement  there  is  a  great  intention  increase.  The 
tongue  trembles  strongly  when  thrust  out  and  this  often  causes  intense 
tremor  in  the  muscles  of  the  face.  The  eye  muscles  remain  free  from 
tremor  and  the  head  as  a  rule  only  takes  part  slightly.  In  slight  de- 
grees it  can  be  controlled  when  the  fingers  are  held  closely  together, 
but  becomes  distinctly  a]iparent  when  they  are  stretched  wide  apart. 
In  convalescents,  after  the  tremor  has  disappeared,  it  can  be  felt  in 
the  interossei  muscles  when  these  are  taken  between  the  index  finger 
and  the  thumb.  The  speech  often  shows  a  distinct  ataxia;  besides 
trembling  of  the  voice,  there  is  often  also  a  stumbling  over  syllables 
and  words,  and  mispronunciation,  which  is  as  apparent  in  voluntary 
speech  as  it  is  in  reading  aloud.  The  handwriting  shows  some  disturb- 
ance; besides  the  tremor,  words  and  syllables  are  left  out  and  an  in- 
ability to  follow  straight  lines  with  the  tumbling  of  words  above  or 
below  each  other  is  seen.  Sometimes  in  the  morning  tremor  of  drunk- 
ards, a  glass  of  alcohol  Avill  steady  the  hand,  so  that  the  handwriting 
becomes  clearer. 


ALCOHOL  185 

There  is  a  great  tendency  to  sweating  and  often  the  slightest  exertion 
brings  on  a  profuse  perspiration.  The  tendon  reflexes  are  as  a  rule 
not  changed.  The  sleeplessness  continues  throughout  the  entire  extent 
of  the  delirium  and  ceases  as  the  delirious  period  comes  to  an  end.  As 
has  been  said,  the  temperature  usually  rests  near  the  normal  line  during 
the  deUrium;  it  is  however,  in  some  cases  raised,  usually  not  above 
101°,  except  in  patients  in  whom  the  motor  impulses  are  very  intense 
and  there  is  a  consequent  incessant  muscular  movement.  Under  these 
conditions  temperatures  of  103°  and  104°  are  not  uncommon;  tempera- 
tures of  105°  from  these  causes  are  of  serious  prognostic  significance. 
Magnan  describes  febrile  delirium  tremens  as  a  special  form  of  the 
disease  but  it  would  seem  that  he  has  classified  as  a  special  group  the 
patients  in  whom  the  most  intense  motor  symptoms  are  evident,  and 
it  would  seem  that  they  differ  from  the  other  forms  of  delirium  tremens 
only  in  the  intensity  of  the  delirium  or  of  the  motor  impulses  produced 
by  the  vividness  of  their  hallucinations.  They  differ  only  in  degree, 
and  not  in  kind,  from  other  cases  of  delirium  tremens.  During  the 
summer  months,  in  periods  of  great  heat  in  New  York,  it  is  noticeable 
that  this  form  of  febrile  delirium  is  most  common  when  the  motor  ex- 
citement is  very  intense.  The  patient  may  pass  into  a  condition  of 
heat  stroke,  the  temperature  may  rise  to  108°  F.,  and  the  patient  die. 

During  the  delirium  the  pulse  runs  from  80  to  110  when  the  heart 
muscle  is  in  fair  condition.  In  patients  showing  much  emotion  or  in 
those  showing  intense  motor  activity,  the  pulse  is  correspondingly  in- 
creased. Its  quality  is  usually  soft,  and  according  to  Kriickenberg, 
often  dicrotic.  Constipation  is  the  rule.  Several  German  observers  lay 
great  stress  upon  the  frequency  of  albumen  in  the  urine  of  delirium 
tremens  patients,  with  no  other  signs  of  nephritis,  which  disappears 
after  the  delirium  has  ceased.  This  albumin  appears  in  about  half 
the  cases  in  the  beginning  of  the  delirium,  and  in  others  on  the  second 
and  third  day,  it  is  transitory  and  may  cease  a  day  or  so  before  the 
delirium  or  it  may  last  a  day  or  two  after  the  cessation,  but  as  a  rule,  is 
small  in  amount.  Leipmann  found  albumoses  in  about  15  percent,  of 
the  delirious  patients,  and  toward  the  end  of  the  delirium,  they  are 
found  in  addition  to  the  albumin.  Microscopically  the  urine  contains 
few  formed  contents,  a  few  round  epithelial  cells  and  rarely  hyaline 
casts.  Bonhoeffer  quotes  Elsholz  as  having  found  in  the  examination 
of  the  blood  an  increase  in  the  polynuclear  leukocytes  and  a  dimin- 
ishing of  the  mononuclear  but  no  leukocytosis.  In  cases  of  severe  de- 
lirium the  eosinophiles  were  absent. 

The  duration  of  an  attack  in  mild  cases  is  two  or  three  days;  it  averages 
probably  three  to  five  days  and  may  continue  for  eight  or  ten  days.  The 
cessation  of  the  delirium  usually  follows  a  deep  sleep  which  may  last  un- 
interruptedly for  twelve  to  thirty  hours.  Some  authors  describe  this  sleep 
as  coming  on  in  the  midst  of  the  delirium  but  it  is  usually  preceded  by  a 
period  of  weariness  and  relative  quiet.  When  the  patient  awakens  from 
the  critical  sleep  he  is  sensible,  the  hallucinations  have  gone  and  his 
orientation  is  usually  complete;  his  mental  condition  however  is  not  fully 
recovered;  the  power  of  retention  is  diminished  and  the  ability  to  combine 
thoughts  is  distinctly  diminished  for  a  few  days.  The  memory  of  the  recent 
illness  is  never  complete  but  it  is  accurate  for  the  essentials ;  it  is  very  rare 


186  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

that  complete  forgetfulness  occurs.  As  to  the  duration  of  his  illness,  the 
patient  rarely  has  an  accurate  idea,  deeming  the  time  shorter  than  it  really 
was.  In  general  the  emotional  and  fantastic  occurrences  are  better  re- 
membered than  the  ordinary  ones  hut,  after  four  or  five  days,  even  these 
lose  their  distinctness.  Often  for  several  days  therapeutic  measures,  which 
were  necessary  during  the  stage  of  delirium,  are  remembered  and  still 
misunderstood  as  forms  of  persecution.  In  old  alcoholics,  who  have  had 
previous  attacks  of  delirium,  there  is  at  times  a  certain  appreciation  of  the 
disease  during  the  entire  delirium  and  they  also  show  a  corresponding 
clearness  as  to  its  occurrences.  On  the  other  hand  these  same  patients  are 
very  prone  to  consider  hallucinations  as  realities  and  retain  these  mis- 
apprehensions for  a  long  period.  In  not  a  few  patients  there  is  a  recru- 
descence of  the  deliriiuii  for  a  few  nights,  while  remaining  free  of  it 
during  the  day;  any  unusual  excitement  producing  mental  exhaustion 
may  often  during  the  day  time  bring  back  some  of  the  hallucinations. 
Meningeal  Symptoms,  Serous  Meningitis,  "Wet  Brain." — In  all 
forms  of  chronic  alcoholism,  but  especially  following  acute  and  chronic 
delirium,  a  condition  develops  which  has  rarely  been  noted  and  Dana  is 
the  only  one  who  has  deemed  it  worthy  of  mention.  This  is  the  alco- 
holic meningitis  or  serous  meningitis,  the  so-called  "wet  brain."  It 
occurs  with  relatively  equal  frequency  in  men  and  women.  There 
is  no  true  inflammatory  process  and  the  condition  is  called  a  menin- 
gitis from  the  excessive  amount  of  fluid,  but  this  is  a  transudate,  and 
meningitis  is  a  misnomer.  The  most  probable  cause  seems  to  be  the 
degeneration  of  the  vessels,  the  paralysis  of  vasomotor  control  and  the 
weakened  condition  of  the  heart.  It  usually  follows  an  attack  of  delirium 
tremens,  though  it  may  develop  in  any  chronic  alcoholic  after  a  debauch, 
without  previous  delirium.  When  it  follows  delirium  tremens,  the  patient, 
after  a  few  days  of  delirium,  sinks  sloAvly  into  a  semi-coma.  The  delirium 
becomes  of  a  low,  muttering  type,  and  the  patient  retains  sufficient  con- 
sciousness to  have  the  delusions  and  hallucinations  of  sight  and  hearing. 
He  is  roused  with  difficulty,  though  he  will  still  take  food.  The  pulse  is 
rapid,  the  temperature  remains  normal  or  is  slightly  raised,  but  seldom 
over  a  degree.  The  pupils  are  usually  diminished  in  size.  The  skin  is 
hyperaesthetic  and  pressure  on  the  muscles  of  the  arms  and  legs  and  over 
the  abdomen,  causes  pain.  Conjunctivitis  and  keratitis  often  develop.  In 
some  patients  the  condition  slowly  progresses  for  several  days,  in  others  the 
effusion  increases  rapidly,  and  they  sink  into  a  more  profound  coma  from 
which  they  cannot  be  roused.  The  arms  and  legs  become  stiff,  the  reflexes 
are  all  exaggerated,  the  neck  is  stiff,  slightly  retracted,  and  attempts  to  move 
it  cause  pain.  The  abdomen  is  retracted  and  the  skin  and  muscles  are  still 
hyperaesthetic.  The  lids  are  closed;  the  pupils  are  contracted  and  react 
slowly  if  at  all.  The  tongue  is  dry  and  brown,  and  there  is  usually  incon- 
tinence of  faeces  and  urine.  The  pulse  is  frequent  and  feeble,  and  the 
extremities  are  cold.  He  may  continue  in  this  condition  for  several  days 
and  gradually  fade  out,  or  improvement  may  slowly  begin,  the  mind  be- 
come clearer,  the  neck  less  rigid,  the  hjqjeraesthesia  diminish,  and  recovery 
slowly  take  place.  Often  three  or  four  weeks  are  required  before  the 
patient  is  really  convalescent.  Pneumonia,  especially  inhalation  pneu- 
monia, is  apt  to  develop;  the  temperature  may  rise  to  101°-104°F.,  and 
the  patient  dies.    In  709  cases  of  delirium  in  Bellevue  Hospital,  New 


ALCOHOL  187 

York,  this  condition  developed  in  108  instances  (15  per  cent.);  of  these, 
37  recovered  and  71  died — a  mortahty  of  G5.7  per  cent.  The  prognosis 
is  alv^ays  grave  when  the  coma  and  rigidity  have  become  w^ell  developed. 
Dana  gives  the  stiffness  of  the  neck  as  a  useful  prognostic  criterion;  if 
the  patient  has  not  a  stiff  neck  he  will  recover,  but  when  it  comes  on, 
the  patient  dies. 

Prognosis. — The  prognosis  of  delirium  tremens  depends  greatly  upon 
whether  it  is  complicated  by  trauma  or  infectious  diseases,  especially 
pneumonia.  Bonhoeffer  gives  122  deaths,  or  a  mortality  of  about  11 
per  cent,  out  of  1,077  cases;  of  these,  40  per  cent,  were  caused  by  pneu- 
monia, 17  per  cent,  by  other  acute  pulmonary  diseases,  4  per  cent,  by 
acute  intestinal  affections,  5  per  cent,  by  burns  and  injuries  of  the  body, 
2  per  cent,  by  erysipelas,  while  of  the  32  per  cent,  remaining,  autopsy 
showed  no  acute  somatic  affections,  but  a  considerable  number  had 
clinical  evidences  of  cardiac  collapse  and  anatomically  friable  yellow- 
colored  heart  muscle.  In  his  own  uncomplicated  cases,  this  author  had 
scarcely  a  1  per  cent,  death-rate.  In  709  cases  of  delirium  occurring  in 
Bellevue  Hospital,  there  were  143  deaths  or  about  20  per  cent.  Of  these, 
61  died  of  pneumonia,  about  36  per  cent.  There  were  125  cases  of  pneu- 
monia in  these  709  patients,  and  after  deducting  these  in  the  584  remain- 
ing, the  death-rate  was  about  14  per  cent.  Of  the  125  cases  of  pneumonia, 
64  recovered,  leaving  a  mortality  of  48.8  per  cent.  In  uncomplicated 
attacks  in  young  individuals  the  prognosis  is  fairly  good.  In  the  begin- 
ning of  any  attack  of  delirium  tremens  a  guarded  prognosis  should  be  given. 
If  the  delirium  develops  into  a  severe  form  and  the  motor  symptoms  are 
very  intense,  the  prognosis  is  correspondingly  grave.  The  so-called 
moderate  drinkers,  who  develop  delirium  tremens  after  trauma,  have  a 
bad  prognosis, — in  the  experience  of  the  writer  about  50  per  cent.  die.  In 
true  delirium  tremens,  as  differentiated  from  acute  alcoholic  hallucinosis, 
the  tendency  to  suicide  is  unusual.  The  changing  character  of  the 
delirium  prevents  the  fulfilment  of  any  transitory  morbid  train  of  thought. 
The  premonitory  stage  of  delirium  tremens,  when  there  is  great  intensity  of 
painful  emotions,  anxiety  and  unrest,  is  the  time  in  which  the  tendency  to 
suicide  is  most  apt  to  develop.  It  is  difficult  in  these  early  stages,  to  say 
whether  the  patient  is  developing  true  delirium  tremens  or  an  acute 
alcoholic  hallucinosis,  so  that  the  statement  that  in  true  delirium  tremens 
suicide  is  rare,  remains  true. 

Treatment. — We  must  realize  that  there  is  no  specific  and  treat  it 
symptomatically.  Most  of  these  patients  have  been  subsisting,  often  for 
long  periods,  on  alcohol,  with  little  or  no  food.  We  must  also  realize  that 
the  danger  is  not  in  the  delirium  but  in  the  diseased  condition  of  the  heart 
muscle  and  vessels  and  that  the  gastric  mucosa  is  in  such  a  condition  that 
substances  given  by  mouth  may  remain  unabsorbed  for  hours,  and  then 
suddenly  be  absorbed  and  the  system  be  overwhelmed  by  the  summa- 
tion of  accumulated  doses.  This  has  always  seemed  to  the  writer  the 
reason  of  the  increased  death-rate  under  the  old  digitalis  treatment. 
Many  drugs  have  been  vaunted  as  causing  sleep  and  cutting  short  the 
delirmm,  but  in  a  disease  in  which  the  critical  cessation  comes  on  with 
sleep,  it  is  really  impossible  to  say  whether  the  sleep  was  coincident  with 
the  crisis  or  whether  there  was  really  any  cause  and  effect  in  the  adminis- 
tration of  the  given  hypnotic.    The  question  whether  alcohol  should  be 


188  DISEASES   CAUSED  BY  ORGANIC  AGEXTS 

withdrawn  at  once  or  continiuHl  is  still  a  mooted  point.  It  is  the  writer's 
belief,  after  trying  both  methods,  basing-  his  judgment  on  the  treatment  of 
several  thousand  patients  by  eaeh,  that  aleohol  should  be  absolutely 
withdrawn  in  all  cases.  First  and  foremost,  all  these  patients  must  be 
treated  from  the  standpoint  of  those  having  a  degenerated  heart  muscle 
and  they  therefore  should  be  stimulated  with  strychnine  (gr.  uo-ao,  gm. 
0.001-0.002)  every  four  hours  or  oftener  or  by  caffeine  or  camphor,  and 
these  are  best  given  hypodermically.  Strong  coffee  or  tea  can  be  given 
in  mild  cases  instead  of  the  pure  caffeine.  The  ])atient  should  be  given  a 
purgative  such  as  compound  cathartic  pills,  com])ound  licorice  powder, 
or  calomel.  In  young,  vigorous  adults,  without  any  appreciable  change 
in  their  arteries,  who  have  recently  been  drinking,  an  emetic  such  as 
copper  or  zinc  sulphate  is  often  an  advantage.  These  should  never  be 
given  in  elderly  persons  or  in  those  who  appear  old  for  their  age. 

In  mild  and  abortive  attacks  a  dose  of  a  dram  of  paraldehyde,  repeated 
if  necessary  in  an  hour,  is  all  that  is  necessary  to  cause  sleep  from  which  the 
patients  frequently  awaken  either  clear-headed  or  with  their  delirium 
lessened.  In  the  severer  cases,  the  paraldehyde  may  be  given  in  dram 
doses,  at  hour  intervals,  even  up  to  three  doses.  Other  hypnotics,  such  as 
sulphonal,  trional,  etc.,  have  in  the  hands  of  the  writer  usually  failed 
utterly  except  in  the  mildest  cases.  Opium  should  be  resorted  to  only  as 
a  last  resort  and  is  especially  contra-indicated  with  pronounced  arterio- 
sclerosis. Hyoscine,  (gr.  125,  gm.  0.0005)  and  morphine  (gr.  |-f,  gm. 
0.01-0.015)  hypodermically,  should  only  be  given  to  young  and  vigorous 
individuals  in  whom  the  motor  symptoms  are  especially  marked.  Hyo- 
scine alone,  tends  to  increase  the  delirium,  especially  in  women.  Often  in 
the  severest  cases  a  mixture  of  hyoscine,  gr.  yX)~o  (S^-  0-0006)  with 
apomorphine,  gr.  -^-^  (gm.  0.006)  and  strychnine,  gr.  -gL  (gm.  0.002)  will 
quiet  them  and  give  at  least  a  few  hours  rest.  Bromides  are  insufhcient 
and  in  the  hands  of  the  writer  have  been  practically  useless.  Chloral 
is  one  of  the  best  drugs  when  properly  administered;  small  doses  are 
useless  and  Lancereaux  claims  that  they  even  tend  to  excite  these  patients. 
When  the  heart  is  properly  stimulated  chloral  hydrate  does  not  have  any 
deleterious  effects.  Lancereaux  recommends  thirty  to  sixty  grain  doses 
(gm.  2-4);  the  combination  of  chloral  and  morphine  is  especially  advan- 
tageous in  that  smaller  doses  of  each  can  be  given  and  the  mixture  be 
more  effective  than  either  singly.  The  mixture  of  morphine,  gr.  J  (gm. 
0.008),  chloral,  gr.  15-30  (gm.  1-2)  with  tincture  of  hyoscyamus,  5ss 
(2  Cc.)  tincture  of  ginger,  npx  (Cc.  0.6),  and  tincture  of  capsicum  rrpiii 
(Cc.  0.2),  and  water  to  oss  (Cc.  15)  is  very  effective  and  can  be  repeated 
at  the  end  of  an  hour.  These  hypnotics,  while  causing  sleep,  do  not  neces- 
sarily cut  short  the  delirium,  but  after  a  sleep  of  some  hours,  the  delirium 
is  often  quieter  and  there  is  the  further  advantage  of  rest  for  the  heart 
from  the  cessation  of  motor  excitement.  Of  late  years  the  writer  has 
used  ergot  hypodermically  in  Livingston's  solution,  which  is  as  follows: 
One  dram  of  the  solid  extract  of  ergot  is  dissolved  in  an  ounce  of  sterile 
water  and  three  drops  of  chloroform  and  three  grains  of  chloretone  are 
added,  and  the  solution  filtered;  this  is  sterile  and  should  be  given 
straight  into  the  muscles  in  the  gluteal  region  or  in  the  deltoid.  It  should 
never  be  given  subcutaneously;  if  carelessly  given,  it  will  produce  painful 
spots.    The  administration  of  thirty  drops  of  this  solution,  hypodermically. 


ALCOHOL  189 

every  two  to  four  hours,  reduces  the  dilated  bloodvessels,  lessens  the 
various  congestions,  and  brings  about  a  better  equilibrium  of  the  circula- 
tion. After  it,  there  is  a  distinct  tendency  to  a  quieter  delirium  and 
less  need  of  restraint;  it  reduces  the  tremor,  less  hypnotic  is  required,  and 
it  diminishes  the  tendency  to  "wet  brain."  The  writcT  has  never  seen 
symptoms  of  ergotism  although  thirty  minims  of  this  solution  were  given 
every  two  hours  for  ten  days  or  longer.  As  soon  as  patients  awake  they 
miust  be  given  food,  best  in  the  form  of  milk  or  milk  and  eggs.  This 
should  be  given  regularly  every  two  or  three  hours  during  the  delirium 
but  if  asleep  they  should  not  be  awakened  for  any  reason. 

The  treatment  for  the  "wet  brain"  condition  should  be  begun  as  soon 
as  it  is  suspected.  Strychnine,  gr.  eo  to  3^0,  and  ergot,  thirty  minims, 
both  hypodermically,  should  be  given  every  two  hours,  and  caffeine  and 
camphor  are  also  of  use.  The  patient  should  be  carefully  fed  every  two 
hours  with  milk,  broth,  and  eggs,  and  thorough  purging  is  advisable. 
Alcohol  seems  to  increase  the  effusion  and  should  not  be  given.  During 
convalescence,  however,  a  little  alcohol  in  the  form  of  egg-nog  two  or 
three  times  a  day  for  a  few  days  is  often  of  benefit. 

Bonhoeffer  recommends  that  delirious  patients  should  be  placed  for 
several  hours  in  a  warm  bath  at  95°  to  97°  F.,  and  that  an  attendant 
should  sit  beside  them  so  that  when  they  attempt  to  get  out  of  the  bath, 
their  attention  can  be  diverted.  He  also  recommends  that  one  or  two 
attendants  should  sit  beside  the  delirious  patients  and  keep  them  in  bed, 
which  is  excellent  treatment  where  there  are  many  attendants  and  few 
patients,  but  where  the  reverse  is  true  in  a  large,  active  service,  restraint  is 
often  necessary.  There  is  no  question  that  these  patients  should  be  con- 
fined to  bed  through  the  entire  delirious  stage,  as  in  the  wilder  delirium  it 
is  often  necessary  to  restrain  them  by  a  sheet  tied  around  their  ankles  and 
then  tied  to  the  foot  of  the  bed,  and  by  another  sheet  which  goes  from  the 
bed  up  over  one  shoulder,  doAvn  through  the  axilla,  across  the  back  to  the 
opposite  axilla,  out  across  the  shoulder,  up  to  the  bed;  the  wrists,  when 
necessary,  can  be  restrained  by  a  muslin  bandage  wrapped  around  over 
cotton  wool  which  thus  prevents  abrasions  and  holds  them  firmly;  some- 
times a  folded  sheet  stretched  across  is  sufficient  to  hold  them  in  bed. 
The  hot,  stiff,  canvass  jacket  is  essentially  bad,  as  it  rigidly  binds  the  pa- 
tient and  prevents  the  radiation  of  heat.  The  question  of  the  isolation  of 
these  patients  and  the  permitting  them  to  wander  about  in  a  padded  room 
is  often  brought  up ;  young  vigorous  persons  can  be  so  treated  for  a  few 
hours,  provided  the  tremor  is  not  too  great  and  the  delirium  not  so  violent 
that  they  will  do  themselves  injury.  We  have,  moreover,  always  to  con- 
sider sudden  collapse,  and  the  degree  of  cardiac  degeneration  cannot  be 
accurately  judged,  so  that  on  the  whole,  it  would  seem  better  to  keep 
all  patients  in  bed  during  their  delirium  and  not  to  isolate  them.  In 
hospitals,  the  patients,  although  in  open  wards,  are  but  little  dis- 
turbed by  their  fellows,  especially  during  their  delirium,  because  they  are 
too  much  occupied  with  their  own  hallucinations  to  pay  attention  to 
the  disturbances  caused  by  others. 

During  convalescence,  stomachics  such  as  capsicum,  nux  vomica,  and 
ginger  are  useful ;  often  a  mixture  of  nux  vomica,  cinchona,  and  gentian 
is  an  excellent  tonic.  In  the  febrile  cases  of  delirium  tremens  a  cold  bath 
is  often  necessary;  the  patients  are  placed  on  a  rubber  blanket  in  bed,  and 


190  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

cold  water  is  slapped  forcibly  upon  them  from  a  whisk  broom;  the  impact 
of  the  water  takes  the  place  of  the  physical  rubbing  in  the  cold  bath. 
Warm  packs  have  been  recommended,  but  often  the  resistance  made  by 
the  patient,  and  the  excitement  produced,  do  more  harm  than  good. 
Usually  eight  or  ten  days  after  the  patient  has  recovered  from  his  delirium 
he  is  fit  to  go  out,  and  in  hospitals  his  treatment  here  ceases.  If  possible, 
they  should  go  to  some  place  where  they  may  live  in  the  open  air  with  good 
food  and  have  moderate  outdoor  exercise.  Total  abstinence  from  alcohol 
is  their  only  hope  for  future  health;  for  this  reason  it  is  inadvisable  to  give 
any  medicine  with  alcohol  in  it.  Tonics  should  be  in  solid  form  containing 
no  alcohol. 

ACUTE  HALLUCINOSIS. 

Acute  hallucinosis  of  drunkards  is  sometimes  called  acute  alcoholic 
hallucinosis,  acute  paranoia,  or  acute  persecutory  insanity.  It  is  closely 
allied  to  delirium  tremens,  and  there  are  cases  which  seem  more  like 
connecting  links  than  belonging  clearly  to  either  one.  The  patients 
suffering  from  this  form  of  alcoholic  psychosis  are  usually  younger  than 
in  delirium  tremens  and  belong  to  the  better  educated  classes,  while 
delirium  tremens  is  most  common  among  those  who  perform  manual 
labor.  The  tendency  of  this  form  of  alcoholic  psychosis  to  develop  as  a 
concomitant  symptom  of  trauma,  pneumonia,  and  other  acute  diseases,  is 
not  so  great  as  delirium  tremens.  Acute  gastric  disturbances  are  the 
most  commonly  observed  physical  ailments  connected  with  it  and  it 
frequently  follows  fright  and  intense  anger.  Patients  have  been  known 
in  whom  one  attack  of  delirium  took  the  form  of  delirium  tremens  and 
another  the  form  of  acute  hallucinosis. 

Symptoms. — These  patients  show  a  predominance  of  the  acoustic 
type  of  hallucination,  although  optic  and  tactile  hallucinations  are  not 
infrequently  present,  but  not  as  prominently  as  in  delirium  tremens. 
There  is,  in  the  beginning,  the  same  irritability,  easily  excited  condition, 
restlessness  and  undefined  dread  as  in  delirium  tremens,  but  they  often 
show  a  peculiar  sensitiveness  to  ordinary  noises;  they  are  sleepless,  their 
dreams  are  bad,  and  they  start  in  their  sleep,  terrified  by  an  unknown 
something.  This  unstable  condition  may  persist  for  days  and  then 
become  somewhat  better,  and  a  further  debauch  cause  all  the  symptoms 
to  return  and  go  on  rapidly  into  a  full  development  of  the  complete 
psychosis.  They  are  often  troubled,  at  first,  with  noises  in  the  ears, 
which  develop  into  the  hallucinations  of  singing,  music,  shooting,  scream- 
ing, etc. ;  finally  they  are  persistently  followed  by  definite  voices,  which 
hold  their  attention  constantly  at  high  tension  and  compel  their  undi- 
vided attention.  Frequently  they  are  brought  into  the  hospital  by  the 
police  because  they  have  fled  from  the  persecution  of  these  voices,  or  they 
go  to  their  rooms  and  refuse  to  come  out  or  allow  any  one  to  approach. 
In  this  early  stage,  suicide  is  very  common,  especially  in  those  in  whom 
the  terror  is  highly  developed.  The  voices  are  sharply  localized,  they 
accompany  the  patient  from  behind,  creep  up  at  him  out  of  the  floor, 
come  to  him  from  a  hole  in  the  wall,  or  seem  to  be  persistently  telephoning 
to  him.  When  he  strives  to  sleep,  they  come  up  out  of  the  pillow,  from 
under  the  bed,  and  they  follow  his  every  movement.    These  voices  have  a. 


ALCOHOL  191 

definite  character;  they  may  be  the  voice  of  a  man,  woman,  or  child,  or  the 
clearly  recognized  voice  of  some  friend,  or  they  may  be  unmistakably  not 
human,  or  the  voices  may  seem  human  and  speak  in  a  foreign  tongue. 
The  rhythmical  character  of  the  hallucinations  is  quite  common  and 
sometimes  the  patient  hears  constant  repetitions  of  the  last  word  spoken 
to  him,  or  the  last  thought  which  he  has  had.  As  he  goes  into  the  street  the 
auditory  hallucinations,  as  in  delirium  tremens,  take  on  the  abusive 
character,  and  he  hears  himself  called  by  name  with  various  epithets 
added,  or  accused  of  various  criminal  acts.  Not  infrequently,  the  patient 
hears  every  thought  as  it  occurs  to  him,  spoken  out  aloud,  and  he  declares 
that  he  knows  the  very  spot  of  the  tongue  out  of  which  his  thoughts  are 
loudly  spoken;  frequently  he  hears  every  movement  he  makes  commented 
upon  by  the  voices. 

Optic  hallucinations  are  present  but  take  a  subordinate  position;  they 
frequently  occur  at  night  and  often  are  the  outlandish,  terrifying,  mixed- 
up  pictures  seen  in  delirium  tremens.  The  sense  of  touch  is  less  often 
involved  and  hallucinations  of  taste  and  smell  are  absent.  These  patients 
are  not  usually  disturbed  by  sensations  from  the  internal  viscera;  some- 
times, however,  they  seem  to  form  an  unimportant  part  of  the  hallucina- 
tions. When  these  last  sensory  regions  give  predominant  hallucinations, 
there  is  always  a  strong  suspicion  that  we  are  not  dealing  with  a  pure 
alcoholic  psychosis,  but  with  a  more  serious  condition.  Frequently  there 
is  a  suspiciously  disturbing  misconception  of  all  acts  that  are  performed 
by  others  in  his  presence;  he  believes  that  people  moving  in  the  street  are 
running  together  to  discuss  him;  he  is  suspicious  of  the  patients  in  the 
hospital,  believes  that  the  motions  made  by  the  nurse  in  handing  him  his 
food  prove  that  he  is  about  to  be  poisoned  and  misinterprets  all  therapeutic 
measures.  The  idea  of  persecution  does  not  go  further  back  than  the 
recent  past;  his  persecutory  system  is  superficial,  changes  during  the 
disease,  and  often  develops  suddenly;  ideas  of  grandeur  are  sometimes 
present. 

Consciousness  is  not  clouded,  and  they  retain  their  power  to  combine 
thought  and  their  powers  of  retention.  Disturbances  in  the  process  of 
thought,  as  in  delirium  tremens,  are  not  present.  Most  authors  seem  to 
believe  that  their  orientation  for  place,  as  a  rule,  remains  intact.  In  the 
patients  who  show  a  type  of  the  disease  tending  toward  the  clinical  picture 
of  delirium  tremens,  there  is  sometimes  disorientation  especially  in  the 
beginning  of  the  attack.  Tremor  of  the  hands  and  tongue,  and  gastritis, 
are  usually  present;  the  symptoms  of  neuritis  are  not  uncommon,  and 
other  disturbances  of  chronic  alcoholism,  such  as  a  tendency  to  perspire 
freely,  etc.,  are  common,  although  they  are  usually  less  marked  than  in 
delirium  tremens,  perhaps  because  this  psychosis  more  often  occurs  in 
younger  individuals.  Bonhoeffer  states  that  the  albuminuria  seen  in 
delirium  tremens  was  not  found  by  him  in  these  cases.  The  duration  of 
this  disease  varies  from  a  few  days  to  weeks.  Rarely  does  it  continue 
more  than  two  months,  accordi  ng  to  Bonhoeffer.  As  the  patients  improve, 
there  are  periods  in  which  they  seem  to  be  free  from  hallucinations, 
Finally  the  voices  in  their  ears  are  recognized  as  such  and  no  longer 
produce  the  hallucinations.  The  various  erroneous  impressions  improve 
coincidently  with  the  disappearance  of  the  voices.  Wernicke  believes, 
however,  that  these  patients  go  though  a  paranoiac  stage  in  some  hallu- 


192  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

cinations  in  wliich  their  systematized  illusions  persist;  however  this  may 
be,  this  stage  is  evidently  of  short  duration,  beeause  the  accurate  appreci- 
ation of  their  psychic  condition  often  occurs  \\\\\\  an  astonishing  rapidity. 
They  remember  their  hallucinations  and  are  often  proud  to  write  a 
descrij)tion  of  them.  Sometimes  these  patients  go  from  these  acute 
hallucinatory  stages  into  a  condition  of  chronic  delirium.  There  are  no 
known  pathological  lesions  characteristic  of  this  psychosis. 

Prognosis. — The  prognosis  as  to  life,  if  they  are  put  into  an  institution, 
is  good,  but  if  they  go  through  the  early  stages  uncared  for,  the  danger  of 
suicide  is  great.  The  liability  to  death  from  intercurrent  disease  is  not 
great,  and  the  more  they  tend  in  their  clinical  j)icture  toward  the  transi- 
tion type  of  delirium  tremens,  the  shorter  seems  to  be  the  duration  of 
their  delirium.  Ideas  of  grandeur  seem  to  tend  to  a  somewhat  longer 
duration.  As  in  delirium  tremens  the  same  patient  may  show  repeated 
attacks  of  this  ])sychosis  following  continued  excesses  of  chronic  alco- 
holism. If  the  paranoiac  condition  has  been  prominent,  continued 
alcoholic  indulgence  is  liable  to  produce  permanent  insanity. 

Diagnosis. — Bonhoeffer  gives  the  following  differential  diagnosis  be- 
tween the  acute  hallucinosis  and  delirium  tremens:  The  acoustic  region 
dominates  in  the  hallucinations  in  hallucinosis,  the  optic  and  tactile 
in  delirium  tremens;  in  hallucinosis  orientation  is  retained,  in  delirium 
tremens  it  is  lost;  in  hallucinosis  the  morbid  occurrences  are  systema- 
tized and  the  patient  has  the  illusions  concerning  his  relations  with 
others;  both  these  conditions  are  lacking  in  delirium  tremens;  the  dis- 
turbances of  retention  and  the  disturbances  of  memory  dependent  thereon 
concerning  time  and  succession,  the  confabulation,  the  disturbances 
of  attention  and  the  power  to  combine  thought  are  lacking  in  hallu- 
cinosis or  at  least  are  scarcely  apparent.  In  spite  of  these  differences, 
transitional  forms  occur  which  are  likely  to  cause  errors  in  diagnosis. 

Treatment. — This  is  the  same  as  for  acute  insanity;  the  tendency  to 
suicide  must  never  be  forgotten  and  isolation  is  ever  contra-indicated. 
They  should  be  kept  in  bed  during  the  delirium;  hypnotics  should  be 
given  to  produce  sleep  as  in  delirium  tremens;  especial  attention  should 
be  paid  to  their  digestion  and  to  frecjuent  feeding;  cathartics  will  usually 
be  necessary.  Bonhoeffer  recommends  frequent  warm  baths  for  these 
patients.  One  can  often  impress  on  them  after  their  recovery,  with  much 
better  hope  of  intelligent  appreciation,  the  necessity  of  total  abstinence 
from  alcohol.  We  are  dealing  Avith  patients,  as  a  rule,  more  intelligent 
than  those  suffering  from  delirium  tremens,  and  have  therefore  a  better 
chance  to  make  them  appreciate  their  condition  and  the  dangers  of 
further  indulgence;  they  are  also  often  less  injured  by  the  lesions  of 
chronic  alcohoHsm. 


CHRONIC  ALCOHOLISM. 

Many  of  the  forms  of  chronic  alcoholism  are  described  under  other 
diseases,  such  as  cirrhosis  of  the  liver,  arteriosclerosis,  etc.,  for  here,  as  in 
all  forms  of  alcoholism,  the  idiosyncrasies  of  the  patient  are  important 
factors  and  the  kind  and  amount  of  the  alcohol  used  also  modify  the 
clinical  picture. 


ALCOHOL  193 

The  amount  of  alcohol  which,  consumed  daily,  will  produce  the  lesion.s 
and  symptoms  of  chronic  alcoholism  varies  with  the  individual;  most 
men  who  partake  of  moderate  doses  dilute  their  alcohol  with  large  amounts 
of  water  and  the  effect  produced  is  less  than  when  the  fluids  are  taken  in 
concentrated  forms.  Many  men  take  moderate  amounts  of  whisky 
through  long  years  with  apparently  no  serious  effects;  many  others 
partake  of  moderate  amounts  with  their  meals  and  seem  to  be  benefited, 
and  not  injured,  thereby.  It  is  a  noticeable  fact  that  the  wine  connoisseur 
rarely  becomes  a  drunkard.  As  soon  as  an  individual  begins  to  take 
alcohol  for  the  effect  produced,  he  is  in  danger  of  continuing  the  practice 
and  becoming  more  and  more  tolerant;  he  requires  more  to  produce  the 
desired  effect  and  soon  partakes  of  amounts  that  necessarily  must  injure 
the  organism. 

When  once  the  condition  of  chronic  alcoholism  is  developed,  the  first 
symptoms  are  those  of  weakening  of  the  will  and  blunting  of  the  moral 
nature;  the  patients  become  untidy  and  slovenly  in  their  personal  habits; 
are  careless  in  their  ways  of  doing  things;  forgetful  of  their  promises  and 
engagements;  lose  their  sense  of  responsibility  to  the  community  as 
citizens,  and  to  care  and  provide  for  their  families.  They  become  more 
and  more  selfish  and  self-centred,  increasingly  incompetent  through 
forgetfulness  and  carelessness,  and  to  cover  up  their  shortcomings  are  at 
first  prone  to  make  excuses  which  are  followed  by  actual  lies  to  escape 
the  responsibility  of  their  misdeeds.  They  lose  their  sense  of  shame  and 
although,  while  the  remnants  of  their  better  nature  remain,  they  may 
promise  to  give  up  drinking,  if  they  break  this  promise,  they  make  excuses 
and  seem  to  be  shameless  regarding  it.  They  are  irritable,  touchy,  and 
liable,  from  slight  causes,  to  intense  fits  of  anger  during  which  they  will 
cruelly  punish  their  children  for  slight  ofPenses;  they  may  abusively 
scold  their  wives  and  families  on  the  slightest  pretext  or  brutally  maltreat 
them.  With  the  weakness  of  will  there  is  a  conceited  self-complacency 
which  causes  them  to  declare  that  they  can  stop  drinking  at  any  time  if 
they  wish,  and  yet  when  pinned  down  to  the  necessity  for  so  doing,  they 
have  a  never-ending  series  of  excuses  to  avoid  doing  it.  There  is  a  very 
characteristic  suspicion  in  the  minds  of  these  patients  of  the  faithlessness 
of  their  wives,  which,  according  to  Kraft-Ebing,  is  produced  by  a  failing 
sexual  desire  and  a  rapidly  occurring  impotence.  Usually  this  does  not 
express  itself  further  than  in  contemptible  and  vicious  vituperations;  it 
may  cause,  however,  in  fits  of  drunkenness,  actual  bodily  harm  and  even 
murder  of  an  innocent  wife  or  of  the  children,  as  suspected  accomplices  of 
their  mother.  These  evidences  of  mental  degeneration  may  continue 
through  years,  and  the  patient  finally  sink  into  early  senile  dementia,  for 
unfortunately  a  degenerated  intellect  does  not  necessarily  produce  death, 
and  as  long  as  the  heart  and  arteries  hold  out,  many  degenerated  alco- 
holics continue  to  live,  a  burden  and  nuisance  to  the  community.  They 
usually  die  before  the  alcoholic  dementia  is  fully  developed,  because  of 
their  liability  to  trauma  and  intercurrent  infectious  diseases,  or  during 
an  attack  of  delirium  tremens  or  other  psychosis,  or  from  visceral  de- 
generations, or  cerebral  hemorrhage. 


13 


194  DISEASES  CAUSED  BY  ORG  AX  I C  AGENTS 

DIPSOMANIA  OR  PERIODIC  INEBRIETY. 

In  some  individuals  alcoholism  exhibits  itself  in  the  form  of  periodical 
crises,  the  dipsomania  or  periodic  inebriety  of  some  authors.  These 
patients  are  often  total  abstainers  between  attacks  and  struggle  against 
the  desire  when  it  comes  over  them.  Some  authors  believe  these  attacks 
are  related  to  periodic  epileptic  explosions.  Thelat  defines  the  chronic 
alcoholic  as  one  who  becomes  drunk  whenever  the  opportunity  is  offered, 
and  the  dipsomaniac  as  one  who  becomes  drunk  only  when  the  attack 
seizes  him.  Often  these  attacks  are  preceded  by  mental  depression, 
restlessness,  irritability,  headache,  anorexia,  sleeplessness  and  precordial 
anxiety,  and  the  desire  to  drink  becomes  irresistible.  They  will  drink 
until  the  attack  is  past  or  until  forced  to  desist  by  restraint.  Some  patients 
will  mix  various  disgusting  substances  in  their  beverages,  hoping  thus 
to  stop  the  craving.  The  periodicity  varies  from  weeks  to  months  or 
even  a  year  or  more.  In  some  men  regular  recurring  tasks  or  business 
stresses  bring  them  on;  in  some  women  the  menstrual  periods  seem  to  be 
the  cause  of  the  outbreaks.  In  others  the  attacks  develop  without  appar- 
ent exciting  causes.  In  some  patients  if  protected  for  some  hours  or  days, 
the  craving  passes  away  and  they  are  safe  until  the  next  attack.  In  the 
beginning  many  patients  drink  only  to  drunkenness,  but  later  their 
debauch  goes  on  until  they  are  forced  to  cease  under  restraint.  In  the 
majority,  the  periods  between  attacks  shorten  until  they  finally  develop 
into  the  characteristic  condition  of  chronic  alcoholism,  with  no  periodicity 
to  their  incessant  indulgence.  During  their  debauch  they  may  develop 
an  attack  of  delirium  tremens  or  other  forms  of  alcoholic  psychosis. 


ALCOHOLIC     TRANCE,      AUTOMATISM     OR      PATHOLOGICAL 

DRUNKENNESS. 

In  psychopathic,  hysterical,  or  epileptic  patients,  or  following  traumatic 
injuries  to  the  skull,  or  after  sunstroke,  alcohol  produces  disturbances  of 
consciousness  which  deviate  greatly  from  the  ordinary  sequences.  The 
same  conditions  are  seen  in  those  who  have  been  injured  through  the 
excessive  use  of  alcohol;  one  of  the  simplest  expressions  of  this  condition 
is  that  in  which  the  patients,  after  much  smaller  amounts  of  alcohol  than 
formerly,  become  drunk  and  are  absolutely  oblivious  next  day  to  every- 
thing that  occurs.  After  the  first  or  second  drink  of  whisky  they  may 
seem  to  their  friends  simply  to  have  been  drinking  and  not  more  than 
usual  under  the  influence  of  alcohol,  or  they  may  in  slightly  more  pro- 
nounced cases,  completely  lose  their  orientation,  misinterpret  entirely 
their  environment,  and  show  an  ugly  disposition,  which  was  foreign  to 
them,  with  evidences  of  a  high  degree  of  emotional  anxiety.  More  pro- 
nounced examples  of  alcoholic  automatism  are  those  in  which  the  patient 
may  start  off  on  a  prolonged  debauch  and  at  the  end  wake  up  in  some  far 
away  city  and  all  occurrences  from  the  time  he  began  until  coming  to 
himself  be  an  absolute  blank.  The  amnesia  is  usually  complete;  some- 
times there  are  faint  recollections  that  he  has  been  recently  in  certain 
places;  for  instance,  one  patient  of  the  writer  remembered  taking  a  drink 
in  Boston  and  ten  days  later,  having  gone  through  a  five  days'  attack  of 


ALCOHOL  195 

delirium  tremens  in  Bellevue  Hospital,  came  to  himself  with  complete 
amnesia  of  everything  which  had  occurred  during  the  ten  days;  another 
who  was  drinking  and  sociably  chatting  with  a  friend,  with  no  intention  of 
taking  enough  alcohol  to  disturb  his  sobriety,  came  to  himself  five  days 
later  while  ascending  the  stairs  of  a  station  of  an  elevated  road,  and  was 
unable  to  remember  any  occurrences  of  those  five  days  except  that  he  had 
been  in  some  bath  establishment.  This  man  was  not  an  alcoholic,  and 
filled  a  responsible  position,  although  some  years  previously  he  had  drunk 
to  excess.  Other  patients,  after  a  single  drink  or  during  a  debauch,  have 
been  known  to  start  off  on  long  journeys  and  come  to  themselves  on  board 
a  railroad  train  or  a  steamer.  Others  have  been  known  to  conduct  com- 
plicated business  transactions  shrewdly  and  successfully,  to  go  into  court 
and  conduct  successfully  a  long  trial,  ending  with  a  prolonged  charge  to 
the  jury,  come  home  and  write  out  a  long  legal  document  concerning  the 
case  with  perfect  clearness  and  conciseness,  and  yet  when  consciousness 
returned,  the  amnesia  was  complete.  In  some  this  will  occur  but  once,  in 
others  it  is  of  recurrent  nature  and  may  be  preceded  by  restlessness  and 
irritability,  and  after  a  single  drink  they  regularly  go  into  this  state  of 
disassociation  of  consciousness.  In  these  conditions  men  have  committed 
forgery,  theft,  and  even  murder,  without  any  recollection  of  them  when 
consciousness  returns,  and  are  stricken  with  a  deep  remorse  when  accused 
of  wrong-doing  and  made  to  suffer  for  their  crimes.  Others  in  this  condi- 
tion of  pathological  drunkenness  will  murder  their  children  for  trivial 
causes  and  show  no  remorse  for  the  act;  calmly  deliver  themselves  up 
and  discuss  the  whole  occurrence  with  no  more  appreciation  or  mental 
disturbance  at  what  they  have  done  than  if  they  had  broken  a  piece 
of  furniture  or  accidentally  injured  some  animal.  Many  of  these  cases 
belong  to  medicolegal  literature  rather  than  to  general  medicine.  There 
is  no  question  as  to  the  reality  of  the  total  amnesia  in  these  cases,  and  the 
responsibility  for  their  acts  should  be  placed  in  the  same  category  as 
those  of  the  acutely  insane. 

ABSINTHISM. 

Lancereaux  described  a  special  form  of  chronic  alcoholism  produced  by 
excessive  indulgence  in  absinthe,  various  liqueurs  and  aromatic  essences. 
The  substances  in  the  absinthe  of  commerce  he  divides  into  two  groups, 
the  convulsive  and  the  stupifying;  in  the  first  are  absinthe,  hyssop  and 
sennel,  and  in  the  second  annis,  angelica,  menthe  and  marjoram. 
Absinthe  and  annis  produce  the  main  symptoms.  He  divides  the  clinical 
manifestations  into  acute,  chronic,  and  hereditary  absinthism.  The  symp- 
toms in  acute  absinthism  come  on  suddenly;  the  patient  becomes  agitated, 
screams,  loses  consciousness  and  falls;  there  is  a  tonic  convulsion  tending 
to  opisthotonos,  followed  by  a  succession  of  clonic  convulsions  for  twenty 
or  thirty  seconds.  He  then  falls  back  heavily,  lies  still  for  a  few  moments 
and  regains  consciousness.  He  has  no  recollection  of  what  has  occurred 
and  is  astonished  that  people  should  be  caring  for  him;  this  lucid  interval 
is  of  short  duration  and  is  succeeded  by  similar  convulsions  lasting  for 
ten  or  twelve  hours.  In  others  the  tonic  convulsions  are  followed  by  clonic 
convulsions,  and  the  patient  throws  himself  from  side  to  side,  grinding  his 


196  ■     DISEASES  CAUSED   BY  ORGAXIC  AGEXTS 

teeth,  screaming  and  foaming  at  the  mouth,  trying  to  bite  tliose  around 
him,  striking  his  chest,  and  tearing  at  it.  These  attacks  are  of  short  dura- 
tion and  followed  bv  a  period  of  calm;  they  end  suddenly  without  cyano- 
sis or  coma.  A  series  of  such  convulsions  leaves  the  ])atient  weary  and 
some\^•hat  stupid:  For  a  day  or  two  he  may  feel  the  effect  but  at  the  end 
of  this  time  he  is  entirely  recovered.  Acute  [joisoning  of  this  kind  is 
usually  recovered  from,  although  death  may  occur  during  the  attack. 

Chronic  Absinthism. — The  patient  not  only  suffers  from  convulsive 
attacks,  but  also  has  neuritis  and  terrifying  hallucinations.  Chronic 
poisoning  develops  often  from  an  indulgence  of  less  than  a  year  and  from 
amounts  of  the  licjueur  which  seem  inadeciuate  to  account  for  the  symptoms 
on  the  ground  of  the  alcohol  consumed.  Women  seem  to  suffer  more 
frequently  than  men,  and  especially  women  below  twenty-five  years  of  age. 
These  patients  have  morning  vomiting  and  marked  dizziness;  there  is 
marked  irritability  of  the  muscles;  the  eyes  are  fixed  and  brilliant;  they 
sweat  easily;  tremor  is  marked;  and  there  is  extreme  hyperalgesia  of  the 
body.  There  is  marked  hyperpesthesia  of  the  skin  over  the  exits  of  the 
spinal  nerves,  diminishing  in  intensity  from  below  upward;  the  plantar 
reflexes  are  extremely  active.  Pressure  on  the  abdominal  wall  is  painful, 
and  tickling  or  touching  in  the  lightest  way  causes  such  agony  that  the 
patient  screams  with  pain.  The  tenderest  points  are  in  the  lower  abdomen 
outside  the  recti  muscles  and  out  into  the  iliac  fosste.  This  is  accompa- 
nied, especially  at  night,  by  the  most  intense  pain  in  the  muscles  of  the  legs. 
In  cases  of  long  duration  the  hyperalgesia  is  succeeded  by  analgesia,  but 
the  pain,  on  pressure  over  the  abdomen,  chest,  or  the  spinal  column,  re- 
mains almost  as  intense  as  at  the  beginning.  These  patients  are  sleep- 
less or,  when  falling  to  sleep,  are  troubled  with  terrifying  nightmares. 
Hallucinations  of  hearing  are  rare,  but  have  a  menacing  character  and 
are  heard  especially  during  the  night;  the  mental  ability,  as  in  all  alco- 
holics, shows  weakness.  One  would  judge  that  they  lapsed  rapidly  into 
the  chronic  delirium  and  not  infrequently  died  in  this  condition. 

Hereditary  absinthism  is  shown  in  children  whose  parents  are  addicted 
to  its  use.  These  children  seem  to  possess  an  unusually  unstable  nervous 
system  and  are  especially  prone  to  convulsions  in  infancy,  and  later  to 
hysterical  manifestations,  and  convulsive  seizures.  It  has  been  noticed 
in  Bellevue  Hospital  during  the  past  few  years  that  patients,  who  give  a 
history  of  drinking  absinthe,  have  shown  attacks  of  convulsions  and  in 
the  majority  there  has  been  marked  hypersesthesia  and  hyperalgesia  of  the 
lower  extremities;  the  extreme  types  as  described  above  have  not  come 
under  the  writer's  observation. 


KORSAKOW'S  PSYCHOSIS. 

For  many  years  there  has  been  recognized  among  chronic  alcoholics  a 
condition  of  delirium  combined  with  a  polyneuritis;  this  was  finally 
classed  as  a  distinct  and  separate  psychosis  by  Korsakow  and  is  now  gen- 
erally called  KorsakoAv's  psychosis  or  syndrome.  Mentally  there  is  loss  of 
orientation  and  a  marked  defect  in  the  power  of  retention  of  new  im- 
pressions, and  loss  of  memory  for  the  recent  past  and  also  for  events  during 
various  periods  of  the  patient's  whole  life.    There  is  a  strong  tendency  to 


ALCOHOL  197 

confabulation,  and  to  fabrications  of  the  most  absurd  character  and  even 
hallucinations,  together  with  a  polyneuritis.  This  usually  occurs  in  the 
prime  of  life  and  is  said  by  some  authors  to  be  more  common  among 
women  than  men,  while  the  statistics  of  others  show  a  preponderance  of 
men  over  women.  It  usually  follows  excessive  indulgence  in  alcohol  for 
long  periods,  although  it  has  also  been  described  as  occurring  as  a  result  of 
infectious  diseases  and  following  poisoning  from  lead  and  arsenic.  In  the 
majority  of  the  patients  the  psychosis  begins  with  the  delirious  stage  and 
this  may  be  so  marked  that  at  first  a  diagnosis  of  delirium  tremens  is  made, 
but  the  critical  sleep,  so  characteristic  of  delirium  tremens,  is  absent  and 
the  delirium  pursues  a  protracted  course.  Acute  hallucinations  fall  into 
the  background  and  the  defects  of  mental  retention  with  the  lack  of  orien- 
tation of  time  and  space,  and  the  foolish  babbling,  become  more  pro- 
nounced. In  other  patients,  and  some  claim  this  to  be  the  usual  course, 
there  is  a  prodromal  period  during  which  there  are  signs  of  forgetfulness, 
mental  aberrations  and  irritability;  in  some  sleeplessness,  and  in  others  a 
stupor  from  which  they  are  aroused  with  difficulty.  The  symptoms  of 
neuritis  may  precede  the  delirium  or  not  come  on  until  after  it.  The  length 
of  this  prodromal  stage  varies  in  different  individuals.  Bonhoeffer  de- 
scribes a  form  which  develops  as  a  very  slow  progressive  weakness  of 
memory  with  a  sudden  exacerbation  of  disturbances  of  memory  to  a 
definite  standpoint.  When  however  the  characteristic  delirium  is  de- 
veloped, there  is  a  distinct  loss  of  memory  for  the  recent  past;  events  of 
their  early  life  may  be  very  clearly  remembered,  or  up  to  a  certain  definite 
time.  This  amnesia  may  be  complete  or  there  may  be  curious  lapses  of 
memory  in  which  the  patient  forgets  some  events  and,  without  any  appar- 
ent reason,  remembers  others  which  occurred  during  the  same  period. 
Many  lose  all  orientation  of  time  or  space;  especially  is  the  time  element 
defective;  they  cannot  tell  whether  an  event  occurred  a  few  moments  or  a 
week  or  several  years  ago.  These  gaps  of  memory  are  filled  in  with  curious 
fabrications.  This  tendency  to  confabulate  and  indulge  in  pseudo- 
reminiscences  is  very  characteristic  of  this  psychosis. 

The  sense  of  recognition  is  much  at  fault;  the  patient  does  not  know 
those  about  him,  or  remember  his  friends  or  even  his  nearest  relatives. 
The  attention  is  easily  obtained  but  kept  with  difficulty.  In  the  early 
stages,  hallucinations,  usually  of  sight,  occur  only  at  night  but  as  the 
disease  progresses  they  become  more  intense  and  may  be  present  during 
the  day.  Optic  and  tactile  hallucinations  are  most  common;  these  may 
or  may  not  be  terrifying  and  may  assume  the  fantastic  forms  seen  in  acute 
alcoholic  delirium.  If  the  delirious  stage  comes  on  early  and  quickly, 
these  hallucinations  are  then  prominent.  The  emotional  condition  of  the 
patients  varies;  some  are  excited,  even  simulating  a  condition  of  paresis; 
others  are  depressed,  having  the  self-accusations  seen  in  melancholia; 
they  are  often  anxious  and  disturbed  and,  later  in  the  disease,  are  apt  to  be 
irritable,  quarrelsome,  or  simply  indifferent;  in  some  there  is  a  tendency 
to  be  silly  and  funny;  they  are  at  times  childish  and  easily  provoked  to 
whining  and  crying;  but  in  very  severe  cases  they  are  practically  emotion- 
less. They  are  noticeably  lacking  in  mental  initiative  and  for  this  reason 
are  very  prone  to  soil  themselves;  here  also  weakness  of  the  bodily 
muscles  and  the  neuritis  play  a  distinct  part.  They  show  a  distinct 
power  of  combination  of  thought  and,  as  far  as  the  power  of  retention 


198  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

permits,  can  reason  correctly,  especially  in  some  purely  intellectual  mat- 
ters. 

The  symptoms  of  neuritis  are  those  which  accompany  polyneuritis; 
they  have  the  various  annesthesias,  paresthesias,  or  hyjieraesthesias;  there 
is  often  an  ataxic  incoordination;  their  gait  is  frequently  unstable  and  they 
walk  with  their  feet  far  apart;  the  regular  pains  and  sensitiveness  to  touch 
and  muscular  weakness  are  present;  the  ])atella  reflexes  are  weak  or  absent; 
the  joints  are  lax  and  the  muscles  soft;  these  neuritic  symptoms  are  usually 
more  pronounced  in  the  lower  extremities  and  when  the  paralysis  becomes 
marked,  an  atrophy  quickly  follows;  there  may  then  be  contractions  and 
permanent  deformities.  Paralysis  of  the  extensors  is  more  frequent  than 
of  the  flexors.  In  very  severe  cases  the  upper  extremities  are  involved  and 
one  finds  a  radial,  ulnar,  or  median  paralysis.  Some  individual  muscles 
may  escape  while  others  may  be  paralyzed.  The  sensory  disturbances  are 
variously  distributed.  One  can  seldom  prove  these  in  single  nerves  but 
can  simply  make  out  well-marked  zones  of  analgesia  and  hyperaesthesia. 
Disturbances  in  the  sense  of  position  not  infrequently  occur;  delayed 
reaction  to  pain  has  often  been  observed,  ataxia  of  the  upper  extremities 
is  often  extremely  marked.  Severe  tropic  disturbances  may  occur.  The 
cranial  nerves  may  be  affected.  The  vagi  are  not  infrequently  involved, 
causing  cyanosis,  tachycardia,  and  a  peculiar  dyspnoea  whicla  produces 
short-breathed  speech.  Double-sided  paralysis  of  the  recurrent  laryngeal 
nerves  has  been  observed,  as  also  disturbances  of  swallowing  and  of  move- 
ment of  the  tongue.  Paralysis  of  the  palate  has  been  seen  and  paralysis 
of  the  external  eye  muscles,  especially  of  the  abducens,  is  especially 
frequent.  Ptosis  is  rare;  the  inner  eye  muscles,  however,  functuate  well 
or  fairly  well,  but  slow  reaction  to  light  has  been  several  times  observed; 
true  nystagmus  has  also  been  noted  and  nystagmus-like  twitchings  are 
very  frequently  seen  in  the  last  stages  of  the  disease. 

Wernicke  has  described  a  cerebral  psychosis  with  paralysis  of  the  eye 
muscles  which  runs  an  acute  and  fatal  course;  this  he  called  polien- 
cephalitis  hemorrhagica  superior.  This  disturbance  of  the  eye  muscles 
went  on  to  complete  paralysis.  Wernicke  believed  this  to  be  a  separate 
psychosis  and  held  that  it  was  characteristic  for  the  clinical  picture  of  the 
disease  to  have  an  associated  ocular  paralysis,  a  progressive  course,  and  a 
rapidly  fatal  ending.  Observations  have  since  shown  that  patients  with 
this  group  of  symptoms  do  not  always  die,  and  several  recoveries  have  been 
reported.  Bonhoeffer,  after  fully  reviewing  the  subject,  concludes  that 
poliencephalitis  hemorrhagica  superior  is  not  a  separate  clinical  entity  but 
that  the  ophthalmoplegia  is  moderate  in  certain  cases  and  is  an  vmusually 
predominating  symptom  of  a  general  disease,  and  he  further  shows  that  it 
is  nearly  related,  if  not  identical,  with  Korsakow's  psychosis. 

The  course  of  this  psychosis  is  a  protracted  one;  the  first  stage  up  to 
the  full  development  of  the  mental  symptoms  continues  for  some  weeks. 
The  neuritis  usually  shows  improvement  before  the  mental  symptoms,  and 
in  the  course  of  several  months  may  go  on  to  full  recovery,  although  in 
some  there  may  be  permanent  atrophy  and  paralysis.  The  mental  im- 
provement does  not  run  parallel  with  that  of  the  neuritis  but  requires  a 
longer  time.  The  powers  of  retention  seem  to  be  the  first  to  improve;  then 
the  orientation  improves  sufficiently  for  the  patients  to  recognize  where 
they  are,  and  they  begin  to  realize  who  the  persons  are  with  whom  they 


ALCOHOL  199 

come  in  contact.  The  length  of  time  during  which  this  improvement 
occurs  is  a  varying  one;  it  may  take  months  or  years  before  complete 
orientation  has  been  obtained.  Some  authors  believe  that  complete 
restitution  can  occur;  others  deny  it.  Most  observers  are  unwilling  to 
commit  themselves  to  a  definite  opinion  in  this  regard.  Even  after  ap- 
parent recovery,  most  patients  show  some  weakness  of  retention  and  a 
forgetfulness  which  often  prevents  them  taking  up  their  former  occu- 
pations. They  are  apt  to  have  a  distinct  lack  of  initiative  and  show 
irritability  and  unstable  emotions  while,  unless  there  is  total  abstinence 
from  alcohol,  they  soon  revert  to  their  former  condition.  These  patients 
are  very  apt  to  die  in  the  delirious  stage  and  in  the  severe  attacks  in  which 
the  mental  symptoms  are  very  pronounced,  death  is  not  often  long  delayed. 
There  is  great  tendency  to  die  of  intercurrent  diseases.  The  prognosis  in 
all  recent  cases  is  doubtful  and  what  is  of  especial  importance,  it  depends 
upon  the  general  condition  of  the  patient  and  the  state  of  his  cardiac 
muscle.  In  the  early  stages  the  severer  the  delirium  the  worse  the  prog- 
nosis and  when  the  neuritis  extends  to  the  cranial  nerves  it  is  especially 
unfavorable;  thus,  when  the  vagus  is  involved  with  tachycardia,  dyspnoea 
and  cyanosis,  death  very  frequently  occurs.  The  prognosis  for  final 
recovery,  if  they  have  passed  the  severe  stages,  should  always  be  given 
with  great  reserve.  Although  they  may  recover  a  fair  amount  of  physical 
vigor  and  of  their  former  mentality,  the  chances  are  always  in  favor  of 
more  or  less  mental  defect  remaining. 

The  treatment  is  in  general  symptomatic.  In  the  early  stages  they  are 
best  cared  for  in  some  institution.  In  the  early  months,  even  in  the 
milder  cases,  rest  in  bed  is  necessary.  The  neuritis  should  be  treated  as 
any  other  polyneuritis.  The  mental  symptoms  can  only  be  treated 
through  improvement  in  the  general  condition.  During  the  severe  de- 
lirious stages  hypnotics  may  be  necessary;  in  the  later  stages  the  milder 
hypnotics  are  sufficient  when  any  are  needed  at  all.  When  their  mental 
condition  improves  and  they  are  able  to  be  about,  it  is  best  to  give  them 
light  and  easy  tasks,  which  is  better  than  attempts  to  improve  the  mental 
state  by  especial  exercises  of  an  intellectual  character.  When  one  may 
be  certain  that  they  will  receive  good  care  at  home  and  can  be  reasonably 
assured  of  their  total  abstinence,  the  patients  may  be  allowed  to  return 
to  their  families. 

In  addition  to  the  clinical  forms  of  chronic  alcoholism  already  described, 
there  are  other  designations  given  to  various  mental  states  in  which  various 
symptoms  predominate.  Occasionally,  in  patients  in  whom  excessive 
indulgence  in  alcohol,  usually  without  food,  has  produced  intense  exhaus- 
tion with  complete  mental  confusion,  a  state  of  amentia  appears  which 
simulates  manic  depressive  insanity.  Following  an  attack  of  delirium 
tremens  or  acute  hallucinosis,  some  sink  directly  into  a  paranoic  state  or 
this  less  often  develops  primarily.  The  ideas  of  suspicion  and  jealousy 
greatly  predominate.  In  most  of  these  the  delusions  are  predominantly 
sexual  and  early  in  the  disease  hypersesthesia  sexualis  is  not  infrequently 
present.  They  have  the  alcoholic  emotional  instability  and  may  be 
dangerous.  Since  alcoholic  excesses  are  at  times  a  symptom  of  paresis, 
the  diagnosis  of  this  condition  from  the  pseudoparesis  of  alcoholism  may 
be  difficult.  The  ideas  of  grandeur,  the  mental  stupidity,  with  failure  of 
memory  and  judgment  of  the  paretic,  are  present  with  alcoholic  hallu- 


200  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

cinations  and  ideas  of  persecution  and  infidelity;  though  the  develop- 
ment is  gradual  and  the  course  ])rotracted,  it  is  not  progressive.  Often 
the  course  is  the  final  differentiation.  If  a  chronic  alcoholic  survives  long 
enough,  the  last  stage  of  many  of  the  above  mental  states  is  early  senility 
and  alcoholic  dementia.  This  often  occurs  without  any  ])revious  delusions 
or  distinctly  insane  stages  and  is  the  final  result  of  the  cerebral  arterio- 
sclerosis and  atrophy  of  the  cerebral  tissues. 


TREATMENT  OF  CHRONIC  ALCOHOLISM. 

It  is  not  always  jiossible  to  olitain  an  accurate  history  of  the  length  of 
a  debauch  or  its  intensity.  If  one  studies  the  tremors  in  connection  with 
the  condition  of  the  tongue,  in  the  experience  of  the  writer  a  fairly  good 
guess  can  be  made  which  is  sufficiently  accurate  to  justify  [one  in  acting 
on  the  conclusions  thus  drawn.  If  the  tongue  is  not  coated  and  there  is 
no  tremor,  the  patient  has  been  drinking  about  three  or  four  days;  if  the 
tongue  is  moderately  coated  and  there  is  no  tremor,  it  means  the  debauch 
has  lasted  about  five  or  six  days ;  a  heavily  coated  tongue  and  no  tremor, 
about  seven  days;  a  moderately  coated  tongue  and  a  slight  tremor,  about 
ten  days;  a  heavily  coated  tongue  and  a  marked  tremor,  about  fourteen 
days;  a  moderately  coated  tongue  with  a  very  severe  tremor,  about 
three  weeks;  a  fairly  clean  tongue  and  a  very  severe  tremor,  about  a 
month;  a  bright  red,  glazed  tongue  and  a  severe  tremor,  from  six  weeks 
to  three  months.  This  is  true  of  young  men  up  to  about  forty-five  years 
of  age;  after  that  the  tremor  comes  on  earlier  and  a  two  weeks'  spree  will 
give  as  much  tremor  in  an  elderly  man  as  a  month's  spree  in  a  young  man. 
In  women  these  rules  are  not  accurate;  the  nervous  system  is  affected 
more  intensely  and  earlier,  while  gastritis  comes  on  sooner.  A  w^eek  or 
ten  days'  spree  brings  usually  an  intense  tremor  and  women  will  inva- 
riably endeavor  to  hide  how  much  and  how  long  they  have  been  drinking. 

The  same  treatment  applies  as  for  delirium  tremens;  if  a  young  patient 
comes  in  the  midst  of  his  spree,  an  emetic  is  very  efficient,  but  this  should 
never  be  given  in  elderly  persons  or  in  those  in  whom  we  suspect  the 
arteries  may  be  atheromatous.  Calomel  (gr.  v,  gm.  0.3)  with  sodium 
bicarbonate  (gr.  15,  gm.  1)  in  single  doses,  or  tw^o  compound  cathartic 
pills,  should  be  given  as  soon  as  the  stomach  has  quieted  down.  If  the 
patient  should  be  in  the  midst  of  the  spree  and  has  recently  taken  alcohol, 
one  or  two  drams  of  paraldehyde  with  a  half  ounce  of  whisky  wall  often 
give  him  a  restful  sleep;  this  may  be  repeated  in  an  hour  if  necessary 
but  if  he  has  not  been  drinking  recently,  paraldehyde  alone  should  be 
given  or  the  mixture  of  chloral,  morphine,  hyoscyamus,  ginger  and 
capsicum.  Hypodermic  injections  of  ergot  are  usually  most  efficient, 
lessen  the  tremors  and  take  away  the  feeling  of  collapse  and  exhaustion 
which  the  withdrawal  of  alcohol  produces.  As  in  delirium  tremens, 
the  writer  is  firmly  convinced  that  alcohol  should  be  withdrawn  im- 
mediately and  absolutely;  if  they  are  collapsed  a  hypodermic  of  strychnine 
and  doses  of  aromatic  spirits  of  ammonia  replace  the  alcohol.  Further- 
more, the  withdrawal  takes  away  the  idea  that  alcohol  is  necessary  or  that 
they  need  it  in  any  w^ay,  and  this  is  an  essential  element  to  be  thoroughly 
emphasized.    When  the  patient  awakes,  stomachics,  such  as  nux  vomica. 


ALCOHOL  201 

ginger  and  capsicum,  should  be  given  with  his  food.  During  the  first  few 
days,  liquor  ammonia  acetatis,  in  half  ounce  doses,  every  three  hours,  is 
often  helpful.  Sometimes,  in  very  nervous  patients,  antipyrine  (gr.v,  gm. 
0.3)  with  the  acetate  of  ammonia  will  help  greatly.  If  the  patient  is  fur- 
iously and  "fighting  drunk," either  from  acute  intoxication  or  at  the  end  of 
a  long  spree,  a  hypodermic  injection  of  apomorphine  (gr.  I'o,  gm.  0.006) 
will  quickly  transform  the  most  pugnacious  into  a  limp  and  docile  object. 
He  can  then  be  put  to  bed  and  in  a  few  minutes  will  drop  off  to  sleep  with  no 
other  medication.  This  rarely  causes  vomiting  unless  the  stomach  is 
full;  if  this  does  occur,  it  is  of  no  disadvantage.  This  is  often  the  best 
means  of  saving  further  struggles  and  the  writer  has  never  seen  any  harm 
come  from  it. 

If  the  patients  have  recovered  from  the  debauch,  the  question  arises  as 
to  the  permanent  cure;  some  may  pull  themselves  together  under  excep- 
tional circumstances;  these  are  undoubtedly  those  in  whom  the  alcohol 
has  not  produced  serious  cerebral  changes,  but  it  can  be  said  that  they 
belong  to  the  curiosities  of  medicine  and  it  is  not  to  be  expected  of  any 
one  who  has  formed  the  alcoholic  habit.  Institutional  treatment,  by 
which  the  patient  may  be  assured  that  he  will  be  protected  against  him- 
self, and  cannot  obtain  any  alcohol  for  a  period  of  one  or  two  years, 
where  he  can  live  out  of  doors  and  bring  his  body  back  into  as  healthy 
a  state  as  possible  with  a  chance  for  the  brain  to  recover  from  the  poison- 
ing of  the  alcohol,  offers  the  surest  means  of  cure.  This  may  sometimes 
be  done  at  home,  if  the  patient  can  be  controlled  and  carefully  guarded, 
but  the  influence  must  be  strong  indeed  and  appeal  intensely  to  his 
moral  nature  to  affect  him.  Taken  all  in  all,  the  influence  of  religion 
has  proved  most  effective  for  this  but  unfortunately  it  is  not  applicable 
in  many  cases.  Most  alcoholics  are  very  open  to  suggestion  and  in  a 
small  number  of  cases,  hypnotism  seems  to  have  been  tried  with  success, 
but  this  more  often  fails  than  succeeds.  Suggestion  does  come  in  play 
in  institutions  where  several  patients  are  endeavoring  together  to  break 
themselves  of  the  habit;  the  concerted  effort  helps  materially  to 
strengthen  the  weak  wills  of  many  of  them.  These  patients  and  their 
families  are  prone  to  turn  to  advertised  quackery  and  nostrums  to  ob- 
tain a  cure  rather  than  to  persuade  the  patient  to  put  himself  under 
regular  restraint.  The  fact  that  legally  in  this  country  an  alcoholic  can 
not  be  restrained  against  his  will  often  adds  to  the  difficulty  of  doing 
anything  that  will  really  assist  him.  A  treatment  has  been  published 
byMcBride  of  Toronto,  which  has  proved  very  successful  in  his  hands. 
The  writer  has  tried  it  in  a  few  patients  and  so  far  the  results  have  been  all 
that  could  be  desired.  It  is  as  follows:  As  soon  as  the  patient  is  over 
the  severe  effects  of  his  debauch  or  if  he  is  steadily  drinking  without  any 
drunken  outbreak,  he  should  be  given,  hypodermically,  three  times  a 
day,  atropine  and  strychnine,  of  each  gr.  iho  (gm.  0.0006);  these  drugs 
should  be  gradually  increased  until  the  full  physiological  effect  of  the 
atropine  is  obtained  and  the  patient  is  taking  a  thirtieth  or  even  a  twen- 
tieth of  a  grain  of  strychnine,  three  times  a  day;  when  the  mouth  is 
continually  dry  and  the  pupils  dilated,  the  atropine  should  be  reduced 
slightly  and  held  at  this  dosage  for  four  or  five  days;  then  both  the 
strychnine  and  atropine  should  be  gradually  reduced,  and  finally  the 
patient  should  be  given  the  drug  twice  daily,  then  once  a  day,  and  then 


202  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

cut  off  entirely;  the  length  of  time  required  for  this  treatment  is  about 
a  month  or  six  weeks.  Often  the  compound  tincture  of  cinchona  is 
added,  especially  in  the  morning  when  the  craving  for  alcohol  is  the 
greatest.  It  is  a  noticeable  fact  that  after  a  few  days,  usually  in  less 
than  a  week,  the- desire  for  alcohol  has  ceased,  and  the  thirst  from  the 
dryness  of  the  mouth  is  easily  satisfied  \A'ith  water.  McBride  reports 
that  he  has  tried  this  for  a  number  of  years  and  the  patients  whom  he 
thus  treated  ten  or  twelve  years  ago  have  remained  abstinent;  this  has 
not  been  universally  successful  but  in  his  hands  it  has  succeeded  in 
such  a  large  majority  that  it  is  worthy  of  the  most  extensive  trial  and 
it  has  the  special  advantage  that  the  patients  need  not  be  confined  or 
absent  from  their  homes  or  even  daily  work. 


CHAPTER  X. 

OPIUM.    MORPHINISM.    COCAINE. 
By  ALEXANDER  LAMBERT,  M.D. 

OPIUM. 

Historical. — There  are  many  legends  connected  with  the  discovery  of 
the  effect  of  opium.  Along  the  Nile  its  use  dates  back  to  very  ancient 
times  as  the  Egyptian  hieroglyphics  seem  to  show.  Homer  mentions  the 
poppy  as  a  garden  plant;  the  ancient  Greeks  knew  the  means  by  which  the 
narcotic  properties  could  be  obtained  from  the  plant  as  appears  from  the 
writings  of  Dioscorides,  and  in  some  parts  of  India  and  Persia  to-day  the 
opium  is  obtained  from  the  poppy  by  the  same  method  that  was  described 
eighteen  hundred  years  ago.  Hippocrates  is  among  the  first  in  whose 
writings  we  find  the  drug  recommended  for  internal  use.  The  Egyptian 
priests  used  it  as  a  nervous  sedative,  believing  that  the  sleep  produced  gave 
opportunities  for  the  soul  to  commune  with  the  gods.  The  Arabian 
physicians  were  the  first  to  study  its  value  in  disease  and  they  seem  to  have 
made  wide  use  of  the  drug.  The  Persians  early  recognized  the  opium 
habit,  for  they  had  a  proverb  that,  although  opium  cured  disease,  it  also 
produced  a  disease.  Serturner,  an  apothecary  in  Germany,  seems  to  have 
been  the  first  to  study  scientifically  the  alkaloids  of  opium  Derosne,  in 
1803,  discovered  narcotin  which  he  called  the  salt  of  opium,  believing  it  to 
be  the  active  principle.  Robequet  showed  this  belief  to  be  erroneous  and 
gave  the  name  narcotin  to  this  alkaloid.  In  1804,  Seguin  isolated  a  crystal- 
line body  which  has  proven  to  be  the  narcotic  principle  but  he  did  not 
seem  to  realize  the  importance  of  his  discovery  and,  in  1817,  Serturner 
again  published  the  existence  of  a  salt  of  opium,  which  he  named  mor- 
phium.  Crothers  says  that,  although  opium  has  been  used  subcutaneously 
for  a  long  time,  morphia  seems  first  to  have  been  thus  used  in  this  country 
by  Drs  Isaac  Taylor  and  Washington,  in  New  York,  in  1839,  and  its  use 
abroad  was  not  generalized  until  a  syringe  was  introduced  into  the  French 
army,  in  1866,  by  Pravaz.  The  dangers  of  morphinism  as  a  habit  seem  first 
to  have  been  realized,  in  England,  about  1864.  Nausbaum  in  the  same 
year  drew  attention,  in  Germany,  to  the  injurious  effects  of  its  continued 
use.  Since  then  the  attention  of  the  medical  profession  has  been  drawn 
more  and  more  strongly  to  the  increasing  dangers  of  morphia  and  opium 
addiction  Not  infrequently  have  physicians,  in  their  efforts  to  relieve 
pain,  been  unconsciously  responsible  for  the  spread  of  this  habit,  and  it  is 
only  in  recent  years  that  the  full  realization  of  this  danger  has  become 
widespread.  The  pernicious  habit  of  giving  a  h}"podermic  s}Tinge  to 
patients,  teaching  them  to  use  morphia  to  alleviate  a  passing  pain,  has  been 
all  too  frequent,  and  has  been  the  cause  of  many  an  unhappy  addiction. 


204  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

Etiology. — The  more  highly  cultivated  and  mentally  developed  a  race 

becomes,  the  more  intolerant  is  it  of  pain.  This  is  especially  trueof  the  male 
sex.  The  Eastern  nations  have  long  used  opium,  thus  in  India  and  China, 
opium,  though  a  curse  from  its  excessive  use,  seems  to  be  more  often  used 
in  moderation  ^vithout  ])roducing  the  same  deleterious  effects  as  in  other 
races.  This  is  not  true  of  all  Eastern  races,  for  the  Burmese  rapidly 
deteriorate  under  its  use.  The  great  majority  of  morphia  addictees  are 
among  the  educated  classes,  especially  those  who  deal  continually  with  it, 
as  druggists,  physicians  and  professional  nurses,  and  among  these,  men 
predominate.  A  large  class  are  those  who  are  neurotic  from  inheritance; 
their  will  and  judgment  are  in  unstable  equilibrium  and  they  are  either 
dominated  by  a  desire  to  gratify  any  momentary  pleasure,  or  they  seek 
comfort  in  anything  that  seems  to  stimulate  and  increase  their  mental 
vigor  for  the  time  being.  They  are  often  the  children  of  alcoholic,  tuber- 
culous, syphilitic,  or  neurotic  individuals,  and  unfortunately  the  alcoholism 
in  the  parent  need  not  be  more  than  the  so-called  moderation.  Many 
persons  of  unusual  intellect,  precocious  in  early  life,  are  pushed  beyond 
their  strength,  mature  early,  and  break  under  the  undue  strain.  These 
seek  relief  from  exhaustion  by  means  of  drugs  and  alcohol.  It  is  not  un- 
common to  find  strong  and  vigorous  men,  after  some  severe  shock  or  dis- 
appointment or  after  intense  strain,  given  morphia  to  alleviate  insomnia, 
soon  becoming  addicted  to  its  use.  Many  patients,  suffering  from  chronic 
and  painful  affections  or  incurable  disease,  become  addicted  to  the  use  of 
morphia  from  the  necessity  of  alleviating  pain.  Women  suffering  from 
disorders  of  the  genital  organs  fall  easy  victims,  and  it  is  especially  danger- 
ous to  prescribe  morphia  for  women  at  the  climacteric  period.  Formerly 
many  patients  became  addicted  to  morphia  through  the  widespread 
custom  of  giving  it  to  relieve  pain  following  surgical  operations,  but  the 
number  of  these- is  enormously  diminished  since  the  danger  has  been 
recognized  by  surgeons. 

Among  Western  nations  the  opium  habit  is  indulged  in  more  by  the 
taking  of  morphia  by  mouth  or  hypodermically,  or  by  drinking  laudanum 
or  paregoric,  than  by  the  smoking  of  opium.  Among  Eastern  nations  the 
smoking  of  o])ium  seems  rather  to  predominate.  Of  late  years  codein  and 
heroin  addictions  have  been  recorded.  Compared  with  alcohol,  opium 
may  be  said  to  be  equally  degrading  and  destructive  of  the  moral  side  of 
the  individual,  but  it  does  not  leave  behind  it  the  same  amount  of  organic 
lesions  in  the  individual  nor  transform  the  individual  into  the  same 
vicious,  destructive,  and  abusive  beast  that  alcohol  does. 


ACUTE  OPIUM  POISONING. 

Symptoms. — The  symptoms  of  acute  opium  poisoning  require  little 
detailed  description;  the  infrequent,  stertorous  breathing,  the  livid  cyan- 
otic appearance,  the  pin-point  pupils,  the  cool,  sweating  skin,  give  a  well- 
known  and  easily  recognizable  clinical  picture.  The  respirations  may 
simply  be  infrequent  with  a  rythmical  regularity  or  they  may  be  in  groups 
of  three  or  four  with  many  seconds  between  each  group. 

Treatment. — The  treatment  is  chiefly  a  struggle  to  keep  up  the  work- 
ing of  the  paralyzed  respiratory  centre.    The  old  method  of  walking  a 


OPIUM.      MORPHINISM.      COCAINE  205 

patient  up  and  down,  injecting  large  doses  of  atropine  to  stimulate  the 
respiratory  centre  and  slapping  him  with  wet  towels,  has  always  seemcid 
to  the  writer  ill-advised.  The  incessant  walking  up  and  down,  stagger- 
ing forward  and  back  half  asleep,  exhausts  the  patient  thoroughly 
and  tlie  liability  to  give,  what  is  for  that  patient,  an  overdose  of  atropine 
and  thereby  add  its  poisonous  effects,  appears  to  be  a  dangerous  pro- 
cedure. One  may  see  patients,  brought  to  the  hospital  with  their  hearts 
very  rapid  from  an  overdose  of  atropine,  die  suddenly  in  collapse;  they 
really  died  from  the  antidote  and  not  from  the  opium.  The  slapping 
with  wet  towels  soaks  them  with  cold  water  and  in  the  exhausted  condi- 
tion there  is  a  strong  liability  that  pneumonia  may  follow.  It  seems 
wiser  to  save  the  strength  of  the  patient  and  the  energies  of  the  attend- 
ants for  the  long  and  tedious  period  through  which  artificial  respiration 
must  be  kept  up.  As  soon  as  possible  the  stomach  must  be  washed 
out  with  a  solution  of  potassium  permanganate  (1  to  500);  a  certain 
amount  of  this  should  be  left  in  the  stomach;  whether  opium  be  taken  by 
the  mouth  or  as  morphia,  hypodermically,  the  morphia  itself  is  excreted 
into  the  stomach  cavity  and  is  then  reabsorbed.  It  has  been  proven 
experimentally  on  dogs  that  more  than  half  of  the  morphia  given  sub- 
cutaneously  can  be  recovered  by  simply  washing  out  the  stomach.  Dr. 
Moor,  of  New  York,  has  shown  that  permanganate  of  potassium  prevents 
the  toxic  action  of  morphia.  In  opium  or  morphia  poisoning  it  is  there- 
fore wise  to  wash  out  the  stomach  at  least  every  hour  and  leave  a  little  of 
the  permanganate  solution  in  the  stomach  to  destroy  any  of  the  alkaloid 
that  may  be  excreted  by  the  gastric  mucosa.  In  the  periods  between 
washings  a  strong  infusion  of  coffee  should  be  injected  into  the  bowel. 
Artificial  respiration  should  be  kept  up  until  the  patient  is  able,  when  left 
alone,  to  breathe  eight  or  ten  times  a  minute.  This  may  mean  many 
hours  of  hard  and  tedious  exertion,  but  as  long  as  the  heart  is  beating,  if 
respirations  are  kept  up,  there  is  a  possibility  of  recovery.  To  relieve  the 
cerebral  venous  congestion  produced  by  opium,  the  injection  of  ergot 
hypodermically,  as  described  under  alcoholism,  is  most  effective  and 
satisfactory.    It  equalizes  the  circulation  and  relieves  the  congestion. 

OPIUM  SMOKING. 

The  smoking  of  opium  is  an  ancient  vice.  It  is  claimed  that 
this  habit  came  from  Egypt  and  Arabia  to  India,  but  this  seems 
doubtful.  At  all  events,  it  is  mentioned  by  Barbosa  as  being  found 
in  India  as  early  as  1511;  from  India  it  was  introduced  into  China  and  is 
the  chief  method  in  this  last  country  by  which  opium  is  used.  In  1773,  the 
East  India  Company  first  began  the  exportation  of  opium  from  India  to 
China,  following  the  Portuguese  by  a  few  years.  Since  1860,  the  impor- 
tation of  opium  into  China,  and  the  cultivation  of  the  poppy,  have  greatly 
increased.  Opium  is  smoked  from  a  special  pipe,  the  stem  of  which  is 
usually  twenty-four  inches  long,  generally  made  of  bamboo,  at  the  loAver 
third  of  which  there  is  placed  a  bowl,  usually  of  red  clay,  through 
which  a  minute  hole  runs  down  into  the  stem. 

Compared  with  the  other  forms  of  opium  addiction,  according  to  Kane, 
ismoking  takes  longer  to  form  a  real  habit,  works  less  physical  and  mental 
injury  when  once  formed,  and  is  easier  to  cure.     A  gradual  rise  in  the 


206  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

amount  used  is  necessary  in  order  to  get  the  desired  effect;  the  early 
pleasurable  symptoms  soon  disappear  and  the  evil  effects  on  mind  and 
body  are  similar  in  many  respects  and  the  symptoms  incident  to  abstinence 
are  the  same.  In  smoking  opium,  the  morphia  is  not  all  consumed  and 
a  large  amount  remains  in  the  ash.  Amounts  of  opium  arc  smoked  which, 
if  taken  by  the  stomach,  would  certainly  produce  death.  Kane  quotes  the 
case  of  a  man  who  broke  the  habit  after  consuming  as  a  daily  dose  594 
grains.  He  gives  the  tabulated  statement  of  the  daily  dose  of  1,000 
Chinese  smokers;  046  varied  between  16  and  128  grains;  250  from  160  to 
320  grains;  104  from  480  to  1,600  grains.  To  obtain  the  desired  effect 
5  grains  seem  sufficient  for  a  novice,  while  old  smokers  need  as  high  as 
290  grains.  The  average  American  seems  to  consume  more  than  the 
average  Chinaman  to  obtain  the  desired  effect.  This  vice  among  Amer- 
icans is  of  relatively  recent  origin,  having  been  first  taken  up  in  this 
country  in  186S,  in  San  Francisco;  from  that  time  it  rapidly  spread  through 
the  west  and  from  there  tothe  east,  until  now,  throughout  the  United  States, 
it  is  by  no  means  rare.  Opium  smoking  is  not  confined  to  any  one  special 
class.  It  has  among  its  addictees  the  wealthy  of  both  sexes,  the  sporting 
man,  the  mechanic,  and  the  dissolute.  Neither  all  Chinamen  nor  all  Amer- 
icans who  smoke,  do  so  to  excess ;  some,  especially  the  former,  do  so  but 
once  a  week,  and  persons  are  met  with  who  smoke  for  months  without 
forming  any  habit  and  without  any  apparent  injury.  The  effect  desired  by 
the  opium  smoker  is  not  that  of  slumber  filled  with  fascinating  dreams, 
but  a  condition  of  dreamy  wakefulness  in  which  the  mind  is  lifted  out  of 
the  petty  annoyances  and  cares  of  life. 

Symptoms. — ;The  effect  of  opium  smoking  on  a  novice  is  described  by 
Kane,  who  tried  it  himself  and  experimented  with  two  other  men;  the 
first  effect  was  nausea  and  dizziness,  accompanied  by  a  pleasant  sensation 
of  exhilaration,  followed  by  a  quiet,  easy  contentment;  this  was  after 
deeply  inhaling  four  pipes;  there  was  an  increase  in  the  force  and  fre- 
quency of  the  pulse  from  80  to  110,  hot  flashes  over  the  body  and  face, 
and  after  a  few  more  pipes  came  a  soft  pulse,  lessened  in  frequency,  and  a 
fall  in  temperature,  giddiness,  and  slight  nausea,  with  some  staggering  on 
rising  or  walking,  profuse  perspiration,  ringing  in  the  ears,  and  intense 
itching  over  the  entire  body.  The  profuse  perspiration  and  nausea  con- 
tinued, followed  shortly  by  abundant  and  easy  vomiting;  there  was  also  a 
feeling  of  uncertainty  in  putting  down  the  feet  in  walking,  sleepiness, 
heaviness  of  the  eyelids,  contraction  of  the  pupils,  dryness  of  the  throat, 
and  a  fear  of  crossing  the  street  if  a  wagon  or  car  was  approaching.  The 
sexual  appetite  was  increased.  This  was  followed  by  intense  sleepiness. 
The  doze,  however,  lasted  but  a  moment,  the  awakening  being  sudden ; 
there  were  no  dreams.  The  nausea  was  a  prominent  and  distressing 
symptom  and,  in  his  case,  lasted  for  twenty-four  hours  as  did  also  the 
itching.  The  pulse  dropped  below  sixty,  and  once,  after  ten  pipes  were 
smoked  fell  as  low  as  forty-one,  and  remained  so  for  six  hours.  Some- 
times the  novice  does  not  feel  at  all  sleepy  and  becomes  very  talkative  even 
after  the  tenth  pipe,  and  later,  when  desiring  to  sleep,  although  sleepy,  he 
is  unable  to  do  so  from  intense  fear  that  some  catastrophe  may  occur. 
Among  other  novices  the  drowsiness  may  come  on  after  four  or  five  pipes, 
and  they  sink  back  into  a  heavy  slumber,  lasting  for  some  hours.  Twenty- 
four  hours  after  smoking,  the  novice  frequently  feels  languid,  is  without 


OPIUM.      MORPHINISM.      COCAINE  207 

appetite,  has  an  intense  headache,  and  the  itching  continues.  Old  smokers 
do  not,  as  is  usually  believed,  smoke  a  few  pipefuls  and  then  fall  into  a 
heavy  sleep;  as  experience  grows  into  a  habit,  stupefaction  is  less  speedy, 
and  it  may  require  many  hours  and  many  pipes  before  even  the  coveted 
excitation  is  reached,  and  the  majority  complain  that  they  are  sleeping 
less  than  usual  and  are  troubled  by  distressing  insomnia.  If  the  smoker 
has  gone  to  excess,  sleep  filled  with  horrible  hallucinations  or  a  condition 
of  terrifying  wakefulness  may  follow.  The  stupid,  sleepy  condition  of 
the  next  day  is  removed  by  a  further  resort  to  the  pipe.  The  habitual 
smokers,  who  do  not  use  the  drug  to  excess,  claim  that,  unlike  any  other 
form  of  opium  taking,  a  headache  never  follows. 

The  effect  of  opium  smoking  is  first  seen  upon  the  mind.  The  feel- 
ings of  pleasant  exhilaration  and  contented  indifference  are  gradually 
more  difficult  to  obtain  and,  after  from  three  months  to  a  year,  they 
cease  to  occur  although  the  amount  of  opium  smoked  be  largely 
increased.  If  the  addictee  endeavors  now  to  break  it  off,  distressing 
symptoms  show  themselves  so  intensely  that  he  is  forced  to  continue. 
The  continuance  of  the  smoking  brings  with  it  a  disinclination  for  con- 
tinued mental  effort,  a  weakness  of  the  Avill-power,  a  lack  of  decision. 
and  a  loss  of  memory.  A  certain  indecision,  manifested  by  mentaf  per- 
plexity and  impatience  concerning  the  smallest  actions,  is  often  noticed 
after  smoking.  Dull  mental  hebetude  often  alternates  with  outbursts 
of  violent  anger,  or  there  is  a  gloomy  presentiment  of  impending  evil 
only  allayed  when  indulging  in  a  pipe.  During  these  periods  of  despon- 
dency, suicide,  especially  in  women,  is  not  uncommon.  Neiiralgias, 
noticed  in  other  forms  of  opium  taking,  are  rare  during  opium  smoking. 
Occasionally  colic  is  complained  of  but  this  seems  more  due  to  intestinal 
disturbances  than  to  a  direct  effect  on  the  nervous  system.  Tremor  of 
isolated  muscles  sometimes  occurs,  but  a  general  tremor,  most  marked 
in  the  hands  and  tongue,  is  noticed  when  smoking   is  excessive.     The 

Eupils^  as  a  rule,  are  evenly  contracted.  When  the  effect  of  the  last  dose 
as  worn  off,  the  pupils  are  often  widely  dilated,  and  conjunctivitis, 
with  burning  and  excessive  lachrymation,  is  common.  All  who  have 
smoked  for  any  length  of  time,  complain  that  they  are  getting  near- 
sighted. The  pulse-rate  is  usually  above  normal,  except  that  after 
excessive  smoking  it  falls  below  the  normal  rate.  The  flushing  of  the 
face  with  profuse  perspiration  in  a  novice,  is  replaced,  in  the  old  smoker, 
by  a  sallow  and  deathly  hue.  When  under  the  full  effect  of  the  opium, 
the  respiratory  rate  is  lower  and  prolonged  smoking  produces  a  chronic 
bronchitis  with  cough,  and  pharyngeal  and  laryngeal  catarrh  with  loss 
of  power  in  the  vocal  cords.  In  the  alimentary  tract  there  is  gastritis 
and  constipation,  often  accompanied  by  haemorrhoids  and  an  obstinate 
pruritus.  The  constipation  is  at  times  succeeded  by  a  violent  diarrhoea, 
which  may  become  chronic  and  last  for  months. 

The  vomiting  that  attacks  .the  novice  may  be  only  slight,  come  on 
suddenly  and  unexpectedly,  and  consist  in  a  simple  and  spasmodic 
emptying  of  the  stomach;  later  there  may  be  persistent  and  violent 
attacks  in  which  finally  nothing  but  blood-stained  mucus  can  be  raised. 
The  itching  of  the  skin  varies  with  the  individual;  in  some  it  is  slight 
and  in  others  intense,  especially  in  the  genital  region,  so  that  they  often 
excoriate  themselves     The  average  specific  gravity  of  the  urine  is  low, 


208  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

from  1,004  to  1,010;  the  reaction  is  nsuully  neutral;  there  is  an  increase 
in  the  earthy  and  alkahne  phosphates,  and  in  twenty  examinations  Kane 
found  no  albumen,  sugar,  nor  casts.  For  the  first  few  months  of  smok- 
ing, in  both  sexes  there  is  an  increased  sexual  desire  ■which  is  especially 
marked  in  young. women,  and  opium  smoking  has  been  used  as  a  means 
of  seduction.  After  a  few  mouths  there  is  a  diminution  of  desire  and 
impotence  in  the  male.  In  the  majority  of  women  menstruation  is 
not  interfered  with,  although  in  some  it  is  scant}'  and  irregular  and  there 
may  be  amenorrhoca.  In  this,  oj)ium  smoking  differs  materially  from 
morphia  addiction.  Some  women,  who  smoke  excessively,  habitually 
miscarry;  in  others  it  seems  to  have  no  effect  whatever  upon  their  preg- 
nancy, and  the  children  of  some  oj)ium  smokers,  as  far  as  can  be  learned, 
seem  strong  and  healthy;  this  is  again  in  opposition  to  the  other  methods 
of  taking  ()])ium. 

The  symptoms  of  abstinence  and  the  sudden  cessation  of  opium 
smoking  are  the  same  in  most  respects  as  those  which  follow  the  with- 
drawal of  other  forms  of  ojiiun-".,  but  the  smoker  often  suffers  less  severely 
and  for  a  shorter  time  than  the  opium  eater  or  the  mf)rphia  addictee. 
The  respiratory  tract  and  the  eyes  are  affected  out  of  proportion  to  the  rest 
of  the  body.  The  first  symjjtoms  are  gaping,  yawning,  sneezing,  profuse 
discharge  of  tears  and  mucus  from  the  eyes  and  nose,  irregularity  of  the 
pupils,  ringing  in  the  ears,  followed  by  extreme  restlessness,  intense  pain 
in  the  joints,  nausea,  vomiting,  and  purging;  the  vomiting  and  purging  may 
become  almost  constant.  A  peculiar  dull,  drawing,  dry,  and  burning 
ache  in  the  pharynx  and  larynx  occurs,  which  is  followed  by  distressing 
tearing  pains  in  the  muscles,  especially  in  the  calves  of  the  legs  and  be- 
tween the  shoulders.  Chills,  followed  by  flashes  of  heat,  are  felt  along 
the  spine  and  are  followed  by  profuse  perspiration.  In  some  cases,  if 
no  opiate  is  used,  the  vomiting  and  diarrhoea  continue  and  the  restless- 
ness and  flushed  face  give  place  to  complete  relaxation,  a  ghastly  pallor 
with  sunken  eyes,  collapse,  and  death;  but  in  less  severe  cases  or  when 
proper  remedies  are  used,  the  distressing  or  dangerous  symptoms  cease 
one  by  one.  Sleeplessness  persists  for  a  long  time;  the  bronchitis  and 
catarrhal  inflammations  of  the  throat  usually  last  for  months;  the  pains 
in  the  legs  and  body  gradually  disappear;  the  sexual  power  returns;  the 
ap])etite  gradually  improves  and  becomes  ravenous;  an  increase  in  the 
weight  is  manifested;  a  return  to  natural  buoyancy  of  mind  begins,  and 
the  patient  regains  his  health  and  strength.  Under  proper  treatment 
these  symptoms  can  be  cut  short  and  the  sufferings  much  reduced, 
but  it  is  rare  for  individuals  by  themselves  to  carry  out  a  cure  to  a  suc- 
cessful issue.  When  once  cured,  it  is  difficult  to  say  what  proportion 
relapse,  but  a  single  indulgence  may  be  sufficient  to  start  them  again 
into  the  habit.  Rarely,  individuals  are  found,  who  once  having  broken 
the  habit,  return  to  it  and  smoke  but  one  pipe  a  week  and  do  so  for 
years  without  apparent  injury. 


OPIUM  BY  MOUTH. 

This  is  much  more  widespread  in  this  country  than  is  generally  realized. 
Dr.  A.  P.  Grinnell  recently  ascertained  the  amount  of  opium,  paregoric, 


OPIUM.      MORPHINISM.      COCAINE  209 

and  laudanum,  sold  by  the  various  druggists  in  a  single  month  in  sixty- 
nine  towns  in  the  State  of  Vermont.     The  figures  show  that  the  amount 
consumed  would  be  sufficient  to  average  a  dose  to  every  man,  woman,  and 
child,  in  the  State  of  Vermont,  every  day  in  the  year.     By  a  dose  is  meant, 
1  grain  of  opium,  \  grain  of  morphia,  ^  ounce  of  paregoric  and  20  drops 
of  laudanum.     Probably  the  most  of  the  opium  takers  are  those  suffering 
from  rheumatism,  neuralgias,  migraine,  hepatic  or  renal  colic,  dysmenor- 
rhoea  or  other  troubles  which  at  first  caused  only  a  temporary  indulgence 
in  the  drug.     Later,  however,  especially  in  elderly  people,  the  habit  is 
insidiously  formed.     Opium  is  often  used  at  intervals  for  insomnia  or  to 
allay  grief  and  mental  suffering.     It  is  given  up  when  the  strain  is  past, 
and  taken  up  again  for  any  reason  that  seems  sufficient.     Often  in  these 
cases  the  only  symptoms  seem  to  be  a  mental  and  physical  restlessness 
and  anorexia,  with  a  disposition  to  sleep.     The  opium  taker  shows  cer- 
tain differences  from  the  individual  taking  morphia.     There  is  more 
excitement  and  exaltation  following  morphia,  while  with  opium  there 
is  more  a  feeling  of  quiet  contentment,  lasting  over  a  long  time.     The 
morphinist,  after  the  feeling  of  satisfaction  has  worn  off,  is  more  apt 
to  dread  the  slavery  of  his  habit,  while  the  opium  taker  never  seems 
fully  conscious  of  the  danger.     The  opium  taker  rarely  consumes  as 
much  as  the  morphinist  and  the  duration  of   his  existence,  after  the 
habit  is  once  formed,  is  usually  much  longer.     He  may  indulge  for  a 
year  or  more  without  apparent  injury,  but  the  morphinist,  in  a  relatively 
short  time,  shows  evidences  of  his  degeneration  and  succumbs  quicker. 
Gradually  the  effects  of  the  opium  begin  to  show  when  used  to  ex- 
cess.    There    is   a  change    in  the    disposition;   they  become    irritable, 
peevisli,  somnolent  and  show  evident  dishonesty  in  little  matters,  espe- 
cially concerning  the  use  or  the  procuring  of  the  drug.     They  are  prone 
to  develop  a  sallow  parchment-like  complexion,  although  in  the  early 
stages  their  faces  may  be  flushed,  with  a  tendency  to  cutaneous  erup- 
tions, and  this  last  condition  of  the  skin  is  apt  to  persist;  the  hair  tends 
to  become  gray  early  and  they  have  an  old,  worn-out,  exhausted,  or 
cachectic  appearance.     There  is  often  general  feebleness  of  the  mus- 
cular system  with  tremors,  and  this  may  be  so  pronounced  as  to  resemble 
ataxia.     The  visions  so  vividly  depicted  by  De  Quincey  do  not  seem 
to  occur  among   western  nations.     Sometimes  the  imagination   seems 
stimulated  for  a  while,  producing  a  dreamy,  visionary  state,  but  it  is 
extremely  doubtful  if,  under  the  influence  of  opium,  the  mind  is  capable 
of  more  intellectual  vigor.     No  new  thoughts  arise,  no  new  levels  of 
intellectual  abihty  are  reached,   and  there  develops  simply  a  dreamy 
selfishness,  producing  an  inclination  to  live  apart  from  others,  and  to 
shun  companionship.     There  is   a  tendency  to  ignore,  and  to  break, 
appointments  and  social  engagements.     If  the  opium  taker  is  found  in 
company,  it  is  usually  among  those  who  are  below  him  in  intellectual 
and  moral  development.     His  self-respect  is  gone,  he  is  careless  of  his 
appearance,  indolent  in  his  habits,  and  neglectful  of  the  decencies  of 
life.     In  the  end  he  sleeps  poorly,  grows  emaciated,  his  eye  becomes 
lustreless,  and  he  goes  about  shrinking  and  cringing.    In  the  later  stages 
cardiac  degeneration  is  prone  to  occur  with  attacks  of  pseudo-angina 
pectoris  or  with  precordial  anxiety;   constipation  is   common,  and  the 
general  nutrition  is  much  disturbed.     They  are  prone  to  die  suddenly 

14 


210  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

from  acute  infections  as  erysipelas  or  pneumonia,  or  tend  to  go  into 
melancholia  or  dementia. 


MORPHINISM. 

Indulgence  in  morphia  is  a  vice  of  recent  years;  it  has  taken  the 
place,  especially  in  large  cities,  of  the  preparations  of  crude  opium. 
The  readiness  and  cheapness  with  which  morphia  can  be  obtained  and 
the  ease  with  which  hypodermic  syringes  can  be  bought,  have  made 
this  vice  a  widespread  curse.  Physicians,  nurses,  pharmacists,  form, 
unfortunately,  a  large  percentage  of  the  morphia  addictees.  Rodet,  in 
Paris,  in  650  men  addicted  to  moqohia,  found  40  per  cent,  physicians, 
3  per  cent,  students  in  medicine,  3  per  cent,  pharmacists,  15  per  cent, 
idlers  living  on  their  incomes,  8  per  cent,  merchants,  7  per  cent,  officers 
in  the  army,  5  per  cent,  workmen,  and  the  rest  scattered  through  many 
occupations.  In  350  women,  43  per  cent,  were  without  occupation,  14 
per  cent,  were  prostitutes,  13  per  cent,  were  working  women,  10  per 
cent,  were  wives  of  physicians,  and  the  others  were  scattered  through 
various  employments.  As  regards  age,  Rodet  found  in  324  cases  that 
between  twenty-five  and  forty  the  greatest  number  (GO  per  cent.)  oc- 
curred; below  twenty-five,  11  per  cent.;  from  forty  to  fifty,  13  per  cent, 
and  the  remainder  after  sixty  years  of  age.  Rodet  also  tabulated  the 
maximum  daily  dose  of  569  addictees;  25  per  cent,  took  from  50  centi- 
grams to  a  gram  (7J  to  15  grains) ;  8  per  cent,  took  below  10  centi- 
grams, that  is,  less  than  2  grains;  15  per  cent,  from  10  to  30  centigrams; 
14  per  cent,  from  30  to  50  centigrams;  12  per  cent,  from  1  full  gram  to 
IJ  grams;  10  per  cent,  from  1^  grams  to  2  grams,  and  9  per  cent, 
from  2  to  3  grams;  the  proportion  rapidly  diminished  above  this  amount, 
there  being  individuals  on  record,  however,  who  took  from  9  to  12  grams 
a  day.  In  studying  the  duration  of  the  habit,  Rodet  found  that  in  270 
individuals,  41  per  cent,  showed  a  duration  of  from  two  to  four  years; 
on  the  other  hand,  there  were  individuals  who  had  been  addicted  to 
the  habit  for  ten,  twenty,  thirty,  and  even  forty  years. 

There  are  no  pathological  lesions  which  are  characteristic  of  chronic 
morphia  poisoning.  Fatty  degeneration  of  the  heart  muscle  has  been 
described  and  Schweneger  has  found  hypertrophy  of  the  left  ventricle 
and  dilatation  of  the  right  ventricle  and  pulmonary  artery.  Fatty  de- 
generation of  the  liver  is  reported  as  occurring  in  a  marked  degree  in 
those  dying  of  chronic  morphinism.  These  various  lesions  can  not  be 
considered  as  characteristic.  The  cause  for  which  morphia  is  taken 
often  modifies  the  habit  which  sooner  or  later  is  acquired;  thus  those 
who  take  it  to  soothe  the  agony  of  some  chronic  disease  probably  resist 
longest  its  baneful  effects.  Many  who  take  it  only  to  assuage  pain, 
knowing  full  well  the  habit  and  its  effects,  often  bear  moderate  pain 
without  turning  to  morj^hia  for  aid  and  only  use  it  when  the  pain  be- 
comes almost  unbearable.  The  dosage  in  these  patients  is  increased 
only  as  the  need  demands,  and  often  the  same  dose  will  suffice  for  many 
months  or  years.  In  the  end,  many  of  these  show  the  symptoms  of 
chronic  morphinism,  but  French  writers  differentiate  this  class  of  pa- 
tients from  those  who  take  morphia  for  pleasure,  in  whom  the  habit 


OPIUM.     MORPHINISM .     COCAINE  211. 

rapidly  grows,  and  the  demand  becomes  more  and  more  urgent  with 
increase  in  the  dosage.  These  authors  designate  the  first  class  as  mor- 
phinists and  the  second  class  as  morphinomaniacs.  The  question  may 
arise  in  the  case  of  a  patient  suft'ering  from  a  painful  and  incurable 
disease,  whether  a  physician  is  justified  in  giving  morphia,  knowing 
that  if  once  used  it  must  be  given  for  the  remainder  of  the  ])atient's 
life.  People  are  often  opposed  to  having  it  said  that  members  of  their 
family  died  with  the  morphia  habit.  In  many  cases  it  is  simj>ly  cruelty 
to  refuse  to  give  it,  and,  under  certain  circumstances,  the  formation  of 
the  habit  in  some  sufferers  is  of  absolutely  no  consequence. 

The  hypodermic  use  of  morphia  is  the  most  seductive  form  of  the 
habit  and  the  hardest  to  break;  some  patients  seem  to  require  the  sen- 
sation of  the  needle  thrust  in  order  to  be  satisfied  What  is  sought  in 
most  cases  is  the  feeling  of  exaltation,  strength,  and  mental  vigor,  with 
relief  from  pain  or  ennui,  the  drowning  of  sorrow,  or  the  killing  of 
the  hopeless  realization  of  despair  and  failure.  Morphia  does  this  as 
long  as  the  desired  effect  lasts.  The  duration  of  this  varies  in  different 
individuals  and  is  longer  in  the  beginning  because  the  toleration  for 
the  drug  is  rapidly  acquired  and  the  time  between  doses  must  be  con- 
tinually shortened  or  the  dosage  increased,  and  finally  both  of  these 
means  must  be  used  to  obtain  the  desired  results.  In  many  who  take 
enormous  doses  it  would  seem  that  all  the  morphia  does  not  act,  but 
some  must  remain  inert  and  be  excreted  without  action. 

In  the  morphia  addictee  there  are  practically  three  stages  which,  al- 
though shading  into  each  other,  can  still  be  recognized;  exaltation,  in- 
toxication and  cachexia.  The  first  is  one  of  enjoyment,  happiness,  and 
satisfaction.  When  the  effect  has  subsided  it  is  followed  by  malaise, 
a  feeling  of  restiveness,  and  painful  anxiety,  which  a  renewal  of  the  dose 
takes  away.  The  effects  of  a  single  dose  will  sometimes  last  for  twenty- 
four  hours,  but  this  is  soon  reduced  to  twelve,  then  to  six,  then  to  three 
hours,  then  to  minutes  instead  of  hours,  and  finally,  the  exaltation  ceases, 
and  he  must  take  the  drug  to  quiet  the  intense  craving  and  the  pains 
of  abstinence.  When  the  period  of  intoxication  is  reached,  a  dryness 
of  the  mouth,  nausea,  and  anorexia  supervene.  The  habitu6  then  notices 
that  an  injection  taken  just  at  meal  time  will  give  him  the  appetite 
which  he  lacks.  The  voice  becomes  hoarse,  and  singers  can  no  longer 
use  their  voices.  Digestive  troubles  appear;  constipation  is  obstinate; 
there  is  a  loss  of  sexual  desire,  and  amenorrhoea  in  women.  The  memory 
begins  to  be  treacherous;  insomnia  becomes  marked;  the  patient  passes 
his  nights  reading,  although  worn  out  with  fatigue,  and  if  he  sleeps,  it 
is  not  a  refreshing  slumber.  In  the  daytime  he  is  peevish  from  fatigue, 
ill-humored,  and  seems  stupified  and  benumbed.  He  takes  no  interest 
in  anything  which  does  not  pertain  to  himself,  and  his  character  is  notice- 
ably changed.  There  is  moral  inertia,  absence  of  will-power,  and  com- 
plete self-centred  selfishness.  The  nights  become  more  and  more 
dreaded,  and  soon,  if  he  sleeps  at  all,  he  wakes  constantly  from  his 
nightmares,  which  become  more  terrifying,  and  always  of  a  distressing 
nature.  His  hair  begins  to  fall  out,  the  teeth  to  decay,  and  the  body 
to  emaciate.  The  face  is  drawn  and  aged;  the  eyes  are  lustreless,  and 
the  breath  foul.  Even  from  this  stage  it  is  possible  to  recover  If  he 
goes  on,  the  cachexia  develops,  emaciation  becomes  extreme,  and  the 


212  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

secretions  arc  })ractically  suppressed;  cedema  of  the  legs  aj)pears  and 
the  shghtest  exertion  causes  oppression  and  a  sense  of  constriction  in 
the  chest.  The  pulse  becomes  small  and  irregular.  The  heart's  action 
is  enfeebled;  there  is  increased  precordial  dulness  and  the  apex  impulse 
is  diminished.  There  is  a  diminution  in  the  amount  of  urine  and  often 
a  marked  albuminuria.  He  is  morose,  sullen,  and  in  a  state  of  semi- 
stupor,  gazing  with  dull,  lacklustre  eyes,  scarcely  conscious  of  his  en- 
vironment. The  mental  degeneration  is  complete  and  a  continual 
delirium  may  be  present.  The  condition  of  his  heart  and  kidneys  is 
such  that  restitution  to  a  normal  condition  is  impossible.  Death  occurs 
if  the  morphia  is  cut  ofi",  and  the  drug  invariably  kills  if  it  is  continued. 

Considering  the  symptoms  more  in  detail,  memory  is  one  of  the 
faculties  first  affected  and  the  amnesia  is  similar  to  the  beginning  senile 
dementia.  Names  are  the  first  to  go;  the  mor})hinist  will  relate  occur- 
rences early  in  his  life,  but  will  forget  what  he  has  done  during  the  past 
week.  He  will  forget  the  familiar  names  of  streets,  the  details  of  his 
profession;  thus  the  physician  forgets  the  dosage  of  medicines  and  the 
scientific  terms  with  which  he  is  familiar.  Others  will  make  such  errors 
in  their  daily  work  that  they  lose  their  positions.  Amnesia  of  the  well 
marked  stage  of  morphia  intoxication  is  only  equalled  by  the  amnesia 
of  paresis.  The  will  power  is  enfeebled  and  the  patients  spend  days 
in  bed  without  sleeping  and  without  stupor;  their  minds  are  perfectly 
clear  but  their  power  to  do  is  gone.  They  perceive  the  motive  of  actions 
and  reason  sanely,  but  all  motive  and  reasoning  is  insufficient  to  pro- 
duce effective  volition.  In  some  patients  this  is  continuous  and  perma- 
nent; in  others  it  seems  to  run  in  crises,  lasting  over  two  or  three  days. 
There  is  psychic  asthenia.  The  sense  of  responsibility  is  wiped  out 
and  is  replaced  by  the  indifference  of  perfect  egotism.  Their  character 
is  modified  and  they  are  discontented  grumblers,  obstinately  "ugly,"  often 
given  to  explosions  of  intense  rage,  quarrelling  without  cause,  and  even 
destructive  and  dangerous  to  those  with  whom  they  come  in  contact. 
They  may  become  misanthropic,  hypochondriacal,  annoyed  at  trifles, 
and  prone  to  seek  solitude.  Often  the  morphinists  are  individuals  of 
more  than  average  ability  and  intelligence,  realizing  fully  their  condition, 
and  appreciating  their  progressive  degeneration.  It  is  for  this  reason 
that  they  resent  criticism  and  accept  reproaches  about  their  habit  with 
bad  grace,  because  they  are  already  filled  with  remorse.  Morphinists 
will  invariably  lie  about  their  vice,  because  in  the  early  stages,  they 
feel  the  disgrace  and  have  enough  moral  sense  left  to  endeavor  to  hide 
it.  If,  however,  they  have  just  taken  their  morphia  or  are  assured  of 
sufficient  dosage  to  keep  them  comfortable,  they  do  not  necessarily  lie 
about  other  matters.  But  when  the  craving  for  the  drug  is  upon  them, 
there  is  nothing  to  which  they  will  not  stoop  to  obtain  it.  Lying,  thiev- 
ing, begging  in  the  street,  prostitution  itself,  are  to  them  all  justifiable 
means  to  obtain  the  drug  and  smother  the  irresistible  craving. 

Contrary  to  what  is  often  supposed,  morphinists  do  not  sleep  well; 
they  are  subject  to  nocturnal  hallucinations  which  render  their  nights 
times  of  dreaded  fear  and  terror;  thus  they  endeavor  to  keep  them- 
selves awake  by  reading,  and  during  the  daytime,  when  overcome  by 
fatigue,  are  prone  to  fall  asleep  whenever  they  remain  quiet,  sitting  in 
a  chair,  no  matter  in  what  place  or  company.     These  hallucinations 


OPIUM.     MORPHINISM.     COCAINE  213 

are  extremely  rare  in  the  daytime.  The  hallucinations  of  sight  are 
always  terrifying,  being  composed  of  various  animals,  spectres,  and  of 
all  sorts  of  revolting  and  gruesome  combinations.  Contrary  to  the 
hallucinations  of  alcoholism,  those  of  morphinism  are  not  occupation 
deliriums.  The  hallucinations  of  sight  are  much  the  most  frequent; 
next  those  of  hearing;  those  of  taste  and  smell  are  rare,  and  those  of 
general  sensibility  are  exceptional,  which  last  is  also  contrary  to  what 
occurs  in  alcoholism.  The  sense  of  taste  itself  is  often  dulled  and 
sometimes  even  abolished.  The  sense  of  hearing  is  often  noticeably 
diminished  and  the  sight  is  affected,  sometimes  making  walking  difficult. 
Reading  and  writing  become  impossible  because  objects  appear  clouded 
and  deformed,  and  when  the  endeavor  is  made  to  fix  an  object,  it  dances 
or  trembles  or  approaches  or  retrogrades,  and  this,  together  with  a  fre- 
quent distinct  photophobia,  causes  great  distress.  Ophthalmoscopic  ex- 
amination does  not  seem  to  reveal  any  distinct  lesion.  There  is  at  times 
contraction,  and  at  times  dilatation,  of  the  pupils;  an  ansemia  of  the 
retina  has  been  described;  sometimes  the  arteries  seem  scarcely  visible 
with  the  venous  congestion.  These  visual  disturbances  disappear  when 
the  morphia  is  permanently  withdrawn.  The  reflexes  are  very  variable. 
Disturbances  of  the  general  sensibility  are  often  marked  and  vary  greatly; 
there  are  often  pareesthesias  and  sometimes  intense  neuralgic  pains. 
Others  show  marked  anaesthesia,  which  may  be  confined  to  one  side 
of  the  body.  More  often  there  is  hypersesthesia,  and  the  sole  of  the 
foot  becomes  so  painful,  that,  when  it  is  touched  to  the  floor,  it  gives  a 
sensation  of  burning,  and  the  patient  can  only  walk  with  short,  jumping 
steps.  Rodet  considers  this  form  of  hypersesthesia  as  very  characteristic 
of  chronic  morphinism.  The  tactile  sensibility  is  usually  diminished 
or  abolished.  The  question  often  arises  whether  indulgence  in  morphine 
impels  the  individual  to  suicide.  At  times  when,  inadvertently,  too  large 
a  dose  is  taken,  the  patient  succumbs,  but  as  long  as  he  can  obtain  his 
drug,  he  is  an  individual  without  will,  apathetic,  and  incapable  of  mak- 
ing sufficient  exertion  to  commit  suicide;  if,  however,  the  morphine  be 
withdrawn  or  he  can  not  obtain  it,  the  condition  entirely  changes  and 
the  symptoms  and  mental  condition  of  morphia  abstinence  are,  in  many 
ways,  the  reverse  of  this. 

Troubles  of  digestion  are  among  those  most  noticed  by  the  patients 
themselves;  in  the  early  stages  there  is  nausea,  vomiting,  and  anorexia, 
which  do  not  persist  for  a  very  long  time.  There  is  often  an  intense  thirst; 
the  breath  is  very  offensive  and  of  a  peculiar  odor,  often  spoken  of  as  being 
so  characteristic  as  to  designate  the  morphinist  by  those  who  are  brought 
in  contact  with  many  of  these  patients.  They  are  markedly  constipated 
and  this  often  alternates  with  attacks  of  diarrhoea;  their  stools  are 
bloody  and,  during  the  period  of  constipation,  may  be  as  infrequent  as 
once  or  twice  a  month.  The  teeth  are  subject  to  caries  which  attacks 
first  the  molars  on  their  grinding  surfaces;  this  extends  to  the  bicuspids, 
then  to  the  incisors,  and  last  of  all  to  the  canines.  This  caries  at  times 
does  not  follow  the  above  course  but  it  is  always  painless,  not  accom- 
panied by  any  periostitis,  and  usually  progresses  with  great  rapidity. 
Its  occurrence  usually  coincides  with  the  falling  out  of  the  hair.  The 
disturbances  of  nutrition  appear  in  some  patients  after  a  few  months 
and  in  others  not  until  after  some  years.     Emaciation  is  perhaps  the 


214  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

the  most  striking  and  may  go  on  to  an  extreme  degree.  Their  faces 
become  Hvid  and  often  sallow,  the  expression  set,  and  there  are  pre- 
mature wrinkles,  which,  with  the  faded,  sallow  look  of  the  skin,  often 
gives  the  look  of  premature  old  age.  The  tissues  lose  their  viability, 
which  accounts  in  a  measure  for  the  ease  with  which  slight  bruises 
cause  ecchymosis,  and  the  greater  liability  to  the  occurrence  of  abscesses, 
to  which  we  will  refer  later.  Often  in  the  skin  there  are  multiple  cica- 
trices and  small  sjjots  from  the  use  of  the  needle;  as  many  as  G3,000 
have  been  counted  on  one  individual. 

The  pulse  of  the  chronic  morphinist  is  slow  and  there  is  a  fall  in  ar- 
terial tension  with,  in  the  last  stages,  distinct  enfeeblement  of  the  heart's 
action  and  diminution  in  the  force  of  the  apex  beat.  The  number  of 
respirations  is  slowed  and,  at  times,  they  are  shorter,  so  that  every  now 
and  then  a  long  deep  inspiration  seems  necessary  to  give  the  required 
amount  of  air.  Dyspnoea  on  exertion,  even  of  the  slightest  kind,  is 
quite  common.  In  the  beginning  of  morphia  addiction,  there  is  polyuria, 
which  later  is  followed  by  a  diminution  of  secretion  below  the  normal. 
In  many  there  is  albuminuria  which  is  ascribed  by  Levinstein  to  a 
special  action  of  morj^hia  on  the  medulla,  to  changes  in  the  arterial 
pressure,  or  to  a  paralysis  of  the  nerves  which  enter  the  kidney  around 
the  renal  artery.  The  effects  in  the  genito-urinary  system  are  much  the 
same  as  those  described  under  opium. 

Most  women  become  sterile,  but  in  spite  of  the  cessation  of  men- 
struation, conception  may  take  place.  Pregnancy  may  run  its  normal 
course,  or  the  morphia  may  cause  a  miscarriage  or  premature  birth. 
Children  born  of  morphinist  mothers  may  be  well-formed  and  normally 
healthy.  Happel,  of  Tennessee,  reports  that  in  his  experience  a  large 
percentage  of  children  born  of  morphinist  mothers  have  congenital  car- 
diac defects.  They  showed,  as  so  often  seen  in  children  of  morphinist 
mothers,  fretfulness,  irritability,  restlessness,  and  colic,  which  could  only 
be  relieved  by  opium.  If  they  are  not  given  opium,  the  restlessness 
and  crying  increase  and  they  may  go  into  a  collapse  in  a  few  hours  or 
live  a  few  days  and  die  from  marasmus.  If  opium  be  given,  they  may 
be  tided  over  for  some  months  or  years  and  perhaps  a  successful  and 
gradual  breaking  off  be  accomplished.  Often  the  children  of  morphia 
addictees  are  idiotic  or  show  a  lack  of  mental  and  physical  development. 

The  accidents  which  may  follow  the  injection  of  morphia  are  those 
of  infection  from  the  use  of  a  dirty  needle  or  of  an  infected  solution. 
These  abscesses  usually  appear  at  the  point  of  injection,  but  sometimes 
at  distant  points,  in  a  portion  oi  "^he  skin  which  has  not  been  perforated. 
They  are  usually  small,  rather  indolent,  and  not  always  as  painful  as 
one  would  expect.  They  usually  heal  under  proper  treatment,  although 
they  may  form  indolent  ulcers.  The  points  of  injection  may  be  the 
starting  point  of  erysipelas,  cellulitis,  or  phlegmon.  Kane  reports  cases 
of  tetanus  developing  from  the  hypodermic  injection  of  morphia.  In 
many  morphinists  the  scars  of  the  abscesses  are  very  numerous  on  their 
legs  and  arms  and  even  over  the  body.  Where  the  morphia  has  been 
injected  directly  into  a  vein,  sometimes  a  sudden,  intense  narcotism  fol- 
lows and  the  patient  feels  a  peculiar  tingling  over  the  entire  body.  There 
is  at  times  a  feeling  of  great  fulness  and  throbbing  in  the  head  and 
this  may  be  accompanied  by  difficulty  of  respiration,  swelling  of  the 


OPIUM.     MORPHINISM.     COCAINE  215 

face,  and  loss  of  consciousness.  Death  has  been  reported  as  following 
quickly  when  morphia  is  suddenly  injected  into  the  circulation.  Most 
addictees  increase  the  dose  so  gradually  that  the  accident  of  acute  poison- 
ing and  death  from  an  overdose  is  comparatively  rare.  When,  however, 
an  endeavor  has  been  made  to  reduce  the  amount  taken  and  then  for 
some  reason  a  larger  dose  is  desired,  an  amount,  which  formerly  could 
be  borne  with  impunity,  is  taken  and  death  results. 

When  once  a  person  is  thoroughly  under  the  influence  of  the  habit, 
a  cessation  of  the  use  of  the  drug  produces  symptoms,  both  physical 
and  mental,  of  such  intensity  that  few  are  strong  enough  to  resist  the 
craving  thus  produced  and,  unaided,  break  off  the  habit.  When  the 
effects  of  the  last  injection  begin  to  wear  off,  restlessness,  malaise,  yawn- 
ing, and  sneezing  appear;  the  craving  increases  and  can  only  be  entirely 
relieved  by  a  further  dose.  The  length  of  time,  after  the  last  dose,  at 
which  these  symptoms  will  begin,  depends  on  the  individual.  Following 
quickly  on  the  malaise,  the  eyes  begin  to  water  and  the  eyelids  droop. 
The  eyes  lose  their  lustre  and  vision  is  much  disturbed.  The  face  be- 
comes pale  and  an  expression  of  intense  distress  is  very  noticeable. 
Hearing  is  diminished  and  there  is  a  mental  hebetude  which  prevents 
all  intellectual  work.  There  is  a  trembling  of  the  hands  and  of  the 
arm  in  supination  and  pronation,  varying  markedly  from  the  alcoholic 
tremor.  In  this  condition  there  is  nothing  that  morphinists  will  not 
do,  and  no  means  that  they  will  not  employ,  in  order  to  obtain  morphia. 
As  enforced  abstinence  continues,  the  patient  may  develop  epileptiform 
attacks  or  hysteria,  or  there  may  be,  in  neurotic  individuals,  a  state  of 
choreic  jactitation.  In  extreme  cases  a  form  of  mania  may  develop  in 
which  the  patients  pace  the  room,  shrieking,  crying,  throwing  them- 
selves about,  using  whatever  instrument  comes  to  hand  to  commit 
suicide,  'or  they  may  attack  their  attendants.  Hallucinations  of  sight 
and  hearing  may  develop  and  these  are  always  of  a  terrifying  nature. 
This  is  most  frequently  seen  in  those  who  have  taken  alcohol  with  their 
morphia,  but  it  not  infrequently  develops  in  those  who  have  taken  mor- 
phia alone.  Often,  before  these  mental  disturbances  are  fully  developed, 
the  patients  are  overcome  with  a  sensation  of  extreme  weakness  and 
forced  to  keep  in  bed.  They  are  pale  and  haggard  ;  there  is  nausea  and 
vomiting,  and  almost  invariably  a  diarrhoea  develops,  which  may  become 
extremely  profuse.  This  is  often  accompanied  with  intense  abdominal 
pain  and  hyperesthesia  of  the  skin  so  that  the  patient  can  scarcely  sup- 
port the  weight  of  the  bedclothes;  the  body  is  often  covered  with  a 
cold  sweat,  and  there  may  be  chills  of  great  intensity. 

When  morphia  is  cut  off  abruptly  there  is  great  danger  of  collapse. 
This  may  supervene  on  the  second  or  third  day  and  the  patient  shows  in- 
creased weakness,  appears  pinched  and  haggard,  while  the  pulse  becomes 
small  and  then  disappears.  Or  he  may  show  a  sudden  high  pulse  tension, 
feebleness  of  the  heart  action,  and  suddenly,  while  wandering  restlessly 
around  the  room,  fall  pulseless  to  the  floor.  Sometimes  the  fatal  collapse 
may  occur  without  warning  while  the  patient  is  quietly  talking  or  sitting 
in  bed.  Still  another  form  of  collapse  may  occur;  the  face  becomes  deep 
red,  the  eyes  shine  brilliantly,  the  pulse  falls  to  forty  and  the  patient  loses 
consciousness  after  a  feeling  of  intense  agony.  These  collapses  may  last 
for  fifteen  or  twenty  minutes;  they  may  recur  three  or  four  times  in  the 


21G  DISEASES  CAUSED  BY  OEGAXIC  AGENTS 

twenty-four  hours,  and  the  patient  may  recover  or  he  may  die  in  any  of 
them  unless  morphia  be  given.  Fortunately  these  attacks  are  rare  when 
the  drug  is  withdrawn  grackially  but  they  are  fairly  common  when  this  is 
done  abruptly.  There  are  some  few  cases  on  record  in  which  the  fatal 
collapse  occurred  some  time  after  the  patient  was  convalescent  and  appar- 
ently hatl  passed  through  the  symj^toms  of  abstinence  and  was  well  on  the 
road  to  recovery.  Du.ring  their  periods  of  sutl'ering,  the  patients  are  apt 
to  be  afflicted  with  distressing  insomnia  and,  if  they  sleep,  it  is  only  in 
fitful  dozes.  In  a  loliger  or  shorter  time  the  symptoms  gradually  disappear 
and  the  patient  can  rest  with  some  degree  of  comfort;  the  morbid  craving 
has  gone;  the  appetite  returns  and  often  becomes  excessive;  in  women 
menstruation  is  reestablished,  at  first  painfully,  later  normally.  In  both 
sexes  the  sexual  desire  returns,  often  painfully  and  excessively  and  then 
subsides.  The  patient  goes  into  a  rapid  convalescence.  When  morphia 
is  broken  off,  if  it  has  been  taken  to  quiet  some  neuralgia  or  to  beniunb 
some  unbearable  sensation,  these  pains,  although  quiescent  during  the 
period  of  the  adtliction,  return  in  full  force  when  the  habit  is  broken. 

Treatment. — The  question  often  arises,  whether  the  patient  should  be 
sent  to  some  retreat,  or  whether  a  successful  issue  can  be  followed  out  at 
home.  If  the  home  treatment  is  decided  upon,  the  family  must  be  made 
to  realize  that  they  are  dealing  with  the  most  cunning  and  cleverly  decep- 
tive kind  of  individual,  who  will  stop  at  nothing,  and  who  is  probably  con- 
cealing somewhere  a  supply  of  morphia.  The  suffering  may  be  intense 
and  will  certainly  be  intentionally  increased  in  order  to  obtain  sympathy 
and  to  break  off  the  treatment  whenever  it  is  possible.  Too  much  stress 
cannot  be  laid  upon  the  necessity  of  removing  everything  that  can  possi- 
bly be  used  for  injury  from  the  room  in  which  the  patient  is  to  be.  Even 
projecting  hooks  should  bo  taken  away,  and  the  patient  must  never  for 
a  single  instant  of  time,  day  or  night,  be  left  unwatched.  In  retreats  or 
hospitals,  the  sufferings  can  be  reduced  to  a  minimum  and  when  it  is 
possible  the  treatment  should  always  be  carried  on  in  some  such  insti- 
tution. The  question  of  the  abrupt  withdrawal  or  the  slow  method  al- 
ways comes  into  consideration.  Levinstein,  who  used  the  abrupt  method, 
says  that  he  does  not  believe  that  this  should  be  done  unless  the  patient  is 
otherwise  healthy  and  suffering  only  from  the  symptoms  due  to  mor- 
phia. This  in  ifself  shows  the  intensity  of  the  strain  and  suffering  that  the 
abrupt  method  induces,  and  the  danger  of  a  collapse,  which  may  be  fatal, 
is  most  apt  to  occur  in  this  method.  The  rapid  method,  by  which  the 
morphia  is  reduced  to  half  the  accustomed  dose  the  first  day  and  then 
half  the  next  day  and  so  in  a  few  days  is  entirely  withdrawn,  is  prac- 
ticable in  the  majority  of  cases.  The  slow  method,  by  which  the  drug  is 
very  gradually  withdrawn,  is  useful  for  the  very  weak  patients  or  those 
who  suffer  from  some  chronic  disease  and  have  gradually  become 
addicted  to  excessive  use.  But  in  patients  who  are  not  afflicted  with  any 
chronic  disease,  it  is  apt  to  be  extremely  tedious  and  trying,  really  prolongs 
the  suffering,  and  may  discourage  the  patient,  the  physician,  and  the  family. 

The  best  method  in  the  majority  of  cases,  is  to  endeavor  to  find  approx- 
imately how  much  morphia  the  patient  has  been  accustomed  to  and 
cut  it  at  least  in  half  and  give  this  amount  in  divided  doses  for  the  first 
twenty-four  hours.  It  is  very  necessary  to  bring  the  digestive  tract  into  as 
good  a  condition  as  possible,  in  the  shortest  space  of  time,  which  is  best 


OPIUM.     MORPHINISM.     COCAINE  217 

done  by  the  use  of  castor  oil,  in  half  ounce  doses,  three  times  a  day,  for 
the  first  week  or  ten  days.  When  the  patients  are  very  weak,  it  is  advisable 
to  give  subcutaneous  injections  of  strychnine  (gr.so-n'o,  gm.  0.001-0.002), 
at  first  every  four  hours.  The  best  drug  to  equalize  th(;  circulation  and  to 
reduce  the  physical  craving  and  suffering  to  a  minimum,  is  the  sub- 
cutaneous use  of  Livingston's  solution  of  ergot  as  described  under  alco- 
holism. To  allay  the  nervousness,  warm  baths  are  often  very  efficacious. 
Kane  recommends  that  they  be  given  at  a  temperature  of  112°  F.,  and  the 
patient  rubbed  down  quickly,  placed  in  bed,  and  covered  up  warmly.  To 
combat  the  insomnia,  cold  packs  are  often  useful.  A  tonic  of  nux  vomica 
and  compound  tincture  of  cinchona  with  capsicum,  given  three  or  four 
times  a  day,  is  of  great  assistance.  Often  in  the  first  few  days  champagne 
or  sherry  is  helpful,  but  this  should  not  be  prolonged,  for  these  patients 
are  as  prone  to  take  up  other  habits  as  they  were  originally  to  take  to 
morphia.  Chloral  as  a  hypnotic  has  been  condemned  by  most  writers. 
Levinstein  says  that  it  tends  to  increase  the  excitement.  Kane  recom- 
mends bromides,  given  in  large  amounts  of  water,  even  in  one  hundred 
grain  doses.  The  patient  should  be  fed  with  koumyss  and  eggs  as  the 
most  easily  assimilated  food.  If  accustomed  to  coffee  and  tea  there  is 
no  reason  why  they  should  not  be  continued. 

After  the  patients  are  over  the  worst  of  their  symptoms  and  convales- 
cence is  established,  they  are  by  no  means  finished  with  their  treatment. 
During  the  next  six  months  the  liability  to  relapse  is  very  great  and  a 
single  dose  of  opium  or  morphia  will  start  them  into  their  habit  again. 
The  cause  for  which  they  took  the  drug  should  be  ascertained  as  accurately 
as  possible  and  every  endeavor  made  to  change  these  conditions.  They 
must  fully  realize  that  whatever  mode  of  life  brings  the  same  temptations 
to  them  must  be  given  up.  Men  may  have  to  give  up  their  profession  and 
resort  to  some  out-door  existence  and  many  professional  men  have  suc- 
ceeded in  permanently  curing  themselves  by  going  into  the  country  and 
taking  up  some  form  of  farming,  stock-raising  or  flower-culture.  The 
most  difficult  to  cure  are  physicians  or  pharmacists,  whose  business  leads 
them  into  the  handling  of  morphia.  It  is  said  that  about  80  per  cent,  of 
these  relapse,  and  the  relapse  is  more  difficult  to  treat.  Even  after  years  of 
freedom  the  danger  has  not  ceased  and  the  writer  knows  a  patient,  who 
after  eleven  years  of  abstinence,  fell  into  the  habit  again  because,  during  an 
attack  of  pleurisy,  he  was  given  morphia  by  a  physician  and  this  against 
his  protest.  A  certain  number  can  be  cured  and,  although  the  percentage 
of  relapses  and  failures  is  very  great,  each  individual  should  be  treated  on 
the  supposition,  however  apparently  hopeless,  that  he  may  be  the  one  in 
whom  success  is  possible. 


COCAINE. 

At  the  time  of  the  Spanish  conquest  of  South  America,  the  Indians 
of  Bolivia,  Peru,  and  Colombia,  were  found  to  be  using  the  leaves  of 
Erythroxylon  Coca  to  sustain  their  strength  during  fatiguing  journeys 
and  to  alleviate  the  sense  of  hunger  and  thirst.  Coca  was  used  in  the 
religious  rites  of  the  Incas  and  was  treated  by  them  with  great  rever- 
ence, being  employed  in  their  sacrifices  to  the  Sun,  the  high  priest  chew- 


218  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

ing  the  leaf  during  the  ceremony.  Before  the  arrival  of  the  Spaniards 
it  was  sometimes  used  as  a  medium  of  exchange.  Nicholas  Monardes, 
a  Spanish  physician,  published,  at  Seville,  in  1565,  a  history  of  medical 
simples  brought  from  the  new  world.  He  describes  the  use  of  coca 
among  the  South  American  Indians  as  being  of  three  kinds;  it  was 
chewed  and  mixed  with  the  powder  of  calcined  shells  of  oysters  and 
other  shell  fish;  this  paste,  after  being  allowed  to  ferment,  was  formed 
into  boluses  or  troches  and  allowed  to  dry;  during  long  journeys  these 
were  sucked  and,  under  their  influence,  hunger  and  thirst  were  alleviated 
and  fatiguing  journeys  sustained;  when  eaten  for  i^roducing  pleasure 
or  intoxication,  the  coca  was  chewed  by  itself;  and  third,  it  was  mixed 
w^ith  tobacco  and  smoked.  The  Spaniards,  not  understanding  the  action 
of  coca,  regarded  it  with  superstition  and  the  Council  of  Bishops  at 
Lima,  in  1569,  condemned  its  use  on  the  ground  that  the  belief  enter- 
tained by  the  Indians,  that  chewing  the  coca  gave  them  strength,  was 
a  delusion  of  the  devil.  During  the  last  century  many  observers  noted 
the  extraordinary  endurance  of  the  Indians  under  its  influence,  but  it 
was  not  until  Roller,  in  1884,  discovered  the  local  anaesthetic  properties  of 
cocaine  when  applied  to  the  eye,  that  its  use  became  generalized  as  a 
medicinal  agent.  At  fjrst  it  was  considered  harmless,  but  before  long  it 
was  evident  that  continued  use  brought  with  it  a  seductive  addiction,  which 
was  broken  up  with  difficulty  and  produced  very  rapid  and  destructive 
effects. 

The  pure  cocaine  addictee  is  not  as  commonly  met  with  as  the  mor- 
phinist or  the  alcoholist.  The  drug  is  usually  taken  to  overcome  the 
nervousness  of  an  alcoholic  debauch  or  the  depression  following  mor- 
phine. It  is  not  infrequently  used  to  relieve  the  exhaustion  following 
sexual  and  alcoholic  excesses.  Judging  from  the  statistics  of  drug  store 
sales,  cocaine  addictees  seem  to  be  most  common  among  the  very  poor 
and  among  the  wealthy.  Cocaine  is  contained  in  certain  quack  nos- 
trums ^yhich  are  sold  extensively  in  certain  sections  of  the  country  by 
itinerant  peddlers.  In  the  Southern  states,  cocaine  addiction  is  very 
common  among  the  negroes,  who  speak  of  it  as  "tabs"  because  it  is 
bought  by  them  in  tablet  form.  Snuffing  the  pow^der  or  a  solution  of 
cocaine  is  a  common  method  of  use.  It  is  often  taken  hypodermically, 
and,  when  thus  used  in  impure  form,  it  sometimes  causes  a  green  dis- 
coloration, which  remains  permanent  at  the  site  of  the  injection  in  the 
skin.  One  woman  who  came  under  the  care  of  the  writer  had,  on  her  hips, 
thighs,  and  legs,  so  many  of  these  little,  round,  green  spots,  about  a  centi- 
meter in  diameter,  that  there  was  scarcely  a  square  inch  from  her  waist  to 
her  knees  w^hich  did  not  contain  one  of  them.  Patients  suffering  from 
neuralgia,  local  or  general,  physicians  exhausted  and  ansemic,  who  have 
to  be  tided  over  some  strain,  neurotic  and  psychopathic  individuals,  the 
worn-out  and  failures  of  modern  life,  fall  easy  victims  to  the  pleasing 
and  soothing  effects  of  this  drug. 

Acute  cocaine  poisoning  is  seen  following  the  injection  of  the  drug 
to  obtain  its  local  anaesthetic  effect  in  surgery.  Death  is  reported  as 
having  occurred  in  forty  seconds  following  twelve  drops  of  a  4  per 
cent,  solution  given  hypodermically  to  a  girl  of  eleven  years.  Half  a 
grain  to  one  unaccustomed  to  its  use  seems  often  to  be  a  border-fine 
dose.     Such  small  doses  as  four    drops   of  a  2  per  cent,   solution  in 


OPIUM.     MORPHINISM.     COCAINE  219 

the  eye,  produced  in  an  old  woman  an  intoxication  which  lasted  for 
four  days,  and  eight  drops  of  a  10  per  cent,  solution  in  the  eye  of  a  girl 
of  twelve  produced  violent  sympton)s  of  poisoning,  and  even  one  drop 
of  a  1  per  cent,  solution  in  the  eye  of  a  child  fourteen  years  old  has 
been  followed  by  symptoms  of  active  poisoning.  It  is  evident  that 
there  is  a  strong,  personal  idiosyncrasy,  and  while  such  small  doses 
have  caused  death,  recovery  has  followed  such  large  doses  as  twenty- 
two  grains  by  the  mouth,  and  ten  grains  hypodermically.  In  the  mild 
cases  of  poisoning  the  ordinary  symptoms  are  great  restlessness  and 
nervous  excitement,  with  no  feelings  of  pleasure  or  comfort,  but  rather 
those  of  anxiety  and  even  terror,  an  increase  in  the  frequency  of  the 
respirations,  and  often  a  distinctly  accelerated  pulse  rate,  with  the  patient 
pale,  faint,  and  dizzy.  In  the  more  severe  poisoning  there  has  been 
nausea  and  vomiting,  a  rapid  and  imperceptible  pulse,  great  nervous- 
ness and  jactitation;  the  patient  feels  as  if  the  heart  would  stop  beating; 
intense  perspiration  and  collapse  with  or  without  loss  of  consciousness 
is  seen;  the  pupils  are  usually  dilated;  in  some  they  have  been  reported 
as  contracted,  and,  occasionally,  the  pulse  has  been  slow  and  feeble  with 
slow  and  infrequent  respiration,  or  Cheyne-Stokes  breathing  with  marked 
cyanosis.  After  large  doses,  convulsions  are  frequently  present  and  are 
often  of  a  violent  epileptiform  character.  At  times  these  are  partial, 
with  unilateral  or  bilateral  cramps  in  the  muscles,  chiefly  in  the  flexors; 
these  muscular  spasms  may  go  on  to  general  rigidity  and  opisthotonos 
may  be  produced.  Consciousness  is  usually  lost  but  sometimes  there 
is  mania  with  hallucinations  and  delusions  which  have  frequently  been, 
violent  and  even  homicidal.  The  treatment  of  the  poisoning  is  sympto- 
matic; the  patient  should  be  kept  in  a  horizontal  position  and  given 
aromatic  spirits  of  ammonia,  alcohol,  camphor,  or  caffeine.  If  the 
poisonous  effects  are  manifested  in  the  respiration,  oxygen  or  even 
artificial  respiration  should  be  used.  Intravenous  injections  of  nor- 
mal saline  solution  have  proved  helpful.  If  the  drug  has  been  taken 
by  the  mouth,  the  stomach  should  be  washed  out.  After  the  patients 
have  recovered  from  this  acute  poisoning,  nervous  disturbances,  such 
as  insomnia,  vertigo,  tingling  in  the  limbs,  and  mental  depression,  may 
continue  for  some  days. 

Chronic  poisoning  by  cocaine  is  both  periodic  and  continuous.  The 
periodic  form  is  characterized  by  the  excessive  use  of  the  drug  for  sev- 
eral days  or  weeks,  after  which  it  is  abandoned  and  there  is  a  period 
during  which  there  is  no  desire  for  it.  During  the  free  intervals  the 
patient  remembers  distinctly  the  pleasurable  mental  impression  which 
he  obtained,  declares  that  he  has  broken  from  its  use  and  that  he  will 
not  use  it  again,  but  as  soon  as  the  cause  returns  which  formerly  drove 
him  to  the  use  of  the  drug,  he  will  invariably  reason  that  there  is  no 
danger  in  using  it  for  a  short  time,  and  quickly  returns  to  its  use.  Soon 
the  free  periods  become  shorter,  and  those  of  addiction  longer,  and  its 
use  becomes  continuous.  Few  indeed  of  the  cocaine  addictees  remain 
periodic  takers.  These  persons  also  show  the  peculiarity  which  is  espe- 
cially marked  in  the  addictee  of  cocaine,  that  in  order  to  conceal  its 
use,  they  will  take  other  drugs  such  as  alcohol,  chloral,  and  morphine, 
and  when  they  cannot  obtain  cocaine  they  will  turn  to  any  drug  that 
will  quiet  the  nervous  system.     Some  patients  become  violently  mania- 


220  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

cal,  requiring  several  persons  to  restrain  them  and,  when  given  the  drug, 
almost  instantly  quiet  down,  with  all  symptoms  of  their  mania  gone. 

The  main  pleasurable  action  of  the  drug  is  the  feeling  of  exhilaration 
and  increased  mental  and  nuiscular  strength  and  with  this  there  soon 
develop  delusions  of  great  strength  and  vigor,  the  patient  feeling  as  if 
he  had  absolute  self-possession;  he  shows  great  activity,  talks  freely 
and  enjoys  everything;  each  sense  seems  to  be  greatly  heightened;  there 
is  an  increased  pleasure  in  taste,  and  the  keenness  of  smell  is  heightened. 
Finally  hallucinations  of  voices  begin  to  appear;  there  are  delusions  of 
persecution  and  fears  of  personal  injury;  insomnia  comes  on  with  great 
muscular  restlessness  and  agitation,  which  simulates  the  irregular  spas- 
modic movements  of  chorea  major.  They  show  a  profuse  volubility, 
talking  in  a  wide  discursive  manner  over  all  subjects  and  in  their  writ- 
ing or  speech  there  are  no  pauses,  no  dividing  lines,  no  jnirjioseful  con- 
nection but  a  steady,  connected  flow  of  words,  involved  and  without 
point,  without  direction,  and  without  end.  The  patient  will  endeavor 
to  convey  some  idea  or  belief,  and  after  the  first  few  sentences  the  pur- 
pose is  forgotten  and  he  wanders  on  in  great  prolixity  and  diffuseness. 
Thus  many  cocainists  are  great  letter-writers,  and  in  some  instances 
the  letters  have  taken  on  an  amatory  type.  This  same  prolix  type,  in 
other  instances,  has  taken  on  a  slanderous  form,  but  there  is  a  noticeable 
lack  of  bitter,  sharp  accusations  and  distinct  charges;  the  meaning  of 
the  letters  can  only  be  made  out  by  inference  from  the  involved  mass 
of  words.  Again,  hallucinations  of  sight  and  hearing  develop,  and  the 
patients  see  suspicious  characters  watching  them  and  hear  voices  plot- 
ting to  do  them  injury;  they  begin  to  take  unusual  precautions  and  are 
prone  to  carry  revolvers  and  knives  to  defend  themselves,  and  justify 
such  procedure  by  the  explanation  that  their  lives  have  been,  or  are, 
in  danger. 

In  the  early  stages  of  cocainism,  when  the  effect  of  the  drug  begins 
to  w^ear  off,  the  patients  become  morose,  irritable,  easily  excited,  and 
suspicious;  there  is  insomnia  and  an  impending  sense  of  trouble  and 
danger.  In  the  later  stages,  the  exaltation  periods  are  brief  and  are 
followed  by  stupor  and  restlessness  with  evidences  of  great  mental  dis- 
turbance. The  appetite  fails;  they  are  anaemic,  and  emaciate  very 
rapidly;  look  sleepy  and  tired;  the  skin  becomes  flaccid  and  pale;  the 
senses  of  sight,  hearing,  and  smell,  are  seriously  impaired,  and  there  is 
a  feeling  of  paraesthesia  in  the  skin,  giving  a  sensation  as  if  vermin 
were  crawling  on  it,  which  is  a  very  significant  symptom.  Although 
there  is  increased  sexual  excitement,  the  sexual  power  is  diminished. 
Kraepelin  describes  a  definite  psychosis  wdiich  may  develop  on  the 
basis  of  chronic  cocainism  and  which  bears  a  close  resemblance  to  alco- 
holic delusional  insanity.  It  begins  wdth  a  few  days  of  irritability, 
anxiety,  and  restlessness,  after  which  the  hallucinations  suddenly  appear. 
Threatening  voices  are  heard  compelling  the  patients  to  act  strangely; 
moving  pictures  are  seen  on  the  w^all,  filled  with  large  and  small  objects. 
Minute  black  specks,  moving  on  a  light  surface,  are  very  characteristic 
hallucinations,  and  may  be  mistaken  for  flies,  mosquitoes,  and  other 
small  objects.  ParcTsthesias  of  the  skin  create  the  belief  that  they  are 
under  the  influence  of  electricity,  are  being  punctured  with  needles,  or 
are  poisoned.     Most  characteristic  is  the  sensation  of  foreign  bodies 


OPIUM.      MORPHINISM.      COCAINE  221 

under  the  skin,  particularly  of  the  ends  of  the  fingers  and  palms  of  the 
hands.  The  muscular  twitchings  are  thought  to  be  due  to  poison. 
Auditory  hallucinations  make  them  suspicious  of  their  surroundings. 
They  believe  their  thoughts  are  secretly  being  read  or  they  are  being 
spied  upon  through  holes  in  the  ceiling.  The  patients  may  try  to  kill 
their  alleged  tormentors  or  attempt  suicide.  They  have  characteristic 
delusions  of  infidelity  which  come  on  as  an  acute  symptom.  These 
are  often  obscene  in  character  and  they  will  accuse  their  wives  of  the 
grossest  immorality.  They  are  prone  to  react  to  these  false  ideas  in 
a  vindictive  and  aggressive  manner.  Consciousness  remains  clear  and 
orientation  is  good  except  in  rare  instances  when  the  excitement  is  very 
great  or  after  the  fresh  injection  of  the  drug.  The  emotional  attitude 
of  these  patients  is  dejected,  excitable,  irritable,  and  even  passionate; 
more  rarely  they  are  reserved  and  reticent  concerning  their  delusions. 
Their  actions  are  usually  restless  and  unstable  though  some  may  appear 
orderly. 

Cocaine  delusional  insanity  develops  rapidly  and  may  run  its  full 
course  in  a  few  weeks.  The  symptoms  increase  under  the  influence 
of  a  single  dose.  The  delirious  state  soon  disappears  if  the  drug  be 
completely  withdrawn,  but  the  delusions  may  remain  for  weeks  or 
months.  Morphinism  and  cocainism  in  the  same  individual  often  lead 
to  a  combination  of  symptoms,  but  morphinism,  except  with  cocainism, 
seldom  produces  a  rapid  development  of  pronounced  mental  disturbance. 
The  cocaine  psychosis  develops  more  rapidly,  the  symptoms  are  more 
severe  than  in  the  alcoholic  delusional  insanity,  and  the  delusions  of 
jealousy  appear  earlier  and  are  an  acute  symptom.  A  single  dose  of 
cocaine  produces  an  exacerbation  of  the  symptoms,  while  in  alcoholism 
it  produces  little  or  no  effect.  The  sensation  of  objects  under  the  skin 
is  characteristic  only  of  cocainism. 

Diagnosis. — The  diagnosis  of  cocaine  addiction  is  often  very  difficult. 
In  some  patients  there  is  only  an  increased  buoyancy  of  spirits  and  an 
increased  desire  for  mental  and  physical  exertion,  but  if  their  work  be 
studied  closely  it  will  be  seen  that  its  character,  and  the  judgment  dis- 
played in  doing  it,  are  below  the  former  excellence.  These  patients 
show  defects  of  judgment  and  a  diminished  sense  of  ethical  duties; 
they  are  also  more  prone  to  be  reckless  and  aimless  in  their  thoughts 
and  work,  and  show  a  diminution  of  ambition  and  will-power.  The 
powers  of  connected  application  are  less,  and  often  a  noticeable  symptom 
is  periods  of  buoyancy  varying  with  periods  of  beginning  depression, 
and  a  disposition  on  the  part  of  the  patient  to  go  off  alone;  and  on  his 
return  the  old  buoyancy  and  confidence  have  returned.  Thus  the  cocain- 
ist  differs  from  the  alcoholist,  by  his  periods  of  secretive  solitude,  and 
from  the  morphinist,  in  the  later  stages,  by  his  delusions  of  persecution. 
When  cocaine  is  the  main  drug  and  alcohol  and  morphia  are  taken  to 
relieve  it,  the  periods  of  exaltation  and  delusions  of  persecution  are 
very  noticeable.  If,  however,  cocaine  is  taken  to  relieve  morphia  or 
alcohol,  the  peculiar  symptoms  of  cocaine  are  usually  absent  and  there 
is  simply  a  restlessness  and  insomnia.  Morphine  and  alcohol,  taken 
after  cocaine,  intensify  the  injury  to  the  nervous  system  and  both  mania 
and  dementia  are  apt  to  follow.  Thus  the  combination  of  these  drugs 
renders  the  prognosis  graver  and  the  danger  to  relapse  greater. 


222  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

Prognosis. — As  regards  the  prognosis  in  the  early  stages,  where  cocaine 
is  taken  alone,  if  the  proper  treatment  can  be  instituted,  the  habit  seems 
to  be  more  easily  broken  than  that  of  morphia  or  alcohol  and  the 
chances  of  a  permanent  cure  and  restoration  to  health  are  also  greater. 
If,  however,  the  habit  is  well-established,  the  prognosis  is  unfavorable  for 
complete  recovery.  The  drug  causes  its  destructive  action  more  quickly 
and  more  intensely  than  alcohol  or  opium. 

Treatment. — In  treating  cocainism  we  must  realize  that  there  is  no 
druo-  which  brings  with  it  such  a  blissful  sense  of  satisfaction  and  of 
relief  from  mental  or  physical  pain,  or  gives  such  a  sense  of  increased 
vigor  and  the  ability  to  do  all  that  the  mind  craves  or  hopes  for.  The 
effect  thus  produced  is  very  intense  and,  although  the  patient  may  realize 
the  danger  of  relapsing,  the  mental  impression  made  under  the  influence 
of  the  drug  is  so  strong  that  the  tendency  to  relapse  is  very  great.  The 
amount  taken  by  the  cocainist  varies  and  has  been  given  as  from  thirty 
to  forty  grains  a  day  by  mouth  or  hypodermically;  it  also  varies  widely 
with  the  individual.  The  greatest  amount  which  has  come  under  my  per- 
sonal observation  was  in  a  young  woman  who  took  twelve  grains  of  mor- 
phine and  sixty  grains  of  cocaine  a  day,  by  the  hypodermic  method.  The 
withdrawal  of  the  drug  should  begin  at  once;  sometimes  this  can  be  com- 
plete; at  other  times  tapering-off  must  be  allowed,  especially  in  the  patients 
in  whom  the  symptoms  of  maniacal  excitement  follow  its  withdrawal.  If 
morphinism  and  cocainism  co-exist,  cocaine  should  be  withdrawn  first. 
Substitutes  should  be  used  to  lessen  the  irritability  and  the  distressing 
symptoms  caused  by  withdrawal.  The  best  of  these  seem  to  be  valerian, 
hyoscyamus,  and  vegetable  narcotics  of  this  type.  Bromides  are  often 
useful  in  large  doses  for  a  short  period.  If  there  are  symptoms  of  collapse, 
camphor,  caffeine,  or  strychnine,  must  be  used.  Chloral,  alcohol,  and  opium 
are  unsafe.  The  conditions  are  usually  those  of  starvation  and  cell  poison- 
ing and,  therefore,  the  digestion  should  be  carefully  watched,  and  often,  in 
the  beginning,  continued  doses  of  castor  oil,  such  as  a  half  ounce  or  an 
ounce  three  times  a  day,  are  necessary.  The  insomnia  should  be  treated 
largely  by  food  and  prolonged  warm  baths.  These  patients  should  be 
sent  to  some  asylum  or  retreat  to  be  cared  for  until  the  acute  symptoms 
have  subsided.  After  a  shorter  or  longer  time,  they  may  be  sent  back  to 
the  care  of  the  family  physician,  but  a  long  period  is  required  with  con- 
stant care  and  surveillance,  and  absolute  change  of  surroundings  and 
conditions  of  life.  These  patients  are  especially  prone  to  refuse  co- 
operation with  the  physician  and,  from  fear  or  pride,  conceal  their  real 
condition.  The  closest  study  of  the  causes  and  conditions  which  brought 
about  their  addiction  must  be  made  and  it  is  only  by  the  removal  of 
these  causes,  and  their  prevention,  that  the  patient  will  ever  be  broken  of 
this  habit. 


CHAPTER  XL 

FOOD    POISONS. 
By  FREDERICK  G.  NOVY,  M.D. 

Whenever  a  given  article  of  food  becomes  a  vehicle  for  an  injurious 
agent  it  is  for  the  time  being,  a  poison.  Such  a  food  acquires  its  poison- 
ous property,  in  distinction  from  that  which  is  always  injurious.  In  the 
latter  instance  we  are  dealing  with  plants  or  animals  in  which  the  elab- 
oration of  poisonous  substances  is  a  normal  physiological  process,  as 
in  certain  mushrooms  and  fish.  The  poison  of  such  may  be  said  to  be 
of  endogenous  origin,  whereas  in  the  former  it  is  accidentally  present, 
from  an  outside  source,  and  is  therefore  exogenous. 

Poisonous  metals,  animal  parasites,  and  bacteria,  make  up  the  three 
chief  causes  of  unwholesome  food.  Accidental  poisoning  from  metals 
in  the  food  is  the  least  common  occurrence,  so  much  so,  that  in  nearly 
all  ordinary  intoxications  the  question  of  the  presence  of  metals  may  be 
disregarded.  Nevertheless,  notable  outbreaks  of  this  nature  have  been 
known  even  in  recent  years.  Thus,  the  famous  "beer  epidemic"  of 
Manchester  and  other  English  cities,  in  1900,  was  due  to  the  accidental 
presence  of  arsenic.  Other  poisonings,  caused  by  water  which  had 
taken  up  lead  or  zinc,  are  so  well  knoAvn  as  scarcely  to  need  mention. 
The  wide  use  of  canned  goods  suggests  the  possibility  of  these  becoming 
poisonous  by  the  solution  of  tin  or  solder,  but  the  small  amounts  of  these 
in  solution  could  only  manifest  an  action  after  the  prolonged  and  ex- 
clusive use  of  such  foods,  a  condition  which  never  obtains  in  ordinary 
life. 

The  animal  parasites,  such  as  trichina  and  cysticercus,  are  also  of 
relatively  little  importance,  especially  in  comparison  with  the  group  of 
bacteria.  The  latter  constitute  the  chief  factor  in  poisonous  foods.  At 
times,  food  may  be  derived  from  diseased  animals,  and  injurious  effects 
may  be  directly  due  to  the  presence  of  the  specific  germ,  and  the  poison- 
ing represents  actually  an  infection.  At  other  times,  food  may  become 
accidentally  contaminated  with  germs,  such  as  typhoid  bacilli,  and  may 
give  rise  to  veritable  epidemics.  And  lastly,  food  may  be  invaded  by 
bacteria  which  are  themselves  unable  to  grow  in  the  living  body  but 
form  their  poisonous  products  directly  in  the  food.  The  more  detailed 
consideration  of  these  causes  will  be  given  in  connection  with  each 
kind  of  food. 

POISONOUS  FISH. 

The  ill  effects  following  the  use  of  fish  (Ichthyismus  or  Ichthyotoxismus) 
may  be  due  to  a  number  of  causes,  some  of  which  are  well  understood 
while  others  are  still  far  from  being  satisfactorily  explained.     Obviously, 

223 


224  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

poisonings  of  this  kind  are  relatively  more  frequent  in  countries  in  which 
fish  form  a  large  part  of  the  diet,  notably  Russia,  Japan,  and  the  West 
Indies.  The  several  causes  may  be  grouped  in  the  order  of  their  impor- 
tance under  four  heads.  First,  the  presence  of  normal  or  physiological 
poisons  in  the  fish;  second,  the  presence  of  bacteria  or  their  products; 
third,  invasion  by  animal  parasites;  and  fourth,  contamination  with 
metallic  or  other  poisons. 

1.  Physiological  Poisons. — It  is  well  recognized  that  there  are  many 
fish  which  are  always  poisonous,  while  others  may  become  so  during  the 
spawning  season.  The  consum])tion  of  such  fish  may  lead  to  severe  and 
even  fatal  intoxication.  Thus,  in  Tokio  alone,  from  1885  to  1892,  there 
were  reported  993  cases  of  so-called  fugu  poisoning,  of  which  680  were 
fatal — a  mortality  of  more  than  68  per  cent.  At  times  even,  notably  in 
China  and  Japan,  such  fish  are  taken  for  suicidal  purposes.  The  fugu 
poisoning  of  Japan  and  the  East  Indian  Islands  is  due  to  various  species 
of  Tetrodon  and  Diodon  The  active  agent,  which  resembles  curara 
somewhat  in  its  effects,  is  present  in  the  ovaries  and  testicles.  The  earlier 
Japanese  investigators  designated  this  substance  as  fugin.  The  exact 
nature  of  the  poison  is  not  determined.  The  symptoms  of  fugu  poisoning 
resemble  those  of  curara.  There  is  dyspnoea,  cyanosis,  dilatation  of  the 
pupils,  relaxation  of  the  sphincters,  paralysis  of  speech,  dizziness,  saliva- 
tion, and  vomiting.  After  the  onset  of  the  symptoms  death  may  result 
in  from  one  to  two  hours. 

While  the  organs  of  the  several  species  of  tetrodon  are  always  poison- 
ous, there  are  other  fish  which  become  toxic  only  during  the  spawning 
season.  Under  these  conditions  the  roe  of  different  members  of  the  stur- 
geon family,  of  the  pike,  and  the  barbel,  have  been  known  to  cause  pro- 
nounced and  even  fatal  intoxications.  The  symptoms  are  those  of  an 
acute  gastro-enteritis. 

As  further  illustrations  of  physiologically  poisonous  fish  may  be  men- 
tioned the  cod-fish  (Gadus  morrhua),  Perca  venenosa,  and  Sparus  Maena 
which,  eaten  in  the  raw  condition,  have  been  known  to  cause  grave  in- 
toxications. 

2.  Bacterial  Poisons. — As  might  be  expected,  intoxications  arising 
from  this  cause  are  fairly  common  and  may  be  met  with  under  various 
conditions.  Thus,  the  fish  may  be  diseased^  and  the  infection  be  trans- 
mitted when  the  flesh  is  eaten  raw.  The  fish  when  caught  may  be 
perfectly  wholesome  but,  as  a  result  of  imperfect  preservation,  bacterial 
contamination  may  occur  with  the  production  of  poisonous  products. 
It  is  necessary,  therefore,  to  consider  these  two  types  of  infection  sepa- 
rately, especially  since  a  similar  condition  will  be  noted  in  connection  with 
other  foods. 

Epidemics  among  fish  have  been  repeatedly  observed  in  this  and  other 
countries,  but  it  is  only  within  recent  years  that  they  have  been  studied 
from  the  etiological  standpoint.  It  is  not  within  the  scope  of  this  article 
to  consider  suc"h  outbreaks  except  in  so  far  as  they  throw  light  upon  the 
subject  of  poisonous  fish.  That  the  consumption  of  such  diseased  fish 
may  cause  intoxications,  and  even  actual  infections,  may  be  theoretically 
conceded  even  if  such  occurrences  are  few  in  number. 

Fischel  and  Enoch,  in  1892,  isolated  from  a  carp,  which  died  during  a 
fish  epidemic,  a  spore-bearing  bacillus  (B.  piscicidus)  which  was  patho- 


FOOD  POISONS  225 

genie  for  mice  and  guinea-pigs.  The  toxin  elaborated  by  this  })acillus 
was  readily  destroyed  by  boiling.  From  diseased  trout,  Bataiilon,  in 
1894,  isolated  a  bacillus  closely  related  to  Proteus  vulgaris.  It  was  ap- 
parently pathogenic  for  pike,  crabs,  and  frogs.  In  the  same  year  Emme- 
rich and  Weibel  studied  another  epidemic  among  trout  in  which  they 
found  a  bacillus  (B.  salmonicida)  differing  from  the  preceding.  Similar 
observations  were  made  in  1893  by  Charrin  in  connection  with  a  barbel 
epidemic  in  the  Rhone,  and  by  Canestrini,  who  isolated  from  diseased 
eels  a  bacillus  resembling  that  of  cholera.  This  was  pathogenic  for  fish 
and  frogs,  but  not  for  mammals. 

One  of  the  most  interesting  studies  of  fish  infection  is  that  of  Sieber- 
Schoumow.  Two  outbreaks  occurred  among  the  fish  in  a  palace  reser- 
voir at  St.  Petersburg,  in  1894,  and  on  both  occasions  she  isolated  an 
organism  which  she  named  B.  piscicidus  agilis.  This  germ  was  found 
not  only  in  the  diseased  fish  but  also  in  the  water  and  on  the  bottom 
and  walls  of  the  reservoir.  The  bacillus  was  also  found  in  a  large  num- 
ber of  the  fish  on  the  market  at  the  time,  and  also  in  the  discharges  of 
two  cholera  patients.  An  attempt  at  isolating  the  active  poison  failed, 
although  the  presence  of  cadaverin  and  other  ptomains  was  demon- 
strated. 

During  an  epidemic  in  Lake  Zurich,  in  1898,  Wyss  isolated  a  liquefy- 
ing bacillus  which  he  considered  to  be  identical  v/ith  Sieber-Schoumow's 
bacillus  and  Proteus  vulgaris.  The  organism  was  pathogenic  for  fish, 
mice,  and  guinea-pigs. 

The  outbreaks  mentioned  above  were  not  associated  with  any  in- 
stances of  poisoning  in  man,  though  it  is  reasonable  to  believe  that,  if 
the  fish  had  been  eaten  in  a  raw  or  partially  cooked  condition,  such  results 
might  have  followed. 

In  the  first  place,  the  pathogenic  organism  in  the  fish,  as  is  readily 
conceivable,  may  cause  a  real  infection  in  man.  And  again,  it  will  be 
presently  shown  that  poisonous  fish  may  contain  a  soluble  toxin  which 
is  readily  destroyed  by  heat,  and  consequently,  fish  carrying  ouch  bacterial 
products  would  be  dangerous  only  when  consumed  in  the  more  or  less 
raw  condition.  In  this  and  in  the  preceding  case  an  coc^ntial  factor  is 
that  the  food  be  eaten  in  a  raw  state,  since  cooking  destroys  bacteria  and 
certain  toxins.  On  the  other  hand,  it  is  possible  to  have  toxins  which  re- 
sist boiling,  and  consequently  food  infected  with  bacteria  which  produce 
toxins  of  this  type  might  prove  injurious  even  after  thorough  cooking. 
Thus,  Sieber-Schoumow  found  that  macerations  made  from  infected  fish, 
after  boiling  for  half  an  hour,  were  still  capable  of  causing  fatal  intoxica- 
tion. This  and  similar  observations  indicate  the  necessity  of  distinguish- 
ing between  these  three  types  of  bacterial  action. 

The  observations  of  Arustamow,  made  in  1891,  are  usually  taken  to 
indicate  the  effects  of  diseased  fish.  He  studied  eleven  cases  of  fish 
poisoning  of  which  five  ended  fatally.  These  were  caused  by  the  con- 
sumption of  four  kinds  of  fish  which  were  eaten  in  a  raw,  salted  condition. 
The  fish,  though  somewhat  soft,  were  of  good  appearance  and  showed  no 
sign  of  decomposition.  The  process  of  salting,  however,  was  not  very 
effectual,  since  the  entire  bodies  were  found  to  be  permeated  with  li\ang 
bacteria.  From  the  fish  and  the  organs  of  the  fatal  cases  he  isolated  four 
kinds  of  bacteria,  of  which  two,  however,  were  particularly  studied.    Dur- 

15 


226  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

ing  the  past  year  these  two  organisms  have  been  studied  by  Konstansoff, 
who  arrived  at  the  conchision  that  the  bacillus  obtained  from  the  sahnon 
was  an  ordinary  Proteus  vulgaris,  while  that  isolated  from  the  sturgeon 
was  a  variety  of  the  B.  call. 

The  studies  of  "Konstansoff*  are  particularly  valuable,  inasmuch  as 
they  throw  new  light  upon  the  nature  and  origin  of  the  fish  poison.  His 
material  was  a  sturgeon  which  ])oisoncd  two  })coj)lc.  The  fish  was  of 
good  appearance  and  showed  nothing  abnormal.  All  attempts  at  demon- 
strating the  presence  of  bacteria,  either  in  stained  preparations  or  by  the 
usual  cultivation  methods,  failed;  in  other  words,  the  material  was  sterile. 
This  Avas  due  to  the  fact  that  the  sturgeon  was  well  salted,  containing 
as  much  as  15.6  per  cent,  of  sodium  chloride.  Experiments  made  with 
ten  different  organisms  showed  that  when  these  were  planted  in  broth 
containing  15  per  cent,  of  salt,  no  growth  took  place,  and,  moreover,  all 
died  out  (spores  excepted)  in  from  three  to  five  days.  When  fish  were 
injected  with  such  cultures  and  then  salted  they  were  found  to  be  prac- 
tically free  from  organisms  after  the  twentieth  day.  In  view  of  the  fact 
that  fish  are  not  salted  immediately  after  being  caught  but  are  kept  for 
some  time  and  even  transported  to  a  considerable  distance,  it  is  evi- 
dent that  partial  decomposition  may  set  in,  especially  if  the  fish  were 
infected  or  diseased  when  taken.  The  subsequent  salting  inhibits  the 
further  growth  of  such  organisms  and  even  destroys  them,  but  the  poison 
which  they  have  already  formed  persists  and  can  only  be  removed  by 
boiling. 

An  emulsion  of  the  sturgeon  was  found  to  be  highly  toxic  to  small 
animals,  especially  when  administered  by  injection.  In  rabbits  the  in- 
toxication lasted  for  several  days  and  was  marked  by  nervous  phenomena, 
such  as  clonic  contractions  of  the  extremities.  At  autopsy  the  most 
noticeable  feature  was  the  rose  color  of  the  tissues  and  blood,  a  condition 
which  has  been  observed  in  man  after  fish  poisoning  and  is  suggestive  of 
the  action  of  hydrocyanic  acid.  A  suspension  of  the  fish  after  passage 
through  a  filter  paper  and  then  through  a  Chamberland  filter  gave  a  fil- 
trate which  Avas  as  toxic  as  the  original  liquid,  but  the  solid  residue  after 
washing  was  found  to  be  wholly  inert.  Attempts  at  extracting  the  poison 
by  means  of  alcohol  or  ether  failed.  The  above  filtrate  was  rendered 
inert  by  boiling,  and  even  an  exposure  of  half  an  hour  at  50°  C.  was  suffi- 
cient to  destroy  its  toxicity.  This  behavior  to  solvents  and  to  heat  clearly 
shows  that  the  soluble  poison  is  not  of  the  nature  of  a  ptomain  but  rather 
is  a  toxalbumin  or  more  correctly  a  toxin,  and,  as  such,  approaches  those 
of  diphtheria  and  tetanus.  Like  the  toxin  of  tetanus,  the  fish  poison 
tends  to  accumulate  in  certain  organs  and  tissues.  Thus,  in  a  poisoned 
rabbit  the  toxin  was  found  localized  especially  in  the  muscles  and  to  less 
extent  in  the  nervous  tissue  and  in  the  liver. 

From  Konstansoft''s  investigations  of  the  conditions  under  which  nor- 
mal fish  give  rise  to  this  or  a  similar  toxin,  it  is  certain  that  bacteria  are 
necessary.  In  ordinary  putrid  decomposition  of  fish  various  poisonous 
products  are  formed,  some  of  which  resemble  the  above  toxin  while 
others  are  of  the  nature  of  ptomains.  It  is  generally  recognized,  since  the 
work  of  Brieger,  that  highly  poisonous  products  are  to  be  found  only 

^Archives  d.  sciences  biolog.,  1904,  10,  p.  475. 


FOOD  POISONS  227 

during  the  first  days  of  putrefaction  and  that  they  disappear  as  this  pro- 
gresses, giving  rise  to  relatively  non-poisonous  ptomains.  In  other  words, 
the  products  of  the  initial  changes,  which  are  hardly  recognizable  by  the 
sense  of  smell  or  taste,  are  more  dangerous  than  those  of  advanced  de- 
composition. Konstansoff  showed  that  a  uniform  distribution  of  bacteria 
in  the  fish,  a  condition  which  is  best  realized  when  the  fish  is  diseased  or 
septicsemic,  insures  a  uniform  production  of  toxin  in  the  tissues.  The 
salting  of  the  fish  at  this  stage  arrests  all  further  decomposition,  but  the 
toxin  already  elaborated  remains  unchanged  and,  as  a  result,  such  fish, 
when  eaten  raw,  cause  the  well-known  symptoms  of  intoxication. 

The  symptoms  observed  in  this  type  of  poisoning,  as  well  as  the  prop- 
erties of  the  toxin  m  vitro,  resemble  very  closely  those  of  B .  hotulinus, 
which,  as  will  be  shown,  produces  the  most  severe  type  of  meat  poison- 
ing. The  presence  of  this  organism  in  fish  has  never  been  established, 
and  until  this  is  done  it  will  be  best  to  regard  these  two  kinds  of  intoxica- 
tion as  etiologically  distinct.  The  ill  effects  after  eating  such  raw  fish 
appear  in  from  ten  to  twenty-eight  hours.  The  fatal  result,  when  it 
supervenes,  occurs  only  after  several  days,  and  at  no  time  has  it  been 
observed  within  the  first  twenty-four  hours.  The  quantity  eaten  has 
no  necessary  relation  to  the  severity  of  the  symptoms.  Thus,  a  small 
amount  may  prove  fatal,  whereas  a  larger  portion  may  be  followed  by 
recovery.  This  peculiarity  is  probably  not  due  to  idiosyncrasy  or  to  an 
uneven  distribution  of  the  poison  in  the  fish  but  depends  rather  upon  the 
quantity  of  food  in  the  stomach.  The  dilution  caused  by  the  presence 
of  a  large  amount  of  other  food,  and  the  consequent  retarded  absorption, 
may  favor  the  destruction  of  the  poison  by  the  digestive  fiuids. 

S3nnptoms. — The  symptoms  are  general  weakness,  dull  pain  in  the 
abdomen,  dyspnoea,  mydriasis,  impaired  vision,  diplopia  and  vertigo, 
complete  dryness  of  the  mouth  and  tongue,  inability  to  swallow,  and  loss 
of  speech.  Vomiting  and  diarrhoea  are  absent  and  instead  there  is  ob- 
stinate constipation  and  retention  of  urine.  Vomiting  is  absent  at  first 
but  may  come  on  in  the  later  stages.  There  is  no  rise  in  temperature 
and,  on  the  contrary,  there  may  be  a  fall  of  several  degrees,  especially 
before  death.  Another  type  of  bacterial  poisoning  from  fish  presents  an 
entirely  different  train  of  symptoms.  It  is  of  the  nature  of  an  acute  gas- 
tritis and  gastro-enteritis.  Violent  vomiting,  excessive  diarrhoea,  dizzi- 
ness, tremor,  prostration,  and  cardiac  syncope  are  observed.  Autopsy 
shows  extensive  follicular  enteritis  with  necrosis,  hypersemia  of  many  or- 
gans, fatty  degeneration  of  the  liver,  and  toxic  degeneration  of  the  heart. 
These  symptoms  and  changes  were  observed  in  recent  fish  poisoning  at 
Zurich  in  which  fourteen  persons  were  affected,  two  of  whom  died  within 
twelve  hours.  From  the  fish  and  from  the  spleen  and  blood  of  the  de- 
ceased persons,  an  organism  was  isolated  which  was  identified  with  B, 
enteritidis,  which  is  an  important  cause  of  meat  poisoning.  This  out- 
break therefore,  unlike  the  above,  is  clearly  an  infection  and  intoxica- 
tion. 

In  view  of  the  fact  that  poisonous  products  are  met  with  in  the  raw 
and  imperfectly  salted  fish  it  is  evident  that  like  substances  may  develop 
in  canned  fish.  Indeed,  serious  results  have  followed  the  use  of  canned 
salmon,  as  is  reported  by  Ballard.  In  spite  of  the  fact  that  the  can  was 
"blown"  and  the  contents  partially  decomposed,  they  were  consumed  by 


228  DISEASES  CAUSED  BY  OliGANIC  AGEXTS 

five  persons.  Three  of  these  recovered,  while  one  who  ate  the  most  be- 
came ill  about  ten  hours  after  eating,  and  died  in  three  days.  Another 
who  ate  somewhat  less  died  in  five  days.  No  organism  could  be  obtained 
from  the  fatal  cases,  or  from  mice  which  died  after  being  fed  some  of 
the  salmon.  This  Avould  indicate,  as  in  Konstansoff's  experiments,  the 
presence  of  a  soluble  toxin. 

From  some  canned  salmon  which  caused  poisoning  in  a  man,Vaughan 
isolated  a  micrococcus  which  was  found  to  be  highly  toxic,  especially 
when  grown  under  anaerobic  conditions.  About  twelve  hours  after  eating 
this  fish  the  patient  began  to  suffer  from  nausea,  vomiting,  antl  a  griping 
pain  in  the  abdomen;  and  six  hours  later  he  was  found  vomiting  small 
quantities  of  mucus,  colored  with  bile,  at  frequent  intervals.  The  pulse 
was  140,  the  temperature  102°  F.,  and  the  respiration  shallow  and  ir- 
regular. A  scarlatinous  rash  covered  the  entire  body  but  disappeared 
in  the  course  of  the  next  day;  the  tenijierature  remained  above  the  nor- 
mal for  four  or  five  days,  and  eventually  complete  recovery  followed. 

Summing  up  the  observations  which  have  been  made  thus  far  upon 
the  role  of  bacteria  in  fish  poisoning,  it  is  evident  that  many  bacteria, 
especially  of  the  Colon  and  Proteus  group,  take  part  in  the  process. 
These  may  be  present  in  diseased  fish,  or  they  may  be  introduced  after 
the  fish  are  caught.  In  either  case,  during  the  initial  decomposition 
changes  which  are  scarcely  recognizable,  there  are  formed  poisonous  pro- 
ducts, which  in  some  instances  are  readily  destroyed  by  heat  while  in 
others  they  are  not  aft'ccted.  The  ingestion  of  such  fish  is  followed  by 
a  more  or  less  severe  intoxication,  depending  largely  upon  the  kind  of 
organism  present,  and  at  times  by  actual  infection. 

Animal  Parasites. — Under  this  head  it  is  sufficient  to  mention  the 
numerous  infections  with  Bothriocephalus  latus,  directly  traceable  to 
the  eating  of  fish  infested  with  the  larvae. 

Metallic  and  Other  Poisons.— Poisoning  from  canned  fish  is  some- 
times ascribed  to  the  presence  of  tin  and  other  metallic  poisons  which 
have  been  dissolved  out  by  the  acid  or  ammoniacal  contents.  It  is 
knowm  that  appreciable  amounts  of  tin  can  be  obtained  at  times  from 
canned  goods,  but  that  fact  in  itself  is  insufficient  to  explain  the  effects 
observed.  In  all  such  cases,  decomposition  of  the  contents  by  bacteria 
offers  a  more  rational  explanation. 

Some  cases  of  poisoning  have  been  ascribed  to  the  food  taken  by  the 
fish,  such  as  poisonous  medusae  and  corals,  and  decomposing  proteids. 
Without  doubt,  fish  may  become  infected  by  eating  putrid  food  or  by 
livmg  in  contaminated  waters,  but  when  this  does  occur  the  resulting 
poisoning  properly  belongs  under  the  head  of  bacterial  poisons.  The 
symptoms  w^hich  have  been  noted  in  such  cases,  are  either  those  of  an 
acute  gastro-enteritis  or  are  of  a  nei'vous  order,  and  correspond  to  those 
already  given. 

POISONOUS   SHELL-FISH. 

The  conditions  which  render  such  food  poisonous  are  much  the  same  as 
those  which  have  been  given  in  connection  with  poisonous  fish.  Thus, 
there  is  always  the  possibility  that  the  molluscs  may  be  diseased  at  the 
time  they  are  gathered,  in  which  case  the  infection  is  transferred  to  the 


FOOD  POISONS  229 

consumer.  The  existence  of  such  disease,  however,  has  not  been  estab- 
lished as  clearly  as  in  the  case  of  fish.  A  second  condition  is  to  be 
found  when  such  food  is  })erfectly  wholesome  at  first,  but  on  keeping,  as 
a  result  of  even  slight  decomposition,  becomes  toxic.  With  this,  as  with 
other  foods,  the  initial  products  of  putrefaction  are  the  most  dangerous. 
For  example,  mussels  which  have  been  allowed  to  decompose  for  some 
days  have  been  shown  to  be  free  from  poisonous  substances.  It  would 
appear  that  the  first  products  of  the  cleavage  of  proteids  and  of  leci- 
thins are  especially  poisonous,  and  that  by  the  further  action  of  bacteria 
these  are  then  converted  into  less  toxic,  or  even  inert,  bodies. 

The  most  important  condition  which  bears  upon  the  toxicity  of  molluscs 
is  their  habitat.  It  has  been  repeatedly  demonstrated  that  when  these 
are  grown  or  kept  in  polluted  waters,  they  acquire  toxic  and  even  infec- 
tious properties.  On  being  transferred  to  fresh  clean  water,  they  soon  lose 
their  poisonous  character.  The  fact  that  perfectly  fresh  mussels  at  times 
cause  severe  and  even  fatal  intoxications,  would  seem  to  indicate  that  the 
elaboration  of  the  poison  may  occur  during  the  life  of  the  animal.  It  is 
because  of  this  that  some  writers  consider  such  products  to  arise  by  tissue 
metabolism,  and  hence  designate  them  as  "leukomains."  Others  have 
expressed  a  belief  in  the  existence  of  a  distinct  poisonous  variety  of  mussel, 
while  still  others  have  held  that  the  mussels  had  taken  up  poisonous  food 
material  or  even  metallic  poisons.  Such  views  are,  however,  no  longer 
considered  seriously,  since  the  condition  mentioned  can  be  accounted  for 
more  easily  by  the  known  facts  regarding  the  presence  and  action  of 
bacteria.  Molluscs  living  in  polluted  waters  are  known  to  take  up  large 
numbers  of  difl^erent  kinds  of  bacteria  which  they  may  maintain  in  a 
viable  state  for  a  considerable  length  of  time.  Without  doubt  some  of 
these  organisms  are  able  to  act  upon  the  host,  and  thus  give  rise  to  poisons, 
but  the  exact  conditions  under  which  these  products  are  formed  in  the 
living  mussel  are  as  yet  undetermined. 

Of  far  more  importance  than  the  occasional  poisoning  from  shell-fish 
is  the  fact  that  these  convey  specific  infections  to  man.  It  has  been 
established  beyond  a  doubt  that  oysters  and  other  molluscs  are  a  prolific 
source  of  infection.  A  marked  instance  is  that  afl^orded  by  the  mayor- 
alty banquets  which  were  held  at  Southampton  and  Winchester,  in  1903. 
Of  the  132  guests  at  the  former  55  became  ill,  and  all  but  one  of  these 
had  eaten  oysters;  11  developed  typhoid  fever.  Of  134  guests  at  the 
latter  place  62  became  ill  and  10  of  these  had  typhoid  fever.  The 
evidence  showed  that  the  oysters  had  been  gathered  at  the  same  place, 
from  beds  which  were  polluted  with  sewage.  An  examination  made  by 
Klein  showed  the  presence  of  a  germ  belonging  to  the  B.  enteritidis 
group. 

The  studies  of  Herdman  and  Boyce  have  served  to  call  attention  to 
the  extreme  contamination  which  may  occur.  Thus,  from  the  cavities 
of  oysters  obtained  from  the  neighborhood  of  a  drain-pipe  they  obtained 
as  many  as  17,000  colonies,  against  10  colonies  which  were  present  in 
oysters  secured  in  open  water.  On  placing  oysters  in  water  infected 
with  typhoid  bacilli  it  was  found  that  these  organisms  were  ingested 
and  that  they  could  be  isolated  from  the  cavities  in  some  cases  as  long 
as  fourteen  days  after  the  infection.  Klein  has  found  the  typhoid  bacilli 
to  persist  in  oysters  for  from  two  to  three  weeks.    At  times,  however,  the 


230  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

oysters  may  clean  themselves  Avithin  a  week.  This  is  facilitated  to  a 
marked  degree  by  j^laciiig  them  in  clean  water  which  is  constantly  being 
renewed.  The  disappearance  of  typhoid  and  colon  bacilli  from  infected 
oysters,  Avhile  in  part  the  result  of  elimination,  is  probably  largely  due 
to  destruction  within  the  body  of  the  mollusc.  It  is  evident  that,  under 
favorable  conditions,  self  purification  of  the  oysters  may  be  secured. 

In  view  of  the  above  facts  it  is  reasonable  to  believe  that  other  infec- 
tions, such  as  cholera  and  amocbiasis,  may  in  some  localities  be  spread 
through  the  agency  of  contaminated  molluscs.  Positive  evidence  on  this 
point  is  as  yet  wanting. 

Mussels. — Poisoning  from  the  common  mussel  {Myiilus  cdulis)  is 
by  no  means  a  rare  occurrence  in  England  and  on  the  Continent.  The 
symptoms  of  intoxication  are  subject  to  considerable  variation.  In  gen- 
eral three  types  are  to  be  recognized.  The  first  partakes  of  the  character 
of  a  gastro-enteritis.  The  choleraic  symptoms,  such  as  nausea,  vomiting, 
diarrhoea,  do  not  appear  until  after  the  lapse  of  some  hours.  Death 
may  result,  but  not  as  a  rule.  This  type  corresponds  to  similar  forms  of 
intoxication  caused  by  meat,  cheese,  and  other  foods. 

A  second  type  of  intoxication  presents  essentially  nervous  symptoms, 
and  is  the  most  common  form.  It  begins  with  a  sensation  of  heat.  Itch- 
ing appears,  usually  at  first  in  the  eyelids,  but  before  long  spreads  over 
the  face  and  may  involve  a  large  part  of  the  body.  A  diffuse  exudative 
erythema,  or  general  urticaria,  develops.  Angina  and  dyspnoea  are  at 
times  pronounced.  In  this  form,  recovery  usually  takes  place  after  a 
few  days. 

The  third  type  is  paralytic  and  suggests  the  action  of  a  curara-like 
body.  It  is  less  frequent  and  more  dangerous  than  the  preceding  forms. 
To  a  certain  extent  it  may  be  compared  with  the  intoxication  caused  by 
Konstansoff's  fish  toxin,  or  with  that  of  Van  Ermengem's  B.  hotulinus. 
It  differs  from  these,  however,  in  the  rapidity  of  the  onset  of  the  symp- 
toms and  in  the  fact  that  boiling  does  not  destroy  the  poison.  The 
apparently  perfectly  fresh  mussel  may  cause  a  rapidly  fatal  intoxication, 
as  has  been  noted  in  England  in  several  instances.  Thus,  in  one  case, 
the  symptoms  came  on  almost  immediately  after  eating  boiled  mussels 
and  death  occurred  in  fifteen  minutes.  In  another  case  the  mussels 
"vvere  gathered  from  water  knoAvn  to  be  polluted,  and,  although  they  were 
washed  and  cooked  thoroughly,  in  several  changes  of  water,  yet  they 
poisoned  two  persons,  one  of  whom  died.  Four  hours  after  eating  the 
meal  they  were  seized  with  giddiness  and  were  unable  to  stand  or  sit  up. 
They  showed  mental  excitement  or  delirium,  closely  simulating  early 
alcoholism.  There  Avas  numbness  of  the  extremities,  diminished  sen- 
sation, and  dilated  pupils.  The  abdomen  was  distended  and  tympanitic; 
constipation  was  present.  Dryness  of  the  throat,  constriction  in  the 
neck,  difficulty  in  breathing  and  swallowing,  and  a  tendency  to  syncope 
were  prominent  symptoms.  The  temperature  was  normal,  and  the  pulse 
did  not  go  over  80.    One  recovered  in  two  days. 

One  of  the  most  conspicuous  examples  of  mussel  poisoning  was  at 
Wilhemshaven,  in  1885,  where  a  large  number  of  dock  laborers  and 
their  families  were  affected.  According  to  Schmidtmann  the  symptoms 
developed  shortly  after  the  cooked  mussels  were  eaten,  or  within  a  few 
hours,  according  to  the  amount  consumed.    They  began  with  a  feeling 


FOOD  POISONS  231 

of  constriction  in  the  neck,  mouth,  and  Ups.  The  teeth  were  set  on  edge 
as  if  sour  apples  had  been  eaten.  There  was  a  pricking,  burning  sen- 
sation of  the  hands,  and  later  of  the  feet.  Giddiness  followed  but  no 
headache;  a  feeling  of  lightness  of  the  body,  with  a  sensation  of  flying 
and  general  excitation  similar  to  that  of  alcoholism,  restlessness,  some 
anxiety,  with  slight  distress  in  the  chest,  were  present.  The  pulse  was 
hard  and  rapid  (80-90)  without  any  increase  in  temperature.  The 
pupils  became  dilated  and  reactionless  but  there  was  no  impaired  vision. 
Speech  became  difficult,  broken,  and  jerky,  and  the  limbs  heavy  and  stiff. 
The  patients  became  di^zy,  staggered  and  grasped  spasmodically  at  ob- 
jects which  they  missed,  and  finally  the  legs  were  no  longer  able  to 
support  the  body.  Then  came  marked  nausea  and  vomiting  but  no 
abdominal  pain  or  diarrhoea;  there  was  numbness  of  the  hands  and 
coldness  of  feet  at  first,  gradually  extending  over  the  whole  body,  with 
a  feeling  of  suffocation;  in  some  cases  abundant  perspiration,  followed 
by  quiet,  restful  sleep.  Death  occurred  in  one  case  in  one  and  three- 
quarter  hours;  in  a  second,  in  three  and  one-half  hours;  and  in  a  third, 
in  five  hours,  after  eating  the  mussels. 

The  •  chemical  examination  of  the  poisonous  mussels  was  made  by 
Brieger,  who  succeeded  in  isolating  several  bases  or  ptomains,  one  of 
which  (mytilotoxin)  proved  to  be  highly  poisonous.  The  effect  pro- 
duced by  this  in  animals  was  the  same  as  that  which  followed  the  ad- 
ministration of  boiled  extracts  of  the  mussels.  Therefore,  intoxications 
of  this  type  are  due  to  a  heat-resisting  alkaloid,  or  ptomain,  and  in  a 
sense  are  analogous  to  those  caused  by  poisonous  mushrooms.  The 
production  of  the  poison,  however,  is  not  a  physiological  one,  as  in  the 
latter,  but  the  result  of  the  action  of  bacteria  in  the  polluted  water. 

Oysters. — The  part  played  by  oysters  in  the  spread  of  typhoid  fever 
and  other  infections  has  already  been  given,  and  there  remains  to  be 
considered  the  acute  intoxication  to  which  they  at  times  give  rise.  Gastro- 
intestinal disturbances  of  variable  intensity  have  been  repeatedly  met 
with,  and  have  been  shown  to  be  due  to  oysters  derived  from  sewage- 
polluted  beds.  The  intense  poisoning,  such  as  is  given  above  under 
mussels,is  fortunately  not  a  common  occurrence.  A  striking  instance  is 
reported  by  Brosch,  in  1896,  in  which  an  officer  died  in  twelve  hours 
after  eating  some  oysters  which  at  the  time  were  noted  to  possess  a  bad 
taste.  The  symptoms  began  in  a  few  hours  with  headache,  pains  in  the 
side,  difficulty  in  swallowing,  salivation,  impaired  vision,  and  retention  of 
urine.  The  gait  became  staggering,  deglutition  impossible,  and  speech 
difficult  and  indistinct;  paralysis  of  the  right  side  of  the  face,  including 
dilatation  of  the  pupil  and  ptosis  of  the  right  eyelid,  followed.  Finally, 
cyanosis  set  in,  salivation  ceased,  likewise  respiration,  while  the  heart 
continued  to  beat  for  about  two  minutes.  The  nature  of  the  poison  in 
this  case  was  not  established. 

Lobsters. — Similar  intoxications  have  been  induced  by  lobsters  and 
crabs.  Jaksch  cites  an  instance  where  an  entire  company  partook  of 
lobsters  without  any  ill  effects,  but  the  remnants,  which  were  eaten  next 
morning  by  a  family,  caused  severe  illness  and  two  deaths,  the  early 
stage  of  decomposition  clearly  giving  rise  to  poisonous  products.  An- 
other illustration  is  afforded  by  Georgii,  where  a  number  of  young 
people  ate  a  mayonnaise  made  from  canned  lobsters.     The  symjptoms 


232  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

were  nausea,  vomiting,  much  pain,  severe  headache,  small  rapid  pulse, 
and  a  slightly  sub-normal  temperature.  Urticaria,  eye  symptoms,  or 
paralysiss,  did  not  appear 

POISONOUS  MEAT. 

The  earliest  recorded  observations  regarding  poisonous  meats  were 
made  on  sausages,  the  wide  use  of  which,  especially  in  Germany,  fre- 
quently led  to  extensive  outbreaks.  It  became  customary  to  speak  of 
the  "sausage  poison,"  and  the  condition  itself  was  designated  as  Botul- 
ism, or  allantiasis.  A  better  knowledge  of  the  conditions  leading  to  the 
production  of  poison  in  this  food  has  resulted  in  a  lessening  of  such 
occurrences,  so  that  at  the  present  time  they  are  rather  rare.  The  sau- 
sage is  not  the  only  meat  food  which  may  acquire  poisonous  properties. 
Every  kind  of  meat  is  subject  to  the  same  changes,  and  if  these  are 
more  frequent  in  the  sausage  it  is  merely  because  of  the  method  of  prep- 
aration and  the  conditions  of  keeping. 

The  question  of  a  physiologically  poisonous  meat,  as  in  some  fish, 
and  the  possible  presence  of  metals  can  be  passed  by  in  view  of  their 
very  infrequent,  if  not  altogether  doubtful,  occurrence.  Similarly,  the 
ill  effects  from  the  eating  of  meat  infected  with  animal  parasites,  such 
as  trichina  and  cysticerci,  need  no  special  attention  here.  After  eliminat- 
ing these,  the  entire  phenomenon  of  poisonous  meat  resolves  itself  into 
the  presence  of  bacteria  and  their  products. 

The  infection  of  meat  may  result  in  one  of  two  ways :  First,  the  animal 
may  be  perfectly  healthy  and,  when  slaughtered,  yield  flesh  entirely 
wholesome  and  free  from  bacteria.  Such  meat  can  acquire  poisonous 
properties  only  by  the  introduction  of  bacteria  from  without,  by  contact 
with  unclean  utensils,  vessels  and  the  like.  The  chopping-up  of  meat 
obviously  favors  the  spreading  of  organisms  through  the  mass.  Under 
suitable  temperature  conditions,  the  bacteria  thus  introduced  multiply 
sufficiently  to  give  rise  to  poisonous  products,  and,  as  a  result,  what  was 
wholesome  meat  in  the  beginning,  may  now  be  positively  injurious. 
Obviously,  under  these  conditions  various  species  of  bacteria  may  be 
met  with,  and  among  these  may  be  some  which  are  true  saprophytes, 
such  as  Proteus  vulgaris  and  B.  hotulinus.  The  colon  group  is  most 
frequently  represented. 

A  second  source  of  infection  arises  when  the  animal  is  diseased  at 
the  time  it  is  slaughtered.  In  such  a  case,  a  specific  pathogenic  organism 
is  present,  more  or  less  widely  distributed  in  the  tissues  or  organs,  and, 
for  that  reason,  the  fresh  meat  may  be  toxic,  or,  at  all  events,  it  readily 
becomes  so  on  keeping.  Poisoning  from  such  a  source  may  not  only 
partake  of  the  nature  of  an  intoxication  but  may  also  develop  into  an 
actual  infection.  Abundant  evidence  has  been  brought  forth  during  the 
past  few  years  to  show  that  many  forms  of  gastro-enteritis  are  really 
food  infections,  and  that  poisonous  meat  plays  a  very  important  part  in 
their  etiology.  Such  facts  have  been  adduced  not  only  with  reference  to 
summer  diarrhoeas  but  also  in  regard  to  paratyphoid  infections.  A  large 
number  of  closely  related  organisms  have  been  isolated  from  such  poi- 
sonous meat,  and,  so  far  as  known  means  of  differentiation  is  concerned; 
they  are  not  to  be  distinguished  sharply  from  the  B.  paratyphosus. 


FOOD  POISONS  233 

With  reference  to  the  chemical  products  elaborated  by  the  bacteria 
in  either  form  of  poisoning,  very  little  is  known,  except  in  a  general 
way.  The  old  view  that  such  intoxications  were  due  to  ptomains  is  no 
longer  tenable,  and  such  basic  products  necessarily  play  an  insignificant 
or  very  secondary  role.  The  real  poisons  are  essentially  of  the  same 
character  as  those  of  the  pathogenic  bacteria.  They  may  be  divided 
into  two  groups  according  to  their  behavior  to  heat.  Thus,  in  the  case 
of  B.  hotulinus,  a  soluble  toxin  is  produced  which  is  easily  destroyed 
by  boiling,  and  in  this  respect  it  resembles  closely  the  toxin  of  tetanus. 
In  the  case  of  the  B.  enteritidis,  the  soluble  products  are  not  materially 
affected  by  boiling,  and,  hence,  meat  containing  such  may  still  be  injurious 
even  after  it  has  been  cooked.  The  presence  of  poisonous  products  in 
meat  is  not  necessarily  indicated  by  changes  in  taste  or  odor.  In  fact, 
in  the  majority  of  instances,  such  food  is  in  an  apparently  perfect  con- 
dition, and  it  would  seem  as  if  marked  decomposition  favored  the  de- 
struction of  the  poisons  formed  during  the  early  stages  of  bacterial 
action. 

Notwithstanding  that  many  different  species  of  bacteria  are  concerned 
in  the  formation  of  such  poisonous  products,  it  is  quite  impossible  to 
draw  sharp  differences  clinically  between  the  various  intoxications. 
Two  forms,  however,  are  sharply  contrasted.  In  the  first  the  central 
nervous  system  is  affected  and  the  symptoms  are  therefore  characteristic 
and  well  marked.  Owing  to  the  frequency  of  this  type  among  the 
recorded  cases  of  sausage  poisoning.  Van  Ermengem  designated  it 
aa  true  botulismus.  In  the  second  form  of  intoxication,  the  symptoms 
are  gastro-intestinal.  They  may  be  of  a  mild  type  and  of  short  dura- 
tion, or  of  a  more  severe  character  merging  into  an  actual  infection. 
Such  food  poisonings,  according  to  Trautmann,  represent  the  highly  acute, 
whereas  paratyphoid  fever  represents  the  subacute,  form  of  an  infection 
etiologically  due  to  one  and  the  same  factor. 

Botulismus. — ^This  term,  originally  employed  to  designate  all  forms 
of  poisoning  caused  by  sausage,  is  here  used  in  the  sense  given  by  Van 
Ermengem — namely,  a  specific  intoxication  due  to  B.  hotulinus.  This 
organism  was  first  isolated  by  him,  in  1895,  from  poisonous  ham.  Kemp- 
ner  obtained  it  from  the  faeces  of  a  hog  (1897);  and  in  1900  it  was  found, 
a  second  time,  in  ham  by  Romer.  More  recently  (1904)  it  was  isolated 
from  poisonous  canned  beans,  by  I^andmann.  The  presence  of  the  or- 
ganism in  faeces,  as  well  as  its  close  resemblance  to  the  tetanus  bacillus, 
would  indicate  that  its  natural  habitat  is  in  the  soil,  which  readily  ac- 
counts for  its  presence  in  the  canned  beans  mentioned.  On  the  other 
hand,  the  organism  can  hardly  be  said  to  have  a  widespread  existence 
in  nature,  since  in  a  large  series  of  tests  of  soil,  intestinal  contents  of 
animals,  etc..  Van  Ermengem  obtained  negative  results. 

The  outbreak  studied  by  Van  Ermengem^  occurred  at  EUezelles,  in 
Belgium,  in  1895,  and  affected  fifty  persons,  of  whom  three  died.  Inquiry 
showed  that  the  poisoning  was  due  to  eating  one  ham.  The  flesh  of 
the  hog  at  the  time  of  slaughtering  was  eaten  without  any  ill  effects. 
Moreover,  the  other  ham,  although  in  a  decidedly  decomposed  state, 
was  eaten  with  like  negative  result.  This  non-poisonous  ham  was  in 
the  same  cask  as  the  other,  which  was,  however,  on  the  bottom,  immersed 

1  Zeitschr.  /.  Hygiene,  1897,  26,  1. 


234  DISEASES  CAUSED  BY  ORGAXIC  AGEXTS 

in  a  weak  brine.  A  layer  of  pieces  of  fat  separated  the  two  hams,  the 
lower  one  being  covered  by  the  brine  while  the  upper  was  not,  and  being 
thus  exposed  to  the  air,  it  underwent  ordinary  putrefaction.  The  poison- 
ous lower  ham  was  obviously  under  anaerobic  conditions,  and  the  bac- 
terial changes  which  occurred  were  of  a  ditt'crent  tyj)e  from  those  in  the 
one  above.  It  was  not  putrid,  but  had  a  sharp  odor  like  that  of  rancid 
butter,  and  though  somewhat  macerated  it  was  otherwise  of  good  appear- 
ance.   The  taste  was  said  to  be  bad  by  those  who  partook  of  it. 

The  symptoms  Avhich  followed  the  eating  of  the  suspected  ham  were 
those  of  the  typical  sausage  poisoning.  The  onset  was  rather  late,  the 
first  symptoms  coming  on  from  twenty  to  twenty-four  hours,  and  in 
some  thirty-six  hours,  after  the  meal.  Nausea,  gastric  pains,  and  vomit- 
ing were  the  effects  first  noted.  In  two  instances  there  was  diarrhcea, 
while  in  the  others  there  was  obstinate  constipation,  and  retention  of 
urine.  Visual  disturbances  developed  in  from  thirty-six  to  forty-eight 
hours  in  all  cases.  The  patients  complained  of  a  fogging  of  the  eyes 
and  were  soon  unable  to  recognize  persons  about  them.  More  or  less 
marked  diplopia  came  on.  At  the  same  time  there  was  observed  a 
marked  dilatation  of  the  pupils  with  complete  loss  of  reaction  to  light, 
ptosis  of  both  eyelids,  and  a  peculiar  stony  stare.  There  was  a  sensation 
of  burning  thirst  and  strangling;  the  swallowing  of  solid  food  and  even 
of  liquids  was  difficult  and  led  to  choking  attacks.  The  mucous  mem- 
brane of  the  mouth,  nose,  and  pharynx,  Avas  strongly  reddened  and 
covered  with  a  thick  viscid  secretion  which  caused  violent  attacks  of  cough- 
ing, and  even  of  suffocation.  In  some  there  was  suppression  of  salivary 
secretion,  and  the  mucous  membrane  was  dry  and  shiny.  The  voice 
became  dull,  and  complete  aphonia  was  not  infrequent.  Extreme  mus- 
cular weakness  was  general  and  persisted  for  weeks.  Notwithstanding 
these  severe  symptoms  the  respiration  and  circulation  were  unimpaired. 
The  pulse  never  rose  above  90  and  the  temperature  remained  normal. 
Recovery  was  slow,  extending  over  several  weeks  and  even  months.  In 
the  fatal  cases  collapse,  dyspnoea,  coma,  or  wild  delirium,  were  observed 
shortly  before  death.  Autopsy  showed  a  marked  hypersemia  of  the  or- 
gans and  fatty  degeneration  of  the  liver. 

The  B.  bohdinus  was  isolated  from  the  spleen  of  one  of  the  patients. 
The  same  organism  was  found  in  large  numbers,  thoiigh  irregularly 
distributed,  in  the  poisonous  ham.  It  was  also  obtained  from  the  or- 
gans of  animals  inoculated  with  suspensions  of  the  latter.  Van  Ermen- 
gem  showed  that  the  organism  was  essentially  a  saprophyte  and  incapable 
of  multiplying  to  any  extent  in  the  body.  The  symptoms,  therefore,  are 
not  those  of  an  infection  but  rather  of  an  intoxication,  due  to  the  intro- 
duction of  the  toxin  produced  by  the  germ  in  the  meat,  or  culture. 

The  ham  which  produced  such  marked  effects  in  man  was  also  very 
poisonous  to  smaller  animals.  Rabbits  were  found  to  be  particularly 
susceptible  and  0 . 5  Cc.  was  sufficient  to  cause  death  in  from  six  to  ten 
hours;  while  even  0.001  Cc.  per  kilogram  weight  was  fatal.  Assuming 
that  man  possessed  the  same  susceptibility  as  the  rabbit,  the  calculated 
fatal  dose  for  a  full-grown  person  was  0.03  mg.  When  this  amount  is 
compared  with  the  fatal  dose  of  a  purified  tetanus  toxin,  which  Brieger 
and  Fraenkel  estimated  to  be  0.13  mg.  for  an  average  man,  it  will  be 
seen  that  the  toxin  of  B.  botuhnus  is  not  inferior  to  the  latter.    The  toxin, 


FOOD  POISONS  235 

Or  active  poison,  in  the  ham  was  soluble  in  water  and  could  be  readily 
filtered  through  porcelain.  Like  the  toxins  of  diphtheria  and  tetanus, 
it  is  gradually  destroyed  by  light  and  heat;  on  exjjosure  of  the  solution 
at  70°  C.  for  an  hour,  the  toxicity  was  markedly  weakened,  and  at  100° 
it  was  promptly  destroyed.  The  toxin  dialyzed  rather  slowly  and  re- 
sisted putrefaction.  Acids  appeared  to  have  no  effect,  while,  on  the 
other  hand,  the  addition  of  sodium  hydrate  destroyed  it  in  a  few  minutes. 
The  toxin  is  insoluble  in  alcohol  and  in  ether;  like  that  of  tetanus,  it 
is  fixed  by  brain  tissue;  that  is,  a  mixture  of  the  two  can  be  injected 
without  causing  ill  effects.  By  injecting  the  toxin  subcutaneously  into 
goats,  Kempner  was  able  to  produce  active  immunity.  Moreover,  the 
serum  of  the  immunized  goats  possessed  marked  antitoxic  properties, 
both  as  a  preventive  and  as  a  curative  agent.  The  experiments,  how- 
ever, were  limited  to  animals  such  as  cats  and  guinea-pigs. 

Decomposed  Meats.— While  botulism  as  just  described,  stiictly 
speaking,  is  included  under  this  head,  still  it  seems  best  for  the  present  to 
reserve  this  designation  for  the  more  common  decompositions  of  meat 
which  in  the  beginning  was  perfectly  wholesome  and  did  not  come  from 
a  diseased  animal.  In  the  ordinary  putrefaction  of  animal  foods,  poison- 
ous products  are  not  necessarily  formed,  as  is  seen  from  the  relative 
absence  of  ill  effects  after  eating  "high"  game,  cheese,  and  the  like.  The 
custom  of  eating  fermented,  in  reality  thoroughly  putrid  fish,  described 
by  Morner  for  Norway,  holds  true  for  many  parts  of  the  world.  Actual 
poisoning  from  such  decomposed  foods  is  of  very  rare  occurrence. 

The  bacteria  which  have  been  noted  in  connection  with  such  poison- 
ings are  of  the  Proteus  vulgaris  and  B.  coli  type.  The  part  played  by 
the  Proteus  in  fish  poisoning  has  been  discussed.  Levy,  in  1894,  iso- 
lated a  Proteus  vulgaris  from  the  vomited  matter,  stools,  and  from  an 
ice-chest  in  which  the  infected  food  was  kept.  A  larger  outbreak  was 
studied  by  Wesenberg,  in  1897,  in  which  sixty-three  persons  were  affected 
by  eating  the  meat  from  a  cow  which  was  slaughtered  on  account  of 
illness.  From  the  more  or  less  decayed  meat  he  isolated  Proteus  vul- 
garis. Silberschmidt  obtained  from  a  poisonous  sausage,  in  1899,  cul- 
tures of  B.  coli  and  Proteus  vulgaris.  The  following  year  Pfuhl  examined 
a  "beef  sausage"  which  apparently  was  responsible  for  the  illness  of 
eighty-one  soldiers.  From  this  material,  cultures  of  Proteus  mirabilis 
were  obtained.  Schumburg  also  obtained  from  a  sausage  a  Proteus 
culture.  The  sausage  itself  was  poisonous  to  rats  and  mice  on  feeding; 
so  also  was  meat  infected  with  the  isolated  culture. 

Obviously  the  decomposition  of  meat  products  may  be  induced  by 
other  kinds  of  bacteria.  Thus  in  a  recent  instance  in  Michigan  about 
fifteen  persons  became  seriously  ill  from  eating  poorly  cured  bacon. 
An  examination  by  the  author  showed  that  the  meat  was  permeated  by 
a  large  coccus  which  was  highly  toxicogenic  to  animals. 

Diseased  Meat. — ^Under  this  head  will  be  considered  those  intoxica- 
tions which  are  due  to  the  eating  of  meat  derived  from  a  diseased  animal. 
They  constitute  by  far  the  most  common  form  of  meat  poisoning  and  are 
characterized  by  more  or  less  severe  symptoms  of  gastro-enteritis.  The 
causative  agent  may  be  said  to  be  any  one  of  a  group  of  related  organisms 
which  show  close  affinity  on  the  one  hand  for  the  colon  bacillus,  and  on 
the  other  for  the  hog-cholera  bacillus.    In  other  words,  these  intoxica- 


236  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

tions  represent  a  group  of  closely  allied  diseases  which  it  is  difficult  to 
differentiate  one  from  another. 

The  symptoms  may  come  on  at  once,  but  are  usually  delayed  for  six  to 
twelve  hours.  -Nausea,  vomiting,  colicky  pains,  profuse  diarrhoea,  and 
prostration  are  nearly  always  present.  At  times  there  is  erythema  and 
urticaria  followed  by  des([uamation,  especially  of  the  palms  and  soles. 
Albuminuria  and  catarrhal  pneumonia  are  also  met  with.  The  mortality 
is  much  less  than  that  of  botulism.  Autopsy  usually  shows  marked 
gastro-enteritis  of  a  hemorrhagic  nature,  an  enlarged  spleen,  and  con- 
gested organs. 

Infections  of  this  kind  have  followed  the  use  of  divers  meats,  especially 
beef,  veal,  pork,  and  horse-flesh.  The  use  of  chopped  or  minced  meat, 
sausages,  pork-pies  and  the  like,  is  more  often  followed  by  poisoning  than 
is  the  use  of  the  whole  meat,  for  the  reason  that  the  method  of  manipula- 
tion ensures  the  thorough  dissemination  of  the  organisms  through  the 
mass.  In  such  cases  the  animals  are  often  suffering  from  a  septicsemia  of 
puerperal  or  traumatic  origin,  or  from  intestinal  infections.  The  ill 
effects  usually  follow  the  eating  of  raw  or  imjierfectly  cooked  food.  In 
some  instances,  however,  even  when  the  food  was  thoroughly  cooked 
intoxication  resulted  owing  to  the  presence  of  poisonous  products  which 
were  not  destroyed  by  heat.  The  common  impression  that  boiling  will 
destroy  the  poisonous  properties  which  a  food  may  have  acquired  does 
not  always  hold  good,  as  has  already  been  shown  under  mussel  poisoning. 

Although  poisoning  from  meats  was  noticed  at  an  early  date  and  fre- 
quent attention  called  to  it,  an  exact  inquiry  was  possible  only  after  the 
methods  of  bacteriological  study  had  been  perfected.  The  first  attempt 
to  work  along  the  new  lines  was  made  by  Gaffky  and  Paak,  in  1885,  in 
connection  with  poisoning  caused  by  sausage  made  from  horse-flesh. 
More  than  eighty  persons  developed  gastro-enteritis  and  one  death 
resulted.  The  evidence  indicated  that  the  horse  was  diseased.  Moreover, 
the  sausage  w^as  prepared  in  a  most  careless  manner,  since  the  unused 
portions  were  found  to  be  in  an  advanced  state  of  decomposition.  Macer- 
ations of  the  sausage  caused  death  when  injected  into  mice,  guinea-pigs, 
and  rabbits,  and  from  these  they  isolated  a  bacillus  which  was  closely 
related  to  the  colon  bacillus.  It  differed  from  the  latter  in  not  producing 
indol  and  in  not  coagulating  milk,  in  which  respect  it  resembled  Gartner's 
bacillus,  if  not  identical  with  the  latter.  It  was  eventually  named  B. 
jriedehcrgensis  by  Kruse.  The  fact  that  the  pure  cultures  when  fed  to 
animals,  or  w^hen  injected,  caused  death,  led  Gaffky  and  Paak  to  consider 
it  as  the  specific  cause  of  the  poisoning,  although  its  presence  in  the 
persons  afflicted  was  not  demonstrated. 

Another  colon-like  organism,  designated  as  B.  viorbificans  bovis,  w^as 
isolated  by  Basenau,  in  1893,  from  the  meat  of  a  cow  w^hich  was  slaugh- 
tered while  suffering  from  puerperal  septicsemia.  I^ater  on,  he  cultivated 
this  same  organism  from  the  flesh  of  animals  having  perforative  peritonitis, 
puerperal  paralysis,  and  chronic  pyaemia.  This  bacillus,  which  is  highly 
infectious  to  animals,  has  since  been  studied  by  other  workers  and  shown 
to  be  related  to  the  other  bacilli  causing  intoxication. 

A  similar  and  very  interesting  observation  of  Levy  and  Jacobsthal  may 
be  mentioned  at  this  point.  In  an  apparently  normal  cow  the  spleen  was 
found  to  have  a  large  abscess,  and  smaller  ones  were  present  in  the  liver. 


FOOD  POISONS  237 

They  isolated  from  the  pus  a  germ  which  the  cultural  and  agglutination 
.tests  showed  to  be  the  ty])hoid  bacillus.  This  is  of  importance,  showing 
as  it  does  the  possible  origin  of  sporadic  cases  of  the  disease.  The  part 
played  by  meat  in  the  causation  of  paratyphoid  infections  is  at  present 
well  recognized. 

Of  especial  interest  is  the  food  epidemic  which  occurred  in  1888,  in 
Frankenhausen.  The  source  of  the  infection  was  a  cow  which  was 
slaughtered  on  account  of  a  severe  enteritis.  All  told,  fifty-seven  persons 
became  ill  from  eating  of  the  meat.  Some  of  these  ate  it  raw,  while  most 
of  them  had  it  boiled  or  roasted;  three  partook  only  of  the  broth.  The 
symptoms  were  those  of  a  severe  gastro-enteritis  followed  by  desquama- 
tion. Convalescence  was  long,  in  the  severe  cases  lasting  for  two  to  four 
weeks.  Only  one  person,  who  had  eaten  a  large  amount  of  the  raw  meat, 
died.  He  was  nursed  by  his  mother  who  later  developed  the  same  symp- 
toms, probably  as  a  result  of  infection  from  the  discharges.  Gartner 
cultivated  from  the  spleen  of  the  fatal  case,  also  from  the  flesh  and  intes- 
tines of  the  cow,  an  organism  which  he  named  B.  enteritidis.  This 
organism  resembles  the  colon  bacillus  in  many  respects.  On  feeding,  it 
proved  pathogenic  for  mice,  guinea-pigs,  and  a  goat.  On  injection,  it 
was  more  fatal  to  rabbits,  pigeons,  and  a  canary,  but  not  to  dogs,  cats, 
chickens,  and  sparrows.  The  injection  of  cultures  sterilized  by  heat 
produced  the  same  effects  as  did  the  feeding  of  such  cultures  to  the 
susceptible  animals. 

This  resistance  of  the  toxin  of  B.  enteritidis  to  boiling  is  a  striking 
property,  and  suggests  the  like  behavior  of  the  products  of  the  tubercle 
bacillus.  The  heat-resisting  intracellular  toxin  of  the  colon  bacillus 
studied  by  Vaughan,  affords  another  illustration  on  this  point. 

In  the  following  year  Gartner  found  a  similar  organism  in  another  out- 
break of  food  poisoning  at  Cotta,  near  Dresden.  The  meat  in  this  case 
came  from  a  cow  suffering  from  an  inflamed  udder.  There  were  136 
'  persons  affected,  and  of  these  4  died;  apparently  all  had  partaken  of 
the  raw  meat.  Cultures  were  obtained  from  the  cow  and  from  the  bodies 
of  2  of  the  dead  persons,  and,  though  they  resembled  the  B.  enteritidis 
morphologically,  they  differed  in  being  non-poisonous.  Moreover,  the 
flesh  of  the  cow  lost  its  poisonous  property  when  cooked. 

Gartner's  bacillus  attracted  considerable  attention  and  numerous 
workers  have  since  then  found  the  same  or  a  very  closely  related  organism. 

An  apparently  typical  B.  enteritidis  was  obtained  by  Van  Ermengem 
in  1891  from  the  outbreak  at  Morseele,  Belgium,  in  which  80  persons 
were  affected,  of  whom  4  died.  The  flesh  was  derived  from  two  calves 
which  had  a  severe  enteritis;  one  died  and  the  other  was  slaughtered. 
As  in  Gartner's  case,  the  meat  was  eaten  in  a  boiled  or  roasted  condition, 
though  the  isolation  of  the  germ  from  the  liver,  spleen,  and  intestinal 
contents  of  one  of  the  dead,  would  indicate  that  the  heat  was  not  sufficient 
to  sterilize  the  food.  An  identical  organism  was  obtained  from  the  bone- 
marrow  of  one  of  the  calves.  Feeding  or  injection  of  the  cultures  in  mice, 
rabbits,  guinea-pigs,  and  calves,  produced  severe  and  fatal  infection. 
A  monkey  developed  typical  cholera  nostras,  but  recovered.  Although 
there  were  minor  cultural  differences,  Van  Ermengem  held  that  it  was 
the  same  as  the  enteritidis  bacillus  of  Gartner,  a  view  which  has  been 
confirmed  by  the  subsequent  studies  on  agglutination. 


238  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

In  1892,  Pools  and  Dhont  investigated  a  poisoning  at  Rotterdam,  where 
92  persons  became  ill  after  eating  the  flesh  of  an  apparently  normal  cow. 
The  bacillus  isolated  formed   colonies  which  resembled  those  of  the 
typhoid  bacillus;  like  the  latter  it  did  not  ferment  lactose.    The  sterilized 
cultures  were  poiso.nous  and  the  living  ones  were  pathogenic  for  mice, 
rabbits,  and  guinea-pigs.    A  cow  which  received  an  intravenous  injection 
of  a  culture  was  killed  twenty  minutes  later,  and  some  of  the  meat  after 
being  kept  for  three  days  at  a  low  temperature  was  eaten  by  53  persons. 
Of  these,  15  had  in  a  short  time  headache,  colic,  and  diarrhoea.    In  the 
same  year,  Fischer  obtained  an  apparently  true  B.  enleriiidis  from  a  food 
poisoning  at  Rumlieth.    The  same  organism  was  also  obtained  by  him 
from  meat  which  caused  poisoning  at  Haustedt  in   1895.     This  was 
derived  from  an  ox  which  was  killed  after  suffering  for  two  days  with  diar- 
rhoea and  fever.    Of  more  than  50  people  who  ate  of  the  meat,  chiefly  in 
the  boiled  condition,  27  became  ill  with  severe  gastro-enteritis.    Recovery 
took  place  in  from  three  to  eight  days.    The  following  year  Fischer  again 
met  with  B.  enteritidis  in  the  spleen  of  a  cow  which  had  an  inflamed  udder. 
The  food  poisoning  which  occurred  at  Breslau,  in  1893,  also  furnished 
a  related  organism.     The  meat  was  derived  from  a  cow  which  was 
slaughtered  on  account  of  a  febrile  diarrhoea,  and,  although  condemned, 
was  stolen  and  sold  as  chopped  meat.    As  a  result  of  eating  the  raw  meat 
80  persons  became  ill  in  from  three  to  sixteen  hours  and,   although 
none  died,  recovery  was  slow.     Dizziness,  vomiting,  fever,  and  herpes, 
were  noted.    Kaensche  isolated,  from  the  meat  and  from  infected  mice,  an 
organism  {B.  Breslaviensis)  which  was  apparently  identical  with  that 
found  by  Van  Ermengem  in  the  Morseele  outbreak.    The  toxicity  of  the 
cultures  was  not  affected  by  boiling.     Johne,  in  1894,  isolated  another 
enteritidis-like  organism  from  a  poisoning  in  Saxony.     Scheef  obtained 
apparently  the  same  bacillus,  in  1896,  from  sausage  which  affected  about 
150  people. 

An  interesting  case  of  poisoning  at  Ghent,  in  1895,  was  studied  by  Van 
Ermengem.  A  sausage  made  of  pork  and  beef  was  examined  by  an 
inspector,  who,  on  account  of  its  fresh  appearance,  pronounced  it  un- 
objectionable. He  himself  ate  of  the  raw  sausage  and  others  followed 
the  example.  They  all  became  sick  and  the  inspector  died  in  five  days. 
The  animals  furnishing  the  meat  were  not  known  to  be  sick.  Cultures 
made  from  the  sausage  and  from  the  organs  of  the  dead  showed  a  bacillus 
which  could  not  be  distinguished  from  the  B.  cnieriiidis  or  from  that  of 
INIorseele  or  Breslau.  At  the  same  time  Van  Ermengem  called  attention 
to  the  similarity  which  existed  between  these  organisms  and  that  of  the 
hog-cholera  group,  a  fact  which  subsequent  investigations  have  fully 
demonstrated. 

A  further  instance  of  poisoning  from  pork  sausage  occurred  at  Posen,  in 
1896,  and  cultures  were  obtained  from  a  fatal  case  by  Giinther.  The 
bacillus  differed  from  that  of  Gartner  in  minor  points  only.  In  the  same 
year  Silberschmidt  studied  a  Swiss  outbreak  caused  by  pork  which  came 
from  diseased  animals.  The  bacillus  isolated  was  related  to  B.  enteritidis 
and  of  hog  cholera,  and  for  that  reason  he  inclined  to  the  view  that  the 
flesh  of  animals  sick  of  hog  cholera  could  cause  food  poisoning.  Pouchet 
also,  in  1879,  described  a  hog-cholera  bacillus  as  the  cause  of  a  poisoning 
which  developed  and  involved  forty-eight  persons. 


FOOD  POISONS  239 

Since  1898  the  agglutination  test  has  been  used  in  identifying  the  causa- 
tive organism  in  food  poisonings.  Thus,  in  an  outbreak  of  gastro-enteritis 
at  Aertryck,  in  Belgium,  de  Nobele  isolated  an  organism  which  aggluti- 
nated with  the  serum  of  the  sick  persons  even  in  a  dilution  of  one  to  four 
hundred.  The  sera  from  other  diseases  and  from  normal  persons  had  no 
agglutinating  action  on  this  bacillus.  Unlike  ty})hoid  serum  which  re- 
tains its  agglutinating  action  for  a  very  long  time,  the  sera  of  the  poisoned 
persons  lost  their  agglutinating  power  in  a  few  weeks.  Such  sera  also 
agglutinated  typhoid  bacilli  more  readily  than  does  normal  serum.  The 
sera,  however,  agglutinated  in  greater  dilution  (Aertryck)  than  the  typhoid 
or  enteritidis  bacilli.  The  same  author,  in  1899,  studied  another  case  of 
poisoning  at  Brugge,  caused  by  pork  sausage.  The  serum  from  the 
affected  persons  agglutinated  the  bacillus  isolated  from  the  meat  in  even 
as  high  a  dilution  as  1  to  500,  but  it  had  no  effect  on  the  Aertryck  bacillus. 
The  Gartner  bacillus,  however,  was  agglutinated  by  the  sera,  but  not  to 
the  same  extent  as  the  bacillus  isolated.  Still  more  recently,  de  Nobele 
has  succeeded  in  isolating  essentially  the  same  bacillus  from  the  organs 
of  persons  who  died  at  Brussels  and  Willebroek,  after  eating  smoked 
horse-meat. 

In  England,  the  first  application  of  the  agglutination  test  in  the  study 
of  these  organisms  was  made  in  1898,  by  Durham,  who  had  occasion  to 
investigate  four  outbreaks  of  gastro-enteritis.  In  the  first  of  these,  at 
Hatton,  185  persons  were  affected  but  the  cause  was  not  traced  to  meat 
of  diseased  animals.  From  the  liver  of  a  fatal  case  he  obtained  a  bacillus 
which  was  agglutinated  by  the  sera  of  the  sick  in  varying  dilutions,  in 
some  even  as  high  as  1  to  1000.  The  sera  also  agglutinated  the  typhoid 
bacillus  in  greater  dilution  than  did  normal  serum.  The  Giinther  bacillus, 
and  one  from  a  Vienna  case  of  poisoning,  were  agglutinated  to  about  the 
same  extent,  whereas  the  B.  enteritidis  was  not  clumped  except  by  fairly 
concentrated  sera.  By  making  these  tests  upon  different  organisms, 
Durham  was  able  to  show  that  the  epidemic  was  associated  with,  and 
probably  due  to,  a  variety  of  the  B.  enteritidis.  In  the  three  other  out- 
breaks studied  by  him  the  organism  was  not  isolated,  but  from  the  be- 
havior of  the  sera  of  the  sick  to  various  bacteria  it  was  made  clear  that 
the  cause  was  essentially  the  same,  that  is,  a  variety  of  the  enteritidis 
bacillus.  That  a  meat  infection  was  responsible,  was  particularly 
shown  at  Chatterton  where  veal  pies  were  the  undoubted  cause  of  the 
illness  of  57  or  more  persons,  1  of  whom  died. 

In  the  Derby  outbreak  (1902),  the  cause  was  traced  to  the  eating  of  pork 
pies.  As  at  Chatterton,  no  complaint  was  made  as  to  the  taste  or  ap- 
pearance of  the  pies.  Furthermore,  the  more  severe  cases  resulted  from 
the  eating  of  pies  which  had  been  kept  several  days,  showing  that  the 
organisms,  at  first  probably  present  in  small  numbers,  in  the  interval  had 
multiplied  appreciably.  About  210  persons  became  ill  in  Derby  and  its 
neighborhood  and  at  least  4  deaths  occurred.  From  the  organs  and 
intestines  of  two  of  the  cases  Delepine  isolated  the  B .enteritidis derhiensis. 
This  was  said  to  resemble  more  closely  the  bacillus  of  Gaffky  and  Paak 
than  that  of  Gartner.  The  agglutination  of  this  bacillus  by  the  sera  of  the 
sick  persons  served  to  establish  its  causal  relation  to  the  epidemic.  The 
evidence  seemed  to  show  that  the  hog  was  not  sick  and  that  the  infection 
Was  of  excretal  origin. 


240  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

Another  well  studied  case  of  food  poisoning  is  that  whicli  occurred  at 
Neunkirchen,  in  1903.  Over  30  persons  developed  a  non-febrile  gastro- 
enteritis and  3  died.  Frwn  the  horse-fiesh  whieh  was  used  as  food  and 
from  the  organs  of  2  of  the  fatal  cases,  Drigalski  isolated  a  baeillus 
belonging  to  this  same  group.  The  serum  of  the  sick  rapidly  agglutinated 
this  bacillus  and  that  of  Gartner,  and,  to  a  less  extent,  typhoid  and 
paratyphoid  bacilli.  On  about  the  eighth  day,  all  the  sera  reacted  in  a 
dilution  of  about  1  to  400  and  one  even  in  1  to  4,000.  Even  the  serum  of  a 
dog  that  ate  the  lungs  of  the  horse  and  later  developed  j)rofuse  diarrhoea, 
agglutinated  the  bacillus  in  1  to  100.  The  sera  of  normal  persons  had  no 
such  effect.  He  confirmed  de  Nobele's  observation  regarding  the  rapid 
loss  of  the  s])ecific  agglutinating  power.  Thus,  the  maximum  strength 
was  reached  in  about  ten  tlays,  while  in  about  three  weeks  it  had  fallen  to 
less  than  1  to  100.  The  bacillus  was  shown  to  give  rise  to  heat-resisting 
products;   that  is  to  say,  boiled  cultures  proved  fatal  to  animals. 

From  a  similar  case  of  horse-meat  poisoning  at  Diisseldorf,  in  1901, 
in  which  57  persons  became  sick  and  1  died,  Trautmann  was  able 
to  isolate  a  bacillus.  This  was  obtained  only  from  the  s]:)leen  of  the  child. 
There  was  no  reason  to  believe  that  the  meat  was  derived  from  a  sick 
horse,  and,  on  the  contrary,  the  evidence  showed  gross  lack  of  cleanliness 
so  that  excretal  contamination  was  quite  probable. 

In  the  majority  of  the  cases  of  food  poisoning  mentioned,  the  fact  that 
the  food  was  derived  from  diseased  animals  was  established.  In  some 
instances,  as  where  the  food  was  thoroughly  boiled,  the  ill  effects  were 
those  of  a  plain  intoxication  due  to  poisonous  heat-resisting  products.  In 
the  majority  of  instances,  however,  the  food  was  eaten  raw  or  incompletely 
cooked,  and,  as  a  result,  true  infection  with  the  specific  bacillus  occurred. 
The  relation  of  the  different  organisms  which  have  been  isolated  from 
such  outbreaks  is  important.  In  general  they  may  be  said  to  belong  to 
the  colon-typhoid  group.  Culturally  and  morphologically  they  offer  very 
slight  or  no  means  of  differentiation.  For  that  reason  they  have  all  come 
to  be  regarded  as  varieties  of  the  B.  enieritidis.  With  the  introduction  of 
the  serum  reaction  it  became  possible  to  draw  the  lines  more  closely  and 
to  establish  degrees  of  relationship,  not  only  among  the  bacilli  of  this 
group  but  also  with  typhoid,  paratyphoid,  and  hog-cholera  bacilli. 

The  serum  of  t}q3hoid  fever  agglutinates  Gartner's  bacillus  almost  as 
readily  as  the  typhoid  bacillus,  which  fact  shows  that  a  certain  kinship 
exists  between  these  organisms.  On  the  other  hand  a  typhoid  serum  of 
very  high  potency,  obtained  by  artificial  inmiunization,  will  distinguish 
with  certainty  between  the  two  bacilli.  Mention  should  be  also  made  of 
the  fact  that  the  serum  of  animals  immunized  to  the  B.  enieritidis  agglu- 
tinates the  typhoid  bacillus  though  in  less  dilution  than  its  own  kind; 
moreover,  it  has  no  action  whatever  on  the  colon  bacillus- 
Especial  importance  attaches  to  the  relation  of  this  and  the  paratyphoid 
group  of  bacilli.  Schottmiiller's  two  types  of  the  paratyphoid  bacilli, 
designated  by  Kayser  as  A  and  B,  present  about  the  same  variation  with 
reference  to  the  agglutination  test  as  do  the  several  iy\)QS,  of  bacteria 
from  poisonous  meat.  Thus,  the  serum  obtained  with  type  B,  as  shown 
by  Drigalski  and  by  Trautmann,  readily  agglutinated  the  bacilli  from  the 
Aertryck,  Breslau,  Diisseldorf,  Neunkirchen,  and  Posen  epidemics,  and 
had  much  less  action  on  the  Brugge,  Ghent  and  Rumfleth  bacilli  repre- 


FOOD  POISONS  241 

sented  by  that  of  Gartner.  It  would  appear  that  paratyphoid  infec- 
tions are  essentially  the  same  in  kind  as  the  typical  meat  infections; 
and  Trautmann,  as  a  result  of  his  agglutination  tests,  would  recognize 
several  varieties  of  the  B.  paratyphosus: 

a — enteritiditis,  represented  by  Frankenhausen,  Morseele,  Plaustedt 
and  Hamburg. 

b — Breslaviensis,    represented    by   Breslau,    Posen,    Diisseldorf    and 
Giessen. 

c — Hamburgensis,  represented  by  Schottmiiller's  type  B. 

d — Strassburgensis,  represented  by  Schottmiiller's  type  A. 

e — morbificans  of  Basenau. 
The  probability  of  meat  being  the  conveyor  of  the  paratyphoid  infection 
has  been  pointed  out  by  Fischer.    It  is  of  interest  to  note  that  the  several 
rat  plague  bacilli  behave  the  same  as  the  Aertryck  and  paratyphoid  B 
organisms  with  reference  to  the  agglutination  test. 

The  classification  of  Trautmann  is  practically  the  same,  as  concerns  the 
meat  bacteria,  as  that  which  de  Nobele  had  worked  out  several  years 
before.  From  the  behavior  of  the  different  bacilli  toward  very  active 
agglutinating  sera  he  divided  them  into  two  groups:  Bacillus  enteritidis 
and  Bacillus  Aertryck.  The  latter  might  also  be  called  the  hog-cholera 
type,  since  the  two  organisms  react  in  the  same  way  to  sera.  It  is  of 
interest  to  note  that  Fischer  arrived  at  much  the  same  grouping  of  the 
bacteria  studied  by  him.  On  the  other  hand,  Drigalski  recognized  that 
wholly  unequivocal  results  could  not  be  obtained  even  by  the  biological 
method  of  identification.  While  classifying  some  of  the  bacteria  the 
same  as  de  Nobele  and  Fischer,  he  brought  together  the  Gartner,  Breslau, 
and  Aertryck  bacilli.  The  explanation  of  this  error,  if  such  it  be,  perhaps 
lies  in  the  fact  that  he  employed  relatively  weak  sera  for  his  tests.  A  more 
active  serum  would  probably  have  shown  differences,  as  in  the  case  of 
very  potent  typhoid  serum  in  its  behavior  to  typhoid  and  enteritidis 
bacilli.  The  origin  of  his  Gartner  bacillus,  on  account  of  this  discrepancy, 
may  be  open  to  question. 

POISONOUS  MILK  AND  ITS  PRODUCTS. 

Of  all  the  articles  of  food,  milk  unquestionably  is  most  subject  to 
bacterial  contamination,  and,  for  that  reason,  it  is  a  most  prolific  cause 
not  only  of  acute  poisonings  but  also  of  real  infections.  The  fact  that 
milk  is  used  to  a  large  extent  in  a  raw  state  accounts  for  all  such  acci- 
dents. Certainly,  instances  of  poisoning  from  boiled  milk  are  wholly 
unknown. 

Injurious  bacteria  present  in  the  milk  may  be  derived  from  various 
sources.  They  may  come  directly  from  the  diseased  animal,  as  in  tuber- 
culosis; or  be  introduced  either  by  the  addition  of  impure  water,  or  of 
excretal  and  other  infected  matter.  It  is  unnecessary  to  consider  these 
conditions  at  length,  since  in  a  sense  they  do  not  come  under  the  ordinary 
meaning  of  the  term  poisonous  milk.  And  yet,  even  a  passing  mention 
must  be  given  to  the  part  played  by  milk  in  the  transmission  of  several 
diseases — for  example,  diphtheria  and  scarlet  fever.  Similarly,  several 
epidemics  of  typhoid  fever  have  been  traced  directly  to  its  use.    Above 

16 


242  DISEASES  CAUSED    BY  ORGANIC  AGENTS 

all  else,  the  milk  bacteria  are  responsible  for  most  of  the  gastro-intestinal 
disorders  met  with  during  the  summer  months,  especially  among  in- 
fants; whereas  the  choleraic  conditions  observed  among  the  older  people 
can  be  traced  with  equal  certainty  to  the  use  of  other  contaminated  foods, 
particularly  meats. 

Apart  from  the  real  infections  which  have  been  noted,  acute  intoxi- 
cations not  infrequently  occur.  In  such  instances,  the  bacteria  present 
give  rise  to  active  j)oisonous  ])ro(lucts  of  which  but  little  is  known. 
The  poisonous  ptomain  which  Vaughan  first  obtained  from  cheese  has 
been  found  in  milk  on  several  occasions.  It  must  not  be  sii])posed  that 
in  every  milk  poisoning  the  active  agent  is  tyrotoxicon,  for  such  is  clearly 
not  the  case.  Milk  may  harbor  a  large  number  of  different  bacteria, 
and  each  of  these  will  form  its  own  characteristic  toxin.  Among  the 
organisms  which  have  been  studied  may  be  mentioned  the  virulent  colon- 
like bacilli,  the  B.  cnieriiidis  and  the  B.  cnicritidis  sporognics  of  Klein. 
It  Mill  be  seen  that  essentially  the  same  organisms  are  found  in  toxic 
milk  as  are  noted  in  poisonous  meat.  When  such  toxicogenic  bacteria 
are  once  introduced  into  milk  there  is  but  one  further  condition  neces- 
sary and  that  is  a  temperature  suitable  for  their  development.  The 
warm  weather  of  summer  is  therefore  particularly  favorable  to  the  forma- 
tion of  poisonous  products  in  milk. 

The  usual  result  of  the  growth  of  bacteria  in  milk  is  to  cause  it  to 
sour.  It  is  worthy  of  note  that  acute  poisoning  from  sour  milk  is  rather 
rare,  while  that  from  milk  which  shows  no  apparent  change,  in  other 
words,  one  which  has  an  alkaline  or  amphoteric  reaction,  is  frequent. 
This  is  in  accord  with  the  known  behavior  of  the  enteritidis  group  of 
bacilli  in  milk  which  is  not  coagulated  but  rendered  somewhat  trans- 
parent. 

In  much  the  same  w^ay  that  chopped  meats  and  sausages  are  partic- 
ularly prone  to  become  poisonous,  it  is  obvious  that  preparations  made 
from  milk,  such  as  ice-cream,  frozen  custards,  and  cream  puffs,  may  be- 
come injurious  though  the  original  milk  was  not.  A  few  hours  of  keep- 
ing under  favorable  conditions  of  temperature  may  so  force  the  growth 
of  the  few  bacteria  originally  present  that  the  final  product  may  be  decid- 
edly noxious.  The  popular  notion  that  such  intoxications  are  due  to  the 
presence  of  metals  or  of  injurious  flavoring  extracts  has  no  basis  in  fact. 

The  one  product  of  milk  which  is  most  prone  to  cause  poisoning  is 
cheese.  In  fact  cheese  poisoning  or  tyrotoxismus  claimed  the  atten- 
tion of  the  early  chemists  as  much  as  botulism  or  sausage  poisoning. 
Various  theories  were  propovmded,  but  no  satisfactory  explanation  was 
possible  without  a  recognition  of  the  part  played  by  bacteria.  The  acci- 
dental introduction  of  toxicogenic  bacteria,  and  their  subsequent  growth 
under  favorable  conditions,  readily  account  for  the  phenomena  observed. 
Inasmuch  as  different  bacteria  may  take  part  in  such  changes  it  follows 
that  different  poisonous  products  may  be  met  with,  depending  upon  the 
organism  at  work.  Our  knowledge  of  these  bacteria  is  far  from  being  as 
satisfactory  as  might  be  desired.  It  has  been  shown  by  Vaughan  and 
McClymonds  that  nearly  all  cheese  contains  poison-producing  bacteria. 
Thus,  the  cultures  from  forty-nine  samples  of  cheese  were  found  to  be 
pathogenic  for  white  rats,  rabbits,  and  guinea-pigs.  The  colon  group 
was  particularly  well  represented. 


FOOD  POISONS  243 

The  poisonous  ptomain  Tyrotoxicon,  discovered  by  Vaughan,  was  the 
first  definite  product  of  this  Idnd  obtained  from  such  cheese.  More 
recently,  Le  Pierre  obtained  another  basic  substance,  which,  however, 
was  not  toxic.  Without  doubt  other  poisonous  products  are  present,  as 
in  the  case  of  other  types  of  food  poisoning  and  in  real  infections.  The 
study  of  such  toxins,  as  well  as  of  the  bacteria  to  which  they  owe  their 
origin,  belongs  to  the  future. 


POISONOUS  VEGETABLES. 

The  highly  nitrogenous  animal  products  are  particularly  prone  to 
undergo  those  alterations  which  render  them  dangerous  to  the  con- 
sumer. Similar  changes,  however,  may  occur  in  vegetable  products, 
though  much  less  frequently,  and,  as  a  result,  poisonous  bacterial  sub- 
stances of  different  kinds  may  result.  It  has  been  shown  that  the  same 
organisms  which  cause  meat  to  be  poisonous  may  give  rise  to  exactly 
the  same  effects  when  they  are  introduced  into  vegetable  food.  The 
richer  such  material  is  in  nitrogen,  the  more  likely  is  it  to  give  rise  to 
poison  production,  and,  on  the  other  hand,  with  a  large  amount  of 
sugars  or  carbohydrates  the  formation  of  such  products  is  retarded,  if 
not  suppressed.  A  well  known  illustration  of  this  fact  is  afforded  by 
the  diphtheria  bacillus,  which  produces  a  maximum  of  toxin  when  grown 
on  sugar-free  media.  As  a  further  instance  may  be  mentioned  the 
changes  which  occur  in  whey  and  in  whey  proteids.  In  the  former,  as 
in  normal  milk,  bacterial  action  is  evidenced  by  a  typical  fermentation 
in  which  the  sugar  present  is  the  chief  substance  acted  upon,  and  conse- 
quently no  disagreeable  decomposition  products  of  proteids  form.  By 
contrast,  however,  a  solution  of  the  milk  proteids  alone- — or  what  is  the 
same  thing,  a  dialyzed  whey — will  undergo,  under  exactly  the  same 
conditions,  a  typical  putrefaction. 

Not  infrequently,  the  ill  effects  observed  in  connection  with  plant  food 
are  due  to  the  presence  of  metallic  poisons.  The  strong  acidity  of  many 
vegetables  may,  in  canned  goods,  cause  an  appreciable  solution  of  tin, 
lead,  and  zinc.  Ordinarily  the  amount  of  these  metals  thus  brought 
into  solution  is  small  and  rarely  plays  a  part  in  the  observed  intoxica- 
tion. Criminal  carelessness  or  ignorance  is  more  often  responsible  for 
the  presence  of  dangerous  quantities  of  metals  in  foods. 

A  third  type  of  poisoning  from  vegetable  foods  is  due  to  the  presence 
of  plants  which  are  in  and  of  themselves  poisonous.  Under  this  head 
will  fall  the  1'airly  well  known  ergot,  vetch  and  mushroom  intoxications. 
These  must  be  considered  in  the  briefest  manner  possible. 

Ergot  poisoning  is  practically  unknown  in  this  country,  but  in  Europe 
is  still  occasionally  met  with,  although  not  to  the  same  extent  as  in 
former  times.  The  condition  is  commonly  designated  as  ergot ismus  and 
its  cause  is  a  parasitic  fungus,  Claviceps  purpurea,  which  develops  in 
the  flowers  of  rye  and  other  grains.  From  ergot,  Kobert  was  able  to 
isolate  at  least  three  poisonous  substances,  sphacelinic  acid,  cornutin,  and 
ergotinin.  More  recent  investigations  have  made  it  probable  that  there 
are  other  substances  present  which  constitute  the  real  toxic  agent.  Thus, 
Jacoby  obtained  a  non-nitrogenous  resin,  sphacelotoxin,  w^hich  he  regards 


244  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

as  the  specific  poison.  The  intoxication  may  have  an  acute  or  chronic 
course  and  in  either  type  the  symptoms  may  be  nervous  or  convulsive, 
or  else  trophic  or  gangrenous  in  character. 

Vetch  poisoning,  or  laiJtijrismvs,  is  a  rather  rare  condition,  met  with  in 
some  parts  of  Europe,  notably  Austria  and  Italy,  in  northern  Africa  and 
in  India.  The  vetch  seed  is  used  in  the  form  of  flour  as  a  partial  sub- 
stitute for  that  of  wheat.  The  eating  of  bread  prepared  from  it  is  fol- 
lowed by  sudden  and  severe  pains  in  the  lumbar  region,  girdle  sensation, 
motor  paralyses  of  the  lower  extremities,  tremor  and  fever.  The  nature 
of  the  poison  is  not  known  but  it  is  probably  of  the  nature  of  a  toxal- 
bumose,  of  which  ricin  and  abrin,  the  poisons  of  the  castor  bean  and 
jequirity  seed  respectively,  are  well  known  examples. 

The  ill  effects  from  eating  mushrooms  are  due  to  mistaking  the  poison- 
ous for  the  edible  species.  One  species  of  the  former  contains  the  highly 
toxic  alkaloid  muscarin  which,  with  other  poisonous  constituents,  is 
responsible  for  the  symptoms  induced. 

A  most  unusual  and  severe  form  of  poisoning  from  vegetable  food 
occurred  at  Darmstadt,  where  of  twenty-one  persons  who  ate  of  a  bean 
salad,  eleven  died.  The  canned  beans  when  opened  had  a  peculiar  odor 
but  showed  no  marked  decomposition.  The  symptoms,  as  reported  by 
Landmann,  came  on  twenty-four  to  thirty-six  hours  after  eating.  Visual 
disturbances  such  as  mydriasis,  strabismus,  and  ptosis,  were  the  first  to 
appear.  Then  followed  difficult  deglutition  and  bilateral  paralyses. 
The  pulse  became  greatly  increased,  respiration  superficial,  and  death  re- 
sulted in  from  five  to  fourteen  days  from  bulbar  paralysis.  In  the  non- 
fatal cases  convalescence  lasted  through  some  weeks.  The  symptoms, 
together  with  the  almost  complete  absence  of  gastro-intestinal  irritation, 
led  to  the  diagnosis  of  botulism,  caused  by.  the  toxin  of  the  B.  hotulinus. 
This  was  confirmed  by  the  demonstration  of  the  toxin  and  by  the  iso- 
lation of  the  suspected  organism.  Cultures  made  from  the  salad  gave 
an  anaerobic  bacillus,  apparently  identical  with  the  B.  hoiulinus  of  Van 
Ermengem.  The  presence  of  B.  hotulinus  in  meats  is  common  enough, 
but  this  is  the  first  time  that  the  organism  and  this  type  of  poisoning 
were  observed  in  a  vegetable  food.  Landmann  endeavored  to  account 
for  its  presence  by  assuming  that  it  was  accidentally  introduced  with 
bits  of  meat  into  the  can,  as  might  easily  happen  about  a  kitchen.  The 
fact  remains  that  a  highly  nitrogenous  vegetable,  as  the  bean,  may  be 
acted  upon  by  the  same  organism  as  is  found  in  meats  and  that  the 
resultant  toxin  may  be  fully  as  active  as  that  formed  in  the  latter. 

Another  striking  example,  apparently  due  to  infected  oatmeal,  is  that 
reported  by  Ohlmacher.^  At  the  Ohio  Hospital  for  Epileptics,  in  three 
days,  218  patients  became  ill  and  took  to  bed.  The  cause  of  the  poison- 
ing was  not  positively  determined,  but,  by  exclusion  and  elimination,  it 
was  finally  decided  to  be  a  certain  batch  of  oatmeal,  which  presumably 
had  been  contaminated  by  the  dust  arising  by  the  removal  of  a  large 
section  of  plaster  from  the  ceiling  the  night  before.  This  ceiling  had 
been  exposed  to  clouds  of  dust  from  a  dirt  road,  and  to  the  steam  and 
vapors  in  cooking.  The  surface  of  the  plaster  harbored  B.  coli  and  Pro- 
teus vulgaris  and  these  organisms  were  believed  to  be  responsible  for 

^Journ.  Med.  Research,  1902,  7,  411. 


FOOD  POISONS  245 

the  poisoning.  The  symptoms  appeared  in  from  about  six  to  eighteen 
hours.  There  was  chilliness,  especially  up  and  down  the  spine,  cold 
hands  and  feet;  aching  of  the  limbs,  with  severe  headache  and  sense 
of  pressure  in  the  head;  nausea,  and  vomiting  in  many  cases — but  not 
in  all;  pain  in  the  abdomen,  griping  and  cramps,  and  profuse  watery 
diarrhoea.  There  was  dizziness,  a  staggering  gait,  prostration  and  fever, 
the  latter  ranged  from  100°  to  105°  F.  and  persisted  for  from  four  days  to 
two  weeks.  The  gastro-intestinal  infection  which  clearly  followed  the 
original  intoxication  would  very  properly  be  termed  paratyphoid. 

The  disease  known  as  pellagra,  or  maidismus,  is  an  intoxication 
caused  by  the  continued  use  of  damaged  Indian  corn.  It  was  formerly 
met  with  in  northern  Italy,  southern  Austria  and  in  parts  of  Spain,  not  as 
occasional  poisonings  but  as  veritable  endemics  affecting  many  thousands 
of  individuals.  While  there  is  no  question  as  to  the  fact  that  the  poisoning 
is  due  to  the  corn,  the  actual  cause,  notwithstanding  the  numerous  inves- 
tigations which  have  been  made,  is  by  no  means  established.  It  is  reason- 
able to  believe  that  the  specific  toxic  products  are  formed  by  the  action 
of  some  bacterium  on  the  maize  which  has  been  cut  while  immature  and 
stored  in  a  damp  condition. 


EXAMINATION  OF  SUSPECTED  FOOD. 

It  has  been  customary  to  look  to  the  chemist  for  the  detection  of  the 
cause  of  a  given  poisoning.  So  far  as  a  search  for  metallic  poisons  and 
vegetable  alkaloids  is  necessary,  the  chemical  methods  must  be  used. 
When  the  action  of  bacteria  can  be  excluded  with  reasonable  certainity, 
a  chemical  examination  should  be  given  precedence,  especially  when 
the  clinical  symptoms  point  to  definite  substances,  such  as  lead  or  arsenic. 
In  the  great  majority  of  cases  of  food  poisoning,  a  chemical  examination 
is  of  no  value  and  hence  should  not  be  undertaken,  certainly  not  until 
all  other  methods  of  inquiry  have  failed.  The  reason  for  delaying  such 
an  examination  is  perfectly  obvious,  since  the  amount  of  the  suspected 
food  is  usually  small  and  would  be  completely  used  up  for  the  chemical 
tests,  if  these  are  carried  out  in  the  beginning. 

In  order  to  avoid  secondary  decomposition  the  suspected  food  should 
be  placed  on  ice  until  delivered  for  examination.  Chemical  preservatives 
should  never  be  added.  As  soon  as  possible,  animal  experiments  and 
a  search  for  parasitic  organisms  should  be  made.  The  former  serve  to 
demonstrate  the  fact  that  poisonous  properties  are  actually  present  in 
the  article  suspected.  The  material  should  be  fed  to  animals,  and,  if 
necessary,  introduced  into  the  stomach  by  means  of  a  tube.  In  such 
feeding  experiments,  it  is  well  to  bear  in  mind  that  the  action  of  the 
poison  is  more  pronounced  when  the  stomach  is  empty.  Macerations  of 
the  material  in  sterile  water  should  be  injected  into  other  animals,  and 
in  either  case,  if  they  die,  the  indication  is  that  bacteria  or  their  products 
are  probably  present.  In  that  event  the  experiments  should  be  repeated 
with  macerations  which  have  been  passed  through  a  Berkefeld  or  Pasteur 
filter;  also  with  such  after  boiling,  in  order  to  demonstrate  the  presence 
of  a  soluble  toxin,  or  of  heat-resisting  products. 


246  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

At  the  same  time  cultures  should  be  made  under  aerobic  and  anaerobic 
conditions,  and  grown  at  the  temperature  of  the  room  as  well  as  that 
of  the  incubator.  Litmus-colored  sugar  media  should  be  employed  if 
possible.  The  cultures  thus  obtained  are  to  be  compared  with  those 
isolated  from  the  animals.  Of  special  importance  is  the  application  of 
the  agglutination  test  to  the  organisms  thus  isolated,  for,  if  the  serum  of 
the  poisoned  person  has  a  selective  action  on  the  germ  found,  it  is  con- 
clusive evidence  of  the  relation  of  the  latter  to  the  outbreak.  An  exam- 
ination for  animal  parasites,  such  as  trichina,  should  Tiot  be  omitted  if 
pork  is  present  in  any  form  in  the  food  under  examination. 

Treatment. — The  treatment  in  food  poisoning  must  necessarily  take 
into  ct)nsi(leration  the  cause,  for  it  is  obvious  that  the  metallic  and  physio- 
logical poisons,  as  well  as  the  infections  due  to  animal  parasites,  must  be 
distinguished  from  the  intoxications  and  infections  due  to  bacteria.  As 
in  the  infectious  diseases,  prophylactic  measures  are  of  primary  impor- 
tance, since  with  proper  inspection  of  food  products  much  can  be  done  to 
restrict  the  consumption  of  improperly  preserved  food  or  such  as  is  derived 
from  diseased  animals.  Thorough  cooking,  while  it  suffices  to  destroy 
bacteria,  does  not  always,  or  even  as  a  rule,  destroy  their  chemical 
products  and  hence  cannot  be  relied  upon  exclusively. 

In  the  severe  intoxications  with  rapid  onset,  as  those  due  to  shell-fish, 
free  lavage  of  the  stomach  should  be  used  as  early  as  possible  and  followed 
by  a  brisk  cathartic,  such  as  calomel,  gr.  ij  (gm.  0.13),  followed  by  a  saline. 
Indeed,  it  is  hardly  necessary  to  emphasize  the  importance  in  all  food 
poisonings  of  removing  the  toxic  material  by  lavage,  purgatives,  and 
diuretics  except  in  cases  of  collapse  where  stimulants  may  he  required. 
In  the  very  acute  cases,  where  death  occurs  rapidly,  there  is  little  that  can 
be  done  except  to  employ,  symptomatic  treatment.  In  the  more  pro- 
tracted cases,  accompanied  with  paralyses  due  to  the  toxin  of  the  Bacillus 
botulimis,  artificial  feeding  may  become  necessary,  and,  if  possible,  the 
antitoxic^  serum  for  this  form  of  poisoning  should  be  employed,  though 
the  results  are  not  very  encouraging. 

As  the  more  common  food  poisonings  represent  true  bacterial  infections 
of  the  intestinal  tract,  the  use  of  antiseptics  such  as  calomel,  salol,  and 
like  agents  is  indicated.  Opium  or  morphine  may  be  used  to  check 
excessive  diarrhoea  except  in  threatened  collapse,  and  the  vomiting  may 
be  allayed  by  ice.  A  liquid  diet  consisting  chiefly  of  sterile  milk  and 
albumen  water  is  advisable.  In  the  more  strictly  para-typhoid  infections 
the  diet  and  treatment  is  the  same  as  in  typhoid  fever. 


CHAPTER  XII. 

SNAKE  VENOMS. 
By  HIDEYO  NOGUCHI,  M.  D. 

Classification  of  Poisonous  Snakes.— The  general  division  of  the 

animal  kingdom  known  as  the  class  Reptilia  contains  as  a  subdivision  the 
order  Qphidia,  comprising  all  forms  of  snakes.  This  is  divided  into  two 
suborders,  Ophidia  colubridse  and  Ophidia  viperidse.  The  suborder 
Colubridse  contains,  besides  numerous  poisonous  snakes,  a  large  number 
of  harmless  ones;  both  are  alike  in  general  appearance.  All  members 
of  the  suborder  Viperidse  are  poisonous.  The  only  distinction  between 
the  poisonous  and  non-poisonous  snakes  is  the  presence  in  the  venom- 
ous species  of  poison-glands  and  of  poison-fangs,  with  teeth  especially 
adapted  for  injecting  the  poison. 

The  poisonous  Colubrines,  Colubridse  venenosa,  can  further  be  di- 
vided into  two  groups  by  the  anatomical  differences  in  their  teeth.  The 
first  group  is  called  Opistoglyphia  and  is  characterized  by  the  presence 
of  one  or  more  series  of  long,  mature  poison-fangs  in  the  back  of  the 
mouth,  while  in  the  front,  two  smooth,  non-grooved  teeth  are  present  in 
the  upper  jaw.    This  group  contains  three  families;  viz. — 

Dipsademorphinse,  with  the  nostrils  situated  at  the  sides  of  the  head 
and  with  a  strongly  built  mouth. 

Elachistodontinse,  with  the  rudimentary  teeth  situated  on  the  os 
plattinum  and  os  ptergoideum  in  the  back  part  of  the  jaw.  Nearly  all 
snakes  belonging  to  this  division  are  poisonous,  but  their  venom  is  so 
weak  and  the  position  of  their  poison-fangs  so  unfavorable,  that  they  ate 
scarcely  dangerous  to  human  beings. 

Homalopsinse.  The  nostrils  are  valvular,  and  are  situated  on  the  upper 
part  of  the  snout.  The  eyes  are  small,  with  vertical  pupils.  They  are 
absolutely  aquatic  and  viviparous.  More  than  twenty  different  species 
inhabit  the  rivers  and  estuaries  of  the  East  Indies  and  of  the  northern 
part  of  Australia.  Some  of  them  resemble  the  Hydrophinse  and  swim 
far  out  into  the  sea. 

The  second  group,  Proteroglyphia  (with  grooved  teeth),  is  the  most 
important  among  all  the  colubrines,  as  they  are  furnished  with  strong 
fangs,  provided  with  a  frontal  groove  passing  along  their  entire  length, 
situated  in  the  anterior  part  of  the  upper  jaw;  the  bases  of  the  teeth  are 
connected  with  the  exits  of  the  excretory  ducts  of  the  poison-:glands, 
which  are  often  highly  developed.  To  this  group  the  following  two 
families  belong : 

Hydrophinse,  sea-snakes,  mth  the  flat,  oar-like  tail.  The  head  is  more 
or  less  compressed  at  the  sides.  The  eyes  as  a  rule  are  small  and  have 
round  pupils;  the  nasal  shield  is  on  the  edge  of  the  upper  lip,  which  has 
two  notches. 

247 


248  DISEASES  CAUSED  BY  ORGAXIC  AGENTS. 

Elapin.T,  land-snakes,  with  cvlindrical  tail,  smooth  or  wedge-shaped 
scales,  and  richly  colored.  Some  of  them,  the  Najas,  when  excited  or  sur- 
prised, can  spread  their  necks  until  they  assume  a  jiarachute  shape;  this 
expansion  extends  as  far  as  the  first  ribs ;  in  that  case  the  neck  appears  to  be 
larger  than  the  head.  They  are  found  throughout  Asia,  Africa,  and  North 
and  South  America;  all  snakes  inhabiting  Australia  belong  to  this  family. 

The  suborder  Viperid?e,  comprising  the  viperine  and  crotaline  snakes, 
is  distinguished  chiefly  by  the  triangular  head  and  a  stout  body  with  short 
tail.  The  facial  bones  are  movable;  the  jaw  is  short  and  has  a  joint  with 
the  OS  pterygoideus  externus  and  bears  on  each  side  a  strongly  devel- 
oped poison-fang,  behind  which  are  a  number  of  reserve  teeth,  destined  to 
come  forward  and  to  take  the  place  of  the  princijial  fang,  when  the  latter 
is  broken  or  falls  off  at  the  time  of  shedding.  The  poison-fangs  are  not 
grooved  as  in  the  colubrines,  but  are  traversed  by  a  canal.  Hence  the 
Viperidre  are  also  called  Solenoglyphia  (with  tubular  teeth).  The  upper 
end  of  the  canal  of  the  fang  meets  the  exit  of  the  duct  of  the  poison-gland, 
while  the  lower  opens  near  the  point  on  the  anterior  surface  of  the  teeth. 
The  point  of  the  fangs  is  extremely  sharp.  The  other  teeth  in  the  mandi- 
bles are  small,  curved,  and  solid,  and  do  not  conduct  the  poison.  Members 
of  this  suborder  abound  in  Europe,  America,  Asia,  and  Africa,  but  not  in 
Australia.    This  suborder  is  further  divided  into  two  families: 

Viperinte,  vipers,  which  have  a  very  broad  head  with  a  small  shield  and 
scales,  with,  however,  no  pit  between  nose  and  eyes.    The  pupil  is  vertical. 

Crotalinse,  pit- vipers,  which  have  a  very  broad  head  imperfectly  covered 
with  scales  and  are  characterized  by  the  presence  of  a  deep  depression  or 
pit  between  the  nostril  and  eye  on  each  side  of  the  head.  Some  of  this 
family  have,  at  the  end  of  the  tail,  a  series  of  flat  horny  rings  graduated  in 
size;  the  shaking  of  these  rings,  if  the  snake  is  excited,  produces  the 
sound  from  which  the  name  of  rattlesnake  is  derived. 

GeographicalDistribution  of  Poisonous  Snakes.— The  geographical 
distribution  of  the  snakes  in  general  is  mainly  of  interest  to  the  naturalist, 
but  the  possibility  of  a  specific  antiserum  therapy  makes  it  necessary  to 
include  a  knowledge  of  the  geographical  distribution  of  poisonous  snakes 
in  a  discussion  of  snake  venom  from  the  medical  standpoint. 

America. — Colubridce. — Most  of  the  colubrines  of  America  belong  to 
the  family  Elapidae,  especially  to  the  genus  Elaps.  Many  are  called  by  the 
general  name  of  coral-snake,  but  the  real  coral-snake,  Elaps  corallinus, 
is  found  in  the  forests  of  Brazil,  Venezuela,  Columbia,  Guiana,  and 
Florida.  They  are  alternately  striped  with  about  twenty-five  black  and 
bluish- white  rings  on  a  red  background.  The  length  does  not  exceed 
three  feet.  They  live  among  the  withered  leaves  in  the  woods.  Their 
poison-fangs  are  small  and  are  situated  at  the  back  of  the  jaw,  rendering 
their  bite  less  dangerous.  The  venom  itself  is  very  powerful.  Elaps  ful- 
vius,  the  harlequin  snake,  and  Elaps  eurycanthus  abound  in  Arizona  and 
the  southern  states ;  they  are  found  even  at  the  height  of  6,000  feet.  They 
may  be  often  fatal  to  man  notwithstanding  their  small  size. 

Viperidce. — The  Vipera,  true  vipers,  are  not  found  in  America,  while 
the  family  Ciotalinse,  pit-vipers,  are  very  common. 

The  Crotalinae  are  divided  into  three  genera,  Crotalus,  Lachesis  and 
Anceistrodon.  They  are  large  and  very  vicious,  and  their  venom  is  very 
powerful. 


SNAKE  VENOMS  249 

The  Crotalus. — This  genus  lives  only  in  America,  spreading  over 
Brazil,  Texas,  North  and  South  Carolina,  Florida,  California,  and  even 
as  far  north  as  New^  York.  The  majority  of  this  genus  are  provided  with 
horny  rings  at  the  end  of  the  tail,  which  produce  the  well  known  rattling 
sound.  Crotalus  adamanteus,  the  diamond-back  rattlesnake,  is  the  most 
famous  species  and  is  found  in  Florida  and  the  neighboring  states.  They 
often  grow  over  seven  feet  long.  Crotalus  durissus  abounds  in  the  south- 
ern states  of  North  America  and  in  Mexico,  while  the  Crotalus  horridus 
is  found  in  South  America,  chiefly  in  Brazil,  where  it  is  called  by  the  name 
of  Boiquira.  Both  of  these  last  named  are  the  real  Crotalus  and  are  far 
smaller  than  their  allied  species,  C.  adamanteus. 

The  Lachesis. — The  dangerous  species  belonging  to  this  genus  are, 
the  fer  de  lance,  Lachesis  s.  Bothrops  lanceolatus,  and  the  Jararaca 
of  Brazil.  They  caused  an  annual  loss  of  nearly  two  hundred  human 
lives  among  the  sugar  planters  in  St.  Martinique.  The  Surucucu,  bush 
master,  is  also  dreaded  by  the  colonists  in  Brazil.  The  Lachesis  atrox, 
so-called  Laboria,  abounds  in  Guiana,  Brazil,  Paraguay,  Uruguay,  Argen- 
tine Republic,  and  Buenos  Aires.  It  has  a  short  tail,  the  end  of  which  is 
somewhat  horny  in  nature,  although  there  are  no  rings. 

The  Ancistrodon. — This  genus  is  represented  by  the  following  venom- 
ous species:  Ancistrodon  piscivorus,  water  moccasin,  and  A.  con- 
tortrix,  copper-head  snake.  The  former  species  is  found  in  the  tropical  as 
well  as  the  temperate  regions  and  is  much  feared  by  the  rice  planters  of 
Florida.  Its  length  is  about  three  to  four  feet,  and  it  has  a  powerful 
venom.  The  copper-head  snake  is  much  smaller  than  the  water  moccasin 
but  its  venom  is  equally  poisonous. 

Europe. — There  is  in  Europe  only  one  poisonous  genus,  Vipera, 
which  is  represented  by  various  species.  Vipera  berus  is  the  most  com- 
mon species  and  spreads  over  all  northern  Europe,  mountainous  regions 
of  central  Europe,  northern  Italy,  Spain,  and  Portugal.  The  vipers  of 
Europe  are  small  and  seldom  exceed  two  feet  in  length. 

Asia. — The  tropical  regions  of  Asia  have  many  dangerous  snakes. 
The  most  dangerous  among  them  is  the  famous  cobra  de  capello,  Naja 
tripudians. 

Among  the  Colubrines  the  following  sea  and  land-snakes  are  found: 

Hydro'phinoB,  Sea-snakes. — A  large  number  of  varieties  are  found  on 
the  coast,  where  they  live  in  colonies.  They  are  all  poisonous  and  vi- 
cious, and  do  not  come  on  land  as  a  rule;  when  they  are  taken  out  of 
the  water,  their  motion  is  very  slow,  although  they  swim  swiftly.  They 
float  on  the  surface  of  the  ocean  and  can  dive  very  deeply,  by  virtue  of 
the  large  capacity  of  their  lungs.    They  give  birth  to  living  young. 

ElapinoB,  land-snakes,  comprise  most  of  the  dangerous  varieties  of 
India  and  Indo-China.  The  genera,  Bungarus,  Naja,  and  Callophis,  are 
found  there. 

Bungarus  fasciatus  and  B.  coeruleuse  are  very  common,  and  they 
reach  a  length  of  about  three  to  five  feet.  The  back  is  compressed  like 
a  wedge.  They  are  less  dangerous  than  the  Najas,  as  their  fangs  are 
smaller, 

Naja  tripudians,  cobra,  is  the  best  known  venomous  reptile,  which 
has  a  pattern  resembling  a  pair  of  spectacles  across  the  back  of  the 
neck.    It  spreads  all  over  the  tropical  zone  of  Asia,  extending  from  the 


250  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

southern  part  of  the  Caspian  Sea  to  the  southern  part  of  China;  and 
is  most  common  in  India,  Burma,  and  the  JMahiyan  Archipelago.  The 
Najas  are  oviparous  and  hiy  about  twenty,  soft-shelled,  elliptical  eggs  the 
size  of  a  pigeon's  egg.  They  are  not  afraid  of  man  and  will  hunt  for 
rats  and  birds  after  sunset,  in  the  human  habitation.  They  swim  well 
and  live  near  running  water. 

The  Callophis,  Ilemibungarus,  is  small  and  measures  only  two  feet 
in  length.  It  is  sluggish  and  nocturnal,  and,  while  it  has  never  been 
known  to  bite  man,  its  poison  is  strong  for  animals. 

Viperinoe,  Vipers. — In  India  and  Burmah  there  is  found  a  large,  richly 
colored  viper,  Daboia  russelli  s.  Echidna  elegans,  which  attains  the 
length  of  nearly  six  to  seven  feet. 

Lachesis,  Trimcrcsurus. — It  lives  in  northern  India,  Tibet,  and  also 
in  the  Philijipine  Islands.  In  Japan,  namely  in  the  Riukiu  Islands, 
there  is  another  dangerous  species,  T.  riukiuanus. 

Africa. — Colubridce. — Sepedon  hsemachates  and  Sepedon  rhombeatus 
are  similar  to  the  Naja  and  can  spread  their  cervical  ribs  when  excited. 
The  latter  species  is  found  everywhere  in  equatorial  and  southern  Africa. 
The  natives  believe  that  it  can  throw  its  venom  more  than  three  feet  and 
if  it  should  touch  human  eyes  the  sight  would  be  destroyed.  But  in 
reality,  it  causes  only  a  slight  conjunctivitis. 

Closely  allied  to  the  above  species  there  is  the  Naja  haje,  aspis  or 
Egyptian  cobra,  which  often  reaches  a  length  of  six  feet.  This  species 
is  very  common  in  Egypt  and  is  used  by  the  snake-charmers;  it  was 
once  worshipped  by  the  ancient  Egyptians  and  its  picture  is  to  be  seen 
in  the  old  buildings. 

ViperincE. — This  family  is  well  represented.  In  the  north  of  Africa, 
Vipera  cerastes,  horned  viper,  and  V.  ammodytes,  while  in  equatorial 
districts  the  Bitis  (Vipera)  arietans,  puff  adder,  are  found.  The  last 
named  reaches  a  length  of  about  five  feet,  and  springs  into  the  air  be- 
fore biting.  According  to  the  natives  it  can  jump  high  enough  to  reach 
a  rider  on  horseback.  The  Hottentots  hunt  this  viper  to  get  its  head, 
from  which  they  extract  the  poison,  and  after  mixing  it  with  certain 
plant  juice,  use  the  mixture  for  their  arrow-heads. 

The  Rhinoceros  viper,  Bitis  gabonica,  inhabits  Gabon  district  and 
vicinity  of  the  River  Ogowe;  it  is  brownish-red  in  color,  sluggish,  and 
does  not  bite  man  unless  molested.    Its  poison  is  powerful. 

Cerastes,  or  horned  viper,  has  two  small,  soft,  horn-shaped  growths  near 
the  anterior  edge  of  the  head.  It  is  quick  in  motion  and  very  dangerous 
for  the  bare-footed  Arabians,  who  are  often  fatally  bitten.  The  Sahara, 
Algeria,  and  Tripolis,  is  their  home. 

Echis  carinata,  pyramid  viper,  invades  the  houses  of  the  Egyptian 
villages. 

Australia. — Coluhridw. — The  poisonous  snakes  of  this  continent  belong 
to  the  Colubrines  and  are  peculiar  to  this  land.  The  more  important 
ones  are:  Pseudechis,  Denisonia,  Hoplocephalus,  and  Acanthophis. 
The  head  of  the  Denisonia  is  square  and  has  curved  teeth  situated  on 
the  elongated  part  of  the  upper  jaw.  The  most  common  ones  among 
them  are  Pseudechis  por])hyriacus,  black-snake,  and  Hoplocephalus 
curtus,  tiger-snake.  The  black-snake  can  reach  a  length  of  five  feet 
and  its  bite  is  very  dangerous.     Acanthophis  antarctica  s.  cerastinus, 


SNAKE  VENOMS  251 

death-adder,  is  a  short  reptile  with  decorative  pattern  and  abounds 
near  Sydney. 

No  viperine  snakes  are  found  in  Austraha. 

Oceania. — The  Sunda  isles  and  Papuasia  are  rich  in  the  poisonous 
snakes,  which  are  similar  in  species  to  those  found  in  Asia.  The  sea- 
snakes  are  quite  abundant. 

Poison  Organs. — The  poison-fangs  are  hollow  or  grooved  teeth,  sup- 
plied with  a  canal,  or  furrow,  running  the  entire  length  of  the  tooth. 
The  fangs  of  the  Pmteroglyphia  (with  grooved  teeth)  and  of  the  Solen- 
oglyphia  (with  tubular  teeth)  are  immovably  attached  to  the  upper  max- 
illary bone,  and  completely  covered  with  a  broad  prolongation  of  the 
gingival  membrane;  this,  at  the  same  time,  hides  the  reserve  fangs  in 
their  varying  stages  of  development.  These  are  two  to  six  in  number,  and 
grow  out  in  the  place  of  the  mature  fangs,  in  case  the  latter  are  damaged 
or  shed.  The  upper  maxillary  bone  is  quite  movable  and,  when  drawn 
backward,  erects  the  fangs  to  a  vertical  position;  when  at  rest  they  lie 
horizontally.  At  the  same  time,  the  contraction  of  special  constrictor 
muscles  squeezes  the  poison-glands,  the  excretory  ducts  of  which  open 
into  the  canal  at  the  base  of  the  fangs. 

The  size  and  shape  of  the  poison-fangs  differ  according  to  the  species. 
Thus,  the  Viperinae  have  longer  and  sharper  teeth  with  more  pronounced 
curvature,  which  causes  a  deep  wound.  On  the  other  hand,  the  fangs  of 
the  Elapinse,  and  especially  of  the  Hydrophinse,  are  much  shorter;  the 
poison  of  the  latter  is,  however,  much  more  dangerous  than  that  of  the 
former.  The  fangs  can  attain,  as  in  Bothrops  and  Crotalus,  a  length  of 
25  mm.  The  narrow,  slit-like  opening  of  the  canal  of  the  fangs  on  the 
Solenoglyphia  is  situated  at  the  anterior  end, — on  the  convex  side, — of  the 
tooth.  These  differences,  together  with  the  arrangement  of  the  other 
numerous  small  teeth,  enable  one  to  determine  the  species. 

The  poison-glands  are  similar  in  structure  to  the  salivary  glands,  and 
occupy  a  wide  space  between  the  muscles  below  and  behind  the  eyes,  on 
both  sides  of  the  upper  jaw.  In  the  Naja  the  size  of  the  gland  reaches 
that  of  an  almond.  The  gland  is  covered  with  a  capsule :  fibers  from  the 
masseter  muscle  pass  into  the  interior  of  the  gland,  and,  on  constriction, 
force  the  poison  out  of  the  gland.  The  secreted  venom  accumulates  in 
the  acini,  and  in  a  sac  formed  by  a  dilatation  of  the  mucous  membrane  of 
the  duct.  The  walls  of  this  sac,  also,  contain  a  thin  layer  of  muscle  fibers 
from  the  same  muscle,  which  form  a  constrictor  at  the  exit  of  the  ducts. 

The  non-poisonous  snakes,  as  well  as  the  poisonous  ones,  possess 
parotid  and  supralabial  glands;  the  supralabial  glands  secrete  a  poison. 
The  non-poisonous  snakes  have  no  fangs  but  the  secretion  of  the  venom 
seems  to  be  indispensable  to  the  function  of  digestion. 

The  histological  process  of  the  secretion  of  venom  from  the  gland  cells 
can  be  divided  into  two  phases, — the  development  of  the  cell  nucleus,  and 
the  action  of  the  cell  protoplasm.  So-called  "venogen"  granules, — uni- 
form, round  granules, — are  produced  from  the  nuclear  chromatin;  this 
transformation  can  be  followed  by  the  varying  staining  reactions  of  the 
chromatin  granules  during  the  process.  An  exomosis  of  dissolved  nuclear 
substance  also  occurs,  forming  stored,  or  "ergastoplasmic"  venogen. 
The  nuclear  membrane  takes  an  active  part  in  the  secretion  of  both  these 
forms  of  venogen.    The  venogen  granules  and  the  stored  venogen  dis- 


252  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

appear  during  the  physiological  activity  of  the  cell,  the  venogen  granules 
(characterized  by  their  affinity  for  Unna's  blue,  safranin,  and  fuchsin) 
being  converted  into  the  venom  granules,  which  are  eosinophilic. 

The  act  of  striking  consists  in  <U-awing  the  head  backward,  opening  the 
mouth  widely,  erecting  the  fangs  to  a  vertical  position,  and  exposing  them 
by  drawing  back  the  gingival  sheath  of  the  fangs;  the  snake  strikes  very 
quickly  and  immediately  draws  its  head  back.  At  the  moment  of  striking, 
the  jaws  are  closed  and  the  glands,  together  with  the  venom-sacs  and  the 
excretory  duct,  are  compressed  so  forcibly  that  the  venom  flows  out  in  a 
stream.  The  muscles  concerned  are:  INI.  masseter,  JNI.  temporales,  M. 
pterygoideei  interni  et  externi. 

The  amount  of  venom  yielded  at  one  time  by  a  snake,  either  at  a  single 
bite  or  by  squeezing  the  poison-glands,  is  very  variable.  It  increases, 
however,  in  general,  in  proportion  to  the  size  of  the  snakes,  although  this 
rule  cannot  be  applied  to  the  sea-snakes,  which  secrete  an  amount  which 
is  small  compared  to  their  size.  The  progressive  failing  of  their  health  in 
captivity  causes  a  decrease  of  venom,  both  in  quantity  and  in  toxicity; 
especially  is  this  the  case  where  the  snakes  refuse  to  take  nourishment,  and 
are  subjected  to  repeated  extractions  of  venom.  While  it  is  very  important 
to  determine  the  exact  quantities  of  venom  yielded  at  a  single  bite,  the 
data  bearing  upon  the  subject  are  very  unsatisfactory.  According  to 
Lamb,  the  amount  of  venom  thrown  out  voluntarily  by  a  snake  is  larger 
than  that  obtained  by  the  forcible  squeezing  with  the  fingers. 

The  following  table  will  show  the  amounts  of  venom  yielded,  at  one 
time,  by  certain  important  snakes.  The  venom  was  collected  by  squeez- 
ing the  glands,  and  the  weight  estimated  in  a  dry  state. 

Naja  tri-pudians.  0.254  (Cunningham),  0.231  (Lamb),  0.373-bite  (Lamb), 
0.249  (Rogers). 

Najahaje.    0.048  (Calmette).     PseudecMs  porphyriacus.    0.094-0.046  (Smith). 

Hoplocephalus  curtus.  Enhydrina.  Lachesis,  fer  de  lance, 

0.055-0.017    (Smith).  0.0094-0.0023  (Rogers).  0.127  (Calmette). 

Ancistrodon  piscivorus.  Crotalus  adamanteus. 

0.18-0.125  (Flexner  &  0.309-0.179  (Flexner& 

Noguchi).  Noguchi). 

Physiological  and  Chemical  Properties  of  Venom.— All  snake 
venoms  are  viscid  fluids  which  vary  in  color  from  the  palest  amber  to  a 
deep  yellow;  they  look  alike  when  in  the  fresh  state.  The  amount  of 
pigment  varies  in  the  venom  of  different  snakes,  and  repeated  extraction 
of  venom  from  the  poison-glands  causes  a  decrease  in  color  and  quantity. 
When  fresh  venom  is  allowed  to  dry  slowly  it  cracks  into  small,  yellow, 
very  fragile,  transparent,  or  transluscent,  particles,  which  resemble  an 
aggregation  of  crystals. 

A  number  of  floating  bodies  are  always  seen  in  fresh  venom  when  exam- 
ined under  the  microscope.  These  suspended  bodies  consist  principally 
of  fine,  ovoid,  highly  refractive  granules,  which  are  of  albuminoid  nature. 
A  few  epithelial  cells,  fat  globules,  and  occasional  leukocytes  occur  in 
fresh  venom.  The  chlorides  and  phosphates  of  calcium,  ammonium,  and 
magnesium,  are  present.  The  specific  gravity  varies  between  1,030  and 
1,070,  the  Colubrine  venoms  being  lighter  than  the  CrotaUne.  The  loss 
of  weight  on  drying  varies,  and  it  is  more  marked  in  the  Colubrine 
venom,  65  to  80  per  cent.  (Calmette),  but  is  comparatively  slight  in 
the  Crotaline,— 25  per  cent.  (Mitchell)  to  35  per  cent,  to  50  per  cent. 


SNAKE  VENOMS  253 

(Flexner-Noguchi)  with  Crotalus  adamanteus  and  Ancistrodon  piscivo- 
rus, — while  the  loss  is  estimated  to  be  33  per  cent.  (C.  J.  Martin)  with  the 
Australian  snake  venoms. 

The  reaction  of  fresh  venom  to  litmus  is  faintly  acid,  which  is,  as  a  rule, 
weaker  in  the  Colubrine  than  in  the  Crotaline  venoms. 

Our  knowledge  of  the  chemistry  of  venom  is  still  far  from  being  satis- 
factory. Lucien  Bonaparte  (1843)  announced  that  the  active  principle 
of  a  viper  venom  is  a  proteid,  and  called  it  viperin,  or  echidnin.  Busk 
thought  it  a  ferment  similar  to  ptyalin.  Brunton  and  Fayrer  (1S73) 
stated  that  boiling  does  not  destroy  the  activity  of  the  venom  of  cobra, 
while  Gautier  maintained  that  venom  contains  ptomain.  Mitchell  and 
Reichert  (1886),  working  on  the  venoms  of  Crotalus  adamanteus,  Ancistro- 
don contortrix,  Ancistrodon  piscivorus,  and  Cobra,  separated  several 
active  principles. 

According  to  their  studies  venom  contains  three  principal  proteids — two 
water-soluble,  and  one  water-insoluble,  components.  Of  the  former  two, 
one  is  coagulable  by  heat,  while  the  other  remains  in  solution  upon  boiling. 
The  first  is  venom-albumin  and  is  not  poisonous;  the  latter  stands  very 
close  to  peptone  in  its  chemical  reactions  and  is  called  venom-peptone. 
The  water-insoluble  ingredient  of  venom  has  been  classed  among  the 
globulins  and  is  called  venom-globulin-.  Working  with  these  two  separate 
proteids,  venom-peptone  and  venom-globulin,  they  found  that  the  action 
of  each  constituent  is  different;  venom-peptone  is  responsible  for  the 
production  of  oedema,  putrefaction  and  necrosis  of  the  tissue,  while  the 
action  of  venom-globulin  is  chiefly  upon  the  respiratory  and  circulatory 
system;  it  destroys  coagulability  of  the  blood,  produces  ecchymosis, 
lowers  the  blood  pressure,  and  paralyzes  respiration.  The  venom  re- 
tains its  solubility  and  toxicity  after  being  precipitated  by  absolute 
alcohol. 

C.  J.  Martin  succeeded  in  separating  two  active  components  of  the 
venom  of  Pseudechis  by  filtering  it  through  a  gelatinized  Chamberland 
filter  under  a  pressure  of  50  atmospheres.  One  component  does  not  pass 
through  the  bougie  and  is  coagulable  at  82°  C;  the  other  passes  and  is  not 
coagulable  upon  boiling.  The  first  produces  local  hemorrhage  and 
destruction  of  the  blood ;  the  latter  acts  upon  the  nervous  system.  Accord- 
ing to  Martin  and  Smith,  the  albumoses  of  venom  are  hetero-,  proto-,  and 
perhaps  deutero-albumose.  They  found  no  trace  of  peptone.  Kan- 
thack  stated  that  in  venom  there  is  only  one  primary  albumose  from  which 
other  albumoses — hetero-  and  dysalbumoses — can  be  formed  undercertain 
circumstances,  as  by  dialysis.  Phisalix  and  Bertrand  have  prepared  from 
viper  venom  two  toxalbumins;  one  (echidnin)  which  acts  locally  and  is 
easily  destroyed  by  boiling  for  a  short  time,  the  other  (echitoxin)  is  poison- 
ous to  the  vasomotor  system  and  withstands  boiling. 

The  stability  of  the  active  principles  of  snake  venom  in  a  dry  state  is  one 
of  its  most  remarkable  features.  Mitchell  preserved  crotalus  venom  for 
twenty-three  years;  Christison,  cobra  venom  for  fifteen  years,  and  Vollmer 
for  sixteen  years,  without  any  marked  deterioration. 

The  venom  gives  the  proteid  reactions, — namely,  the  Millon,  xantho- 
protein,  and  biuret  reaction.  On  addition  of  picric  acid  a  precipitate  is 
formed  which  disappears  on  heating  and  reappears  on  cooling.  By 
saturating  with  sodium  chloride,  magnesium  sulphate,  ammonium  sul- 


254  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

phate  and  5  per  cent,  solution  of  copper  sulphate  or  alcohol,  the  venom 
can  be  precipitated. 

Heating. — The  venom  of  colubridie  (in  solution)  can  be  exposed  to  a 
temperature  of  100°  C.  for  a  brief  period;  120°  C.  destroys  its  activity 
with  certainty.  The  viperine  venoms  are  much  more  susceptible  to 
higher  temperatures.  Heating  to  the  coagulating  point  is  sufficient  to 
diminish  their  toxicity  to  a  considerable  extent.  Temjieratures  of  80°  to 
85°  C.  suffice  to  destroy  the  toxicity  of  most  of  the  viperine  venoms.  After 
the  removal  of  the  coagulum  by  filtration  the  clear  filtrate  can  be  precipi- 
tated by  alcohol  but  not  by  boiling.  The  filtrate  from  the  heated  colu- 
brine  and  crotaline  venoms  is  toxic,  especially  to  tlie  nervous  system. 
Bothrop's  venom  loses  its  activity  partially  at  G5°  C.  The  higher  the  con- 
centration of  venom,  the  less  injurious  are  the  higher  temperatures.  The 
action  of  dry  heat  of  130°  C.  upon  dried  venom  does  not  destroy  its 
activity. 

Dialysis  of  venom  is  a  very  slow  process  and  it  is  almost  impossible  to 
accomplish  this  with  animal  membranes, — though  vegetable  tissue  may 
be  used  with  better  results.  Filtration  through  a  Chamberland  bougie  has 
almost  no  perceivable  effect  upon  the  colubrine  venoms,  but  it  reduces  the 
toxicity  of  the  viperine  venoms  nearly  one-half. 

A  constant  electric  current  passed  through  a  venom  solution,  which 
contains  certain  salts,  will  produce  chlorides  and  ozone,  and,  as  a  result  of 
the  ozone  production,  the  activity  of  the  venom  is  destroyed.  Phisalix 
applied  an  alternating  current  of  high  frequency  to  the  venom  solution,— 
with  the  view  of  producing  a  vaccine  by  the  same  process  as  d'Aronval 
and  Charrin  employed  for  preparing  vaccine  for  diphtheria  toxin, — and 
claimed  to  have  obtained  the  same  results.  Marmier,  however,  attributed 
this  modification  of  the  venom  to  the  heat  produced  by  the  cm-rent,  as 
by  using  an  appropriate  apparatus  avoiding  the  rise  of  the  temperature  he 
was  not  able  to  confirm  Phisalix's  work. 

Light  has  no  influence  upon  the  dried  venom.  In  a  state  of  solution, 
venom  suffers  but  little  deterioration  on  being  exposed  to  diffuse  light,  but 
is  gradually  weakened  by  exposure  to  the  direct  sunlight.  Even  in  the  dark 
a  solution  of  venom  undergoes  a  rather  marked  reduction  in  toxicity  when 
kept  at  room  temperature.  Freezing  has  no  marked  destructive  action 
upon  venom.  Radium  produces  a  precipitate  of  the  proteids  of  cobra 
venom  and  at  the  same  time  destroys  its  toxic  properties. 

The  hemorrhagic  principles  of  crotalus  venom  and  the  clotting  prin- 
ciple of  daboia  venom  can  be  made  inactive  by  photodynamic  substances. 
The  hfemolytic  principles  are  less  affected  by  them  (Noguchi). 

Among  the  chemicals  which  are  capable  of  destroying  or  modifying  the 
toxic  properties  of  venom,  there  are  some  which  can  be  injected  into  the 
surrounding  tissue  of  the  bitten  part  in  order  that  the  still  unabsorbed 
portion  of  the  venom  may  be  made  inactive  with  the  least  harm  to  the 
patient,  and  these  are:  potassium  permanganate  1  to  100  (Mitchell, 
Fayrer,  Lacerda,  Richard,  Rogers),  chloride  of  gold  1  to  100,  chloride 
or  hypochlorite  of  calcium  1  to  60  or  72  (Calmette),  chromic  acid  1  to 
100  (Kauffmann)  and  saturated  bromine  water. 

A  finer  analysis  shows  that  venom  owes  its  toxicity  to  the  presence  of 
several  active  principles  which  are  capable  of  producing  profound  alter- 
ation or  destruction  of  susceptible  tissue.    The  changes  brought  about 


SNAKE  VENOMS  255 

by  the  action  of  the  active  principles  of  venom  vary  in  accordance  with 
the  nature  and  the  amount  of  the  latter,  ranging  from  the  slightest  local 
inflammation  to  the  complete  cessation  of  vital  functions.  These  toxic 
components  are  present  in  varying  proportions  in  different  venoms.  The 
greater  number  of  these  principles  can  alone  be  fatal  when  present  in 
sufficient  quantities,  and  one  will  thus  form  the  chief  toxic  principle  of 
a  venom  where  it  predominates  over  the  other  constituents.  The  hitherto 
known  toxic  components  can  be  divided  into  the  chief  toxic  principles 
and  those  of  secondary  importance,  and  these  are: 

1.  The  principle  which  produces  an  instantaneous  intravascular 
thrombosis. 

2.  The  principle  which  attacks  the  nervous  system. 

3.  The  principle  which  produces  the  rupture  of  the  walls  of  capillary 
vessels,  causing  extensive  hemorrhage. 

4.  The  principles  which  attack  the  blood  corpuscles,  causing  haemol- 
ysis and  agglutination  of  the  latter 

5.  A  number  of  cytolytic  principles  for  other  cells. 

6.  The  protective  or  hardening  property  upon  the  red  blood  cor- 
puscles. 

7.  Loss  of  bactericidal  property  of  the  blood. 

1.  The  Blood-Clotting  Component  of  Venom. — The  venom  of  cer- 
tain snakes  has  a  great  influence  upon  the  coagulation  of  blood.  When 
in  sufficiently  large  quantity,  it  produces  an  instantaneous  intravascular 
thrombosis  (positive  phase),  while,  if  in  too  small  quantity  to  cause  this 
change,  it  destroys  the  coagulability  of  the  blood  for  a  long  period 
(negative  phase).  It  is  due  to  this  first  change  that  certain  venoms 
produce  an  instantaneous  death  of  the  victim.  The  venoms  which  are 
able  to  bring  about  this  sudden  clotting  in  vivo  are  Daboia,  Bungarus 
fasciatus,  Hoplocepholus  curtus,  Echis  carinata,  Pseudechis  porphyriacus, 
Trimeresurus  riukiuanus,  and  Crotolus  adamanteus. 

Lamb  has  also  demonstrated  that  the  fluid  plasma,  or  blood  containing 
one  to  two  per  cent,  sodium  citrate,  can  be  coagulated  by  adding  a  small 
quantity  of  daboia  venom  in  vitro. 

The  symptoms  due  to  the  blood-clotting  principle  are  sudden  loss  of 
equilibrium,  violent  general  convulsions,  and  quick  termination  in  death, 
which  follows  within  several  minutes.  At  times  death  may  take  place 
even  in  a  half  minute.  At  autopsy  extensive  intravascular  thrombosis 
is  found,  chiefly  affecting  the  pulmonary  arteries  and  right  heart. 

2.  The  Neurotoxin  of  Venom. — Most  of  the  venoms  of  the  Elapidse 
and  Hydrophinae  contain  a  large  amount  of  neurotoxin,  which  is  richest 
in  the  venom  of  Cobra  and  Bungarus.  When  present  in  large  amount 
death  may  occur  within  fifteen  minutes.  In  cobra- venom  poisoning, 
death  is  caused,  by  one  minimal  lethal  dose,  within  two  or  three  days, 
while  in  the  case  of  Bungarus  venom  the  poisoning  is  to  be  divided  into 
two  forms,  one  an  acute,  the  other  a  chronic  form.  The  acute  form  is 
exactly  the  same  as  in  cobra  poisoning.  With  these  venoms  there  are 
almost  no  local  symptoms  except  a  slight  oedema  and  occasional  ecchy- 
mosis  The  symptoms  are  stupefaction,  paralysis  of  limbs,  accompanied 
by  twitching  of  muscles,  dyspnoea,  and  final  cessation  of  respiration. 
The  heart  may  continue  to  beat  even  for  five  minutes  after  respiration 
has  stopped.     The  longer  death  is  delayed,  the  more  pronounced  will 


256  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

be  the  cedcma  at  the  site  of  injection.  The  chronic  form  is  most  char- 
acteristic in  Bungarus  venom,  but  has  never  been  observed  in  cobra 
venom.  Death  may  follow  after  twelve  days.  In  the  first  several  days 
there  may  be  no  marked  symptoms,  but  after  this  latent  period  the  loss 
of  body-weight  and  appetite,  great  depression,  marked  muscular  weak- 
ness and  atrophy,  and  extreme  emaciation,  advance  progressively,  and  the 
animal  succumbs  in  a  few  days. 

Some  investigators  observed  the  curare-like  action  of  cobra  venom 
upon  the  peripheral  nerves  (Brunton,  Ragotzi,  Fayrer,  and  Jacoby), 
while  the  same  action  is  recorded  with  venom  of  a  sea-snake;  Rogers 
has  found  that  even  a  strong  solution  of  sea-snake  venom  does  not  alter 
the  conductivity  of  the  nerve  fibers,  while  the  end  plates  of  the  muscle, 
especially  those  of  the  diaphragm,  are  quickly  involved. 

With  certain  venoms  the  reflexes  may  disappear  either  before,  or 
simultaneously  with,  the  appearance  of  motor  paralysis.  In  such  cases 
the  reflexes  do  not  reappear  after  the  use  of  strychnine,  nor  does  a  pri- 
mary stimulation  of  the  reflexes  by  strychnine  prevent  the  reflex  paralysis 
caused  by  venom.  In  some  cases  (rabbits,  mice,  pigeons)  slight  accelera- 
tion of  reflexes  can  be  noticed  before  the  paralysis.  Venom  exerts  a 
slight  action  upon  the  motor  ganglion  of  the  heart.  In  warm-blooded 
animals  there  is  rapid  diminution  of  the  blood  content  of  the  right  heart, 
with  incomplete  contraction.  The  left  heart  is  next  aflfected  in  the  same 
manner.  After  the  cessation  of  respiration,  the  heart  stops  in  diastole  or 
semi-diastole.  The  beating  is  made  slow  by  the  stimulation  of  the  vagus 
centre,  then  through  the  paralysis  of  the  cardiac  ending  of  the  vagi  it 
becomes  quicker,  although  the  energy  is  gradually  reduced.  The  conse- 
quence of  this  is  a  fall  of  blood  pressure.  Besides  the  anaemia  of  the 
brain,  a  direct  action  upon  the  vasomotor  centre  contributes  to  this  effect. 

The  histological  changes  produced  by  moccasin  venom  upon  the  ner- 
vous system  of  the  rabbit  have  been  found  to  consist  in  a  true  acute 
degeneration  of  the  ganglion  cell.  Most  of  the  cells  of  the  anterior  horn 
of  the  spinal  cord  were  normal,  but  a  small  number  presented  modifica- 
tions Avhich  were  considered  to  be  an  early  stage  of  acute  degeneration. 
The  histological  changes  in  the  nervous  system  of  monkeys,  rabbits, 
rats,  and  pigeons,  produced  by  the  venoms  of  cobra  and  Bungarus  fas- 
ciatus  are  similar,  but  the  more  acute  action  of  cobra  venom  does 
not  allow  sufficient  time  for  the  destructive  changes  to  become  clearly 
marked.  The  best  pictures  were  obtained  in  the  more  chronic  cases  of 
Bungarus  poisoning.  In  these  there  is  undoubted  evidence  of  an  acute 
chromatolysis  involving  the  motor  ganglion  cells  of  the  cortex,  the  pons, 
the  medulla,  and  the  cord.  There  is  slight  increase  of  connective  tissue 
throughout  the  gray  matter  of  the  central  nervous  system.  The  histolog- 
ical condition  is  that  of  polioencephalitis  and  poliomyelitis.  The  clin- 
ical facts  observed,  such  as  atrophy  and  paralysis  of  the  muscles,  agree 
with  the  histological  changes  found.  The  muscular  atrophy  is  probably 
due  to  functional  disturbances  of  the  trophic  centres. 

The  action  of  the  venom  of  cobra,  water  moccasin,  and  rattlesnake 
upon  the  isolated  ganglion  cells  of  certain  species  of  Gastropod,  have 
been  followed  by  Flexner  and  Noguchi,  directly  under  the  microscope. 
The  effect  is  a  chromatolysis  with  a  final  complete  disappearance  of 
the  cells. 


SNAKE  VENOM&  257 

3.  Hemorrhagic  Principles  of  Venom. — The  most  striking  effect  of  the 
viperine  and  crotaUne  poisoning  is  the  rapid  discoloration  and  swelling 
of  the  site  of  injury,  as  well  as  the  profuse  bleeding  from  the  wound. 
The  extent  of  discoloration  and  swelling  is  variable  according  to  the 
amount  of  venom  injected,  but  as  a  rule  it  spreads  gradually  over  the 
half  of  the  body  in  which  the  wound  was  received,  and  the  intensity 
steadily  increases  even  after  two  days  have  elapsed  since  the  bite. 

A  close  examination  of  the  tissue  v^ill  reveal  the  fact  that  the  dis- 
coloration is  really  due  to  extravasation  of  blood  into  the  skin  and  muscles, 
through  the  rupture  of  the  walls  of  capillary  bloodvessels.  The  bleed- 
ing from  the  open  wound  may  continue  for  a  day  or  two  and  is  one  of 
the  most  conspicuous  features  of  the  Crotalus  poisoning.  The  final 
result  is  generally  a  necrosis  of  the  entire  tissue  affected,  which  may  form 
an  ulcer,  or  heal  with  a  scar. 

Experimentally,  we  can  easily  demonstrate  the  minute  capillary  bleed- 
ing, under  the  microscope,  by  exposing  the  mesentery  of  small  animals 
and  applying  a  small  particle  of  dried  venom  to  the  membrane.  It  is 
rather  difficult  to  follow  the  actual  disunion  of  the  cells  of  the  capillary 
wall  without  staining,  but  when  properly  prepared  we  can  see  the  rup- 
ture of  the  wall  or  the  dislocation  of  the  endothelial  cell  at  the  spot 
where  the  hemorrhage  took  place  (Flexner  and  Noguchi).  In  certain 
fish,  such  as  Mustelus  canis,  the  cerebral  hemorrhage  may  be  clearly 
seen  during  life,  when  an  appropriate  dose  of  the  Crotalus  venom  is 
given  intraperitoneally.  The  effect  of  the  hemorrhagic  principle  of 
venom  is  very  quick.  The  susceptibility  of  various  animals  to  hemor- 
rhagin  is  variable,  but  as  a  rule  warm-blooded  animals  are  more  sus- 
ceptible than  cold-blooded  ones.  Batrachians  are  least  susceptible,  while 
Cheldra  are  moderately  sensitive  to  this  principle.  Hemorrhages  may 
occur  in  any  of  the  organs  of  the  body  and  may  be  the  immediate  cause 
of  death. 

The  hemorrhagins  contained  in  different  venoms  vary  in  amount,  and 
are  not  quite  identical  so  far  as  their  reaction  to  the  antivenins  is  con- 
cerned. The  oedema-producing  principles  of  venom  seem  to  be  inde- 
pendent of  the  hemorrhagins.  There  are  certain  venoms  which  produce 
marked  oedema  but  not  much  hemorrhage,  such  as  those  of  daboia  and 
cobra,  although  it  is  difficult  to  say  whether  some  venoms  producing  strong 
hemorrhage  contain  the  oedema-producing  principle,  as  the  former 
obscures  the  latter.  It  may  be  stated  that  the  oedema-producing  principle 
is  more  resistant  to  high  temperature  than  the  hemorrhagin. 

4.  Haemolytic  and  Haemagglutinative  Principles. — The  influence  of 
venom  upon  the  coagulability  of  blood  both  in  vivo  and  in  vitro  has 
already  been  noted.  The  next  important  property  of  venom,  both  from 
the  theoretical  and  practical  points  of  view,  is  its  action  upon  the  cellu- 
lar elements  of  the  blood.  Many  investigators  paid  attention  to  the 
changes  of  the  blood  corpuscles  in  venom  poisoning,  but  were  unable  to 
find  any  definite  alteration  in  the  cells.  Of  course  it  has  been  repeat- 
edly observed  that  the  destruction  of  the  blood  corpuscles  occurs  in  the 
body,  as  indicated  by  the  appearance  of  hsemoglobinuria,  or  htematuria, 
in  cases  of  venom  poisoning.  But  it  was  a  matter  of  conjecture  that 
there  was  such  a  definite  destruction  of  the  corpuscles  by  venom,  until 
the  blood  was  drawn  directly  from  the  vessel  of  a  victim  and  allowed  to 

17 


258  DISEASES   CAUSED   BY   ORGANIC  AGENTS 

coagulate  or  settle,  when  the  serum  was  found  to  contain  free  haemo- 
globin. 

The  blood  of  a  normal  animal  was  also  mixed  with  venom,  outside  of 
the  body,  in  a  test  tube,  and  there  the  htvmolytic  and  discolorizing  prop- 
erties of  venom  .were  conclusively  and  quantitatively  determined.  The 
very  early  experiments  on  these  projierties  of  venom  were  carried  out  by 
Mitchell  and  Reiehert,  who  used  Crotalus  venom;  they  described  also 
the  agglutinating  property  of  that  venom  upon  the  blood  corpuscles  of 
the  rabbit.  While  the  htcmolytic  and  the  agglutinative  properties  of 
venom  were  not  separated  at  that  time  from  one  another,  the  recent 
studies  indicate  the  independent  nature  of  these  two  principles,  and  also 
the  other  cytolytic  components,  like  neurotoxin,  leukolysin,  ha^morrhagin, 
endotheliolysin,  etc.,  which  are  found  to  be  present  in  snake  venoms  in 
varying  proportions,  according  to  the  source  of  the  venom. 

The  nature  of  the  hsemolytic  action  of  venom  has  been  found  to  be 
analogous  to  the  same  process  produced  by  normal  or  artificial  serum 
haemolysins,  and  in  both  cases  there  are  amboceptors  which  require 
certain  complementary  substances  in  order  to  complete  the  solvent  action. 
In  the  case  with  serum-ha?molysis  the  so-called  complements  or  alexines 
act  as  the  complementary  bodies,  while  with  snake  venom  not  only  the 
ordinary  serum  complements  but  also  certain  thermostabile  constituents 
of  the  blood  can  activate  the  venom  amboceptors.  The  thermostabile 
complements  are  found  to  be  the  substances  belonging  to  the  lipoids ;  and 
lecithin  and  kephalin  are  very  suitable  to  activate  venom.  Kyes  succeeded 
in  preparing  a  crystalline  compound  of  the  hsemolytic  principle  of  various 
venoms  and  lecithin.  This  compound  (venom  lecithid)  is  itself  highly 
hsemolytic. 

5.  Additional  Cytolytic  Principles  in  Venom. — Venom  contains  in 
varying  proportions  a  series  of  other  active  solvent  agents  for  various 
cells.  According  to  Flexner  and  Noguchi,^  these  are  solvent  agents  for 
the  cells  of  the  liver,  kidney,  spermatozoa,  testis,  and  ova,  and  they  re- 
quire certain  complementary  substances  to  perform  their  lytic  action  upon 
the  cells.  These  complementary  bodies,  whose  nature  is  still  not  definitely 
known,  exist  either  in  the  body-juice  or  in  the  cell-body,  and  they  are 
made  inactive  by  heating  to  60°  C.  for  half  an  hour. 

6.  Protective  or  Hardening  Property  upon  trie  Red  Blood  Corpus- 
cles.— It  was  demonstrated  by  Mitchell  and  Stewart  that,  when  Crotalus 
venom  is  employed  in  a  strength  above  certain  concentration,  its  de- 
structive action  upon  the  blood  corpuscles  becomes  gradually  weakened, 
until  a  limit  is  reached  where  no  hsemolysis  takes  place. 

In  a  mixture  of  equal  parts  of  venom  and  physiological  salt  solution 
such  a  non-hsemolytic  mixture  wall  keep  for  a  considerably  longer  period 
than  the  normal  controls  without  the  venom.  Myers  and  Stephens  ob- 
served the  same  phenomenon  with  cobra  venom  and  human  blood; 
Flexner  and  Noguchi  with  rattlesnake;  Lamb  with  deboia;  Ivyes,  and 
Kyes  and  Sachs  with  cobra  venom.  The  last  named  authors  tried  to  ex- 
plain this  phenomenon  by  the  hypothesis  that  the  introduction  of  too 
large  an  amount  of  amboceptors  results  in  a  deviation  of  the  complemen- 
tary substance,  lecithin,  which  is  present  only  in  a  limited  quantity  in  the 
mixture.    Noguchi  has,  however,  shown  that  the  corpuscles,  which  are 

^The  Jour,  of  Path,  and  Bad.,  1905,  x,  ill. 


SNAKE  VENOMS  259 

treated  with  such  strong  venom  sokition,  undergo  a  change  which  not  only 
prevents  the  hsemolytic  process  under  the  solvent  action  of  venom,  but  also 
changes  the  corpuscles  so  that  the  escape  of  haemoglobin  in  hypotonic 
media,  like  water,  does  not  occur.  Certain  hsemolytic  agents,  for  example, 
saponin,  tetanolysin  and  cobra  lecithid,  are  without  solvent  action  upon 
the  corpuscles  thus  modified.  On  the  other  hand,  alkalies  and  acids 
hsemolyse  these  corpuscles  with  readiness.  According  to  his  studies,  venom 
forms  an  insoluble  compound  or  precipitate  with  different  constituents  of 
the  blood;  the  formation  of  such  a  precipitate  seems  to  be  the  immediate 
cause  of  rendering  the  corpuscles  non-ha^molysable.  The  precipitates 
produced  by  bringing  venom  and  different  constituents  of  the  blood  into 
contact  are  soluble  in  alkalies  and  acids,  and  this  would  explain  the  haemol- 
ysis of  the  modified  corpuscles  by  those  chemicals.  Another  remarkable 
feature  is  that  the  corpuscles  treated  with  strong  venom  solution  are  not 
hsemolysed  by  a  high  temperature  maintained  for  a  long  time,  at  which 
the  controls  with  normal  blood  undergo  complete  haemolysis.  Among  the 
constituents  of  the  blood  known  to  be  capable  of  forming  a  precipitate  with 
venom  are  haemoglobin,  globin,  and  globulins.  It  is  of  some  interest  to 
note  that  not  all  kinds  of  blood  are  subjected  to  this  change  under  the 
influence  of  venom.  In  cases  where  there  is  no  protective  phenomena,  it 
is  also  found  that  the  haemoglobin  of  such  blood  is  not  able  to  form  the 
water-insoluble  precipitate  with  venom. 

7.  Loss  of  Bactericidal  Property  of  the  Blood. — After  the  apparent 
recovery  from  the  local  and  general  effects  of  various  venoms,  there  are 
many  instances  in  which  a  secondary  infection  has  developed.  This  is 
attributed  to  the  loss  of  the  bactericidal  property  of  the  normal  blood  due 
to  the  venom  poisoning.  According  to  later  investigations  of  Flexner  and 
Noguchi,  the  antibactericidal  property  of  venom  is  due  to  its  faculty  of 
destroying  (or  rendering  inactive)  the  bacteriolytic  complements  of  the 
serum. 

The  fate  of  venom  in  the  organism  is  not  quite  known.  Some  assume 
that  it  undergoes  decomposition,  as  the  blood  of  a  venomized  animal  does 
not  produce  intoxication  in  a  second,  when  it  is  transfused.  Some  thought 
it  to  be  secreted  by  the  urine,  while  still  others  claim  to  have  found  it  in  the 
contente  of  the  stomach. 

Toxicity  of  Venom. — The  minimal  lethal  dose  of  a  snake  venom  de- 
pends upon  the  kind  of  venom  and  upon  the  susceptibility  of  different 
classes  of  animals.  The  figures  by  different  investigators  do  not  quite 
agree,  possibly  because  of  differences  in  the  source  and  preparation  of 
the  venom  used.  The  minimal  lethal  doses  per  kilo  body- weight  for  some 
common  animals  are  as  follows: — 

Elapinse. 

Naja  tripudians  (Cobra). 

Rabbit:  Intravenous  injection,   0.00025-0.0005     (Calmette),     0.00035  (Lamb), 

0.000245  (Fraser),  0.0007  (Elliot) . 
Guinea  pig:  Subcutaneous  injection,  0.0005  (Noguchi),  0.0004  (Calmette),  0.00018 

(Fraser). 
Rat:  Subcutaneous  injection,  0.0004-0.0007  (Lamb),  0.0006  (Calmette),  0.0005 

(Rogers). 
Dog:  Subcutaneous  injection,  0.0005  (Lamb),  0.0008  (Calmette)., 
Horse:  Intravenous  injection,  0.00009  (Lamb). 
Monkey:  Intravenous  injection,  0.00025  (Lamb). 


260  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

Naja  bu7igarus  (King  Cobra). 
Rabbit:  Intravenous  injection,  0.00035  (Lamb). 

Bungarus  fasciatus. 
Rabbit:  Intravenous  injection,  0.0007  (Lamb). 

Subcutaneous  injection,  0.0025-0.003  (Lamb). 

Bungarus  coeruleuse  (Common  Krait). 
Rabbit:  Intravenous  injection,  0.00004  (Lamb). 

Ho  place  phalus  curius  (Tiger-snake). 
Rabbit:  0.000289  (Calmette),  0.00025  (C.  J.  Martin). 

Pseudechis  porphyriacus  (Black-snuke). 
Rabbit:  0.00125  (Calmette),  0.0005  (C.  J.  Martin). 

Hydrophinse  (Sea-snakes). 
Hydros  platurus. 
Pigeon:  0.000075  (Rogers). 
Mud- fish:  0.00025  (Rogers). 

Enhydrina  bengalensis  s.  valakadien. 
Pigeon:  0.00005  (Rogers). 
Mud-fish:  0.0005  (Rogers). 
Rabbit:  Intravenous  injection,  0.00005  (Lamb). 

Crotalidse  (Pit-vipers). 
Ancistrodon  piscivorus  (Water  Moccasin). 
Guinea  pig:  Intravenous  injection,  0.0025  (Noguchi). 
Goat:  Subcutaneous  injection,  0.0004  (Noguchi). 

Crotalus  adamanteus  (Rattlesnake). 
Rabbit:  Intraperitoneal  injection,  0.0002  (Noguchi). 

Subcutaneous  injection,  0.005  (Noguchi). 
Guinea  pig:  Intraperitoneal  injection,  0.002  (Noguchi). 

Viperinse  (Vipers). 
Viper  a  russelli  (Daboia). 
Rabbit:  Intravenous  injection,  0.0001  (Lamb). 
Guinea  pig:  Intraperitoneal  injection,  0.0002  (Lamb). 
Monkey:  Intravenous  injection,  0.003  (Lamb). 

Vipera  berus  (Common  European  Viper). 
Rabbit:  0.004  (Calmette). 

For  a  man  of  60  to  70  kilos  the  fatal  dose  of  cobra  venom  has  been 
reckoned  by  Lamb,  from  the  experiments  on  monkeys,  to  be  0.015  to 
0 .  0175  gm.  Calmette's  estimate  is  0 .  01  gm.,  while  Fraser  puts  the  figure 
as  high  as  0.031  gm.  Rogers  considers  0.0035  gm.  of  the  venom  of  En- 
hydrina to  be  surely  fatal  for  a  man  of  70  kilos. 

Certain  venoms  present  a  great  difference  in  their  fatal  effects  accord- 
ing to  the  mode  of  injection.  The  action  of  cobra  venom  injected  sub- 
cutaneously  is  much  slower  than  when  injected  intravenously,  but  the 
final  result  is  the  same;  while  the  venom  of  Crotalus  or  daboia  can  be 
injected  in  much  greater  quantities  subcutaneously  than  intraperitoneally, 
or  intravenously. 

Cold-blooded  animals  are  less  susceptible  than  warm-blooded;  many 
of  the  invertebrates  especially  are  not  seriously  or  not  at  all  affected. 

The  immunity  of  poisonous  snakes  to  their  own  venoms  seems  to  be 
general.    They  are  also  relatively  immune  to  alien  venoms.    It  is  inter- 


SNAKE  VENOMS  261 

esting  that  the  venoms  of  the  Colubrine  snakes  are  more  poisonous  to 
the  Reptilia  and  Batrachians,  while  the  viperine  or  Crotaiine  venoms 
are  always  less  active  upon  those  classes  of  animals. 

Symptoms  of  Venom  Poisoning  in  Man.— The  symptoms  observed 
in  man  can  be  divided  into  local  and  constitutional.  The  local  symp- 
toms consist  in  a  rapidly  appearing,  inflammatory  swelling  of  the  site  of 
bite,  followed  by  more  or  less  ecchymosis  and  necrosis,  with  or  without 
pain,  and  often  with  the  appearance  of  lymphangitis  and  local  phlegmon. 
With  Crotalidse,  when  the  local  lesions  are  especially  severe,  there  devel- 
ops, besides  the  oedema,  extensive  hemorrhage  and  gangrene. 

The  constitutional  symptoms  are  fever,  cerebral  and  spinal  disturb- 
ances, especially  of  the  medulla,  including  paralysis  of  the  respiratory 
centre.  The  motor  paralysis  also  advances  steadily.  Htematuria,  haemo- 
globinuria,  hsematemesis,  diarrhoea,  vomiting,  amaurosis,  headache,  ver- 
tigo, violent  dyspnoea,  and  general  convulsions  are  often  observed.  In 
the  viperine  poisoning,  cold  perspiration,  a  small  intermittent  pulse,  and 
final  dyspnoea  are  also  seen.  Cobra  venom  destroys  the  respiratory 
functions  rapidly,  without  affecting  the  pupils,  while  the  daboia  poison- 
ing is  accompanied  by  a  dilated  pupil.  Cobra  venom  causes  more  con- 
vulsions. Fayrer  states  that  cobra  venom  kills  a  man  without  affecting 
the  coagulability  of  the  blood,  while  in  a  sub-acute  daboia  poisoning 
the  blood  remains  permanently  fluid.  If  death  occurs  within  several 
minutes  after  the  bite  of  daboia,  extensive  thrombosis  is  found  in  the 
pulmonary  artery  and  right  heart. 

Mortality.— The  mortality  from  snake  bites  is  naturally  greatest  in 
those  countries  where  poisonous  snakes  are  more  abundant  and  the  condi- 
tions of  human  life  favor  exposure.  Thus  in  India  there  is  an  annual 
loss  of  20,000  human  lives,  or  16  per  100,000.  The  temperament  of 
different  species  of  poisonous  snakes  also  influences  the  degree  of  dan- 
ger. Thus,  for  example,  the  comparatively  slight  danger  from  rattle- 
snakes is  due  to  their  sluggish  temperament.  According  to  Weir  Mitchell 
seven-eights  of  all  cases  of  rattlesnake  bites  will  recover,  as  their  fangs 
are  not  raised  enough  and  the  injuries  are  often  made  only  by  the  lower 
teeth.  On  the  other  hand,  cobra  bites  are  fatal  in  from  25  to  45  per  cent, 
of  cases  (Calmette).  The  depth  and  locality  of  the  wound  are  important 
conditions;  the  deeper  the  wound  the  more  dangerous.  Wounds  in  the 
face,  especially  in  the  lips  and  tongue,  are  more  dangerous  than  in  the 
limbs,  while  bites  of  the  fingers  or  toes  are  again  very  dangerous,  owing 
to  the  fact  that  the  fangs  can  be  driven  deeper  in  the  tissue.  The  alleged 
immunity  of  snake-charmers  to  deadly  Egyptian  and  Indian  serpents  is 
not  quite  understood.  In  some  cases  the  poison-fangs  are  certainly  re- 
moved; that  the  snake-charmer  does  not  enjoy  real  immunity  against 
the  effects  of  the  venom  has  been  frequently  shown. 

The  length  of  time  which  elapses  before  death  is  very  variable  in  dif- 
ferent venoms.  The  quickest  fatal  cases  reported  are  two  minutes  m  a 
Crotalus  poisoning,  and  five  minutes  in  a  Japanese  snake  bite,  but  more 
frequently  death  occurs  after  fifteen  minutes.  In  most  of  the  fatal  cases 
of  cobra  poisoning  the  end  comes  between  six  and  twelve  hours,  although 
quite  often  within  two  hours,  or  even  after  one  or  two  days. 

As  to  the  time  of  death  after  the  bite,  Fayrer  gives  the  following  statis- 
tics taken  from  65  fatal  cases  of  cobra  poisoning : 


2G2  DISEASES   CAUSED   BY   ORGANIC  AGENTS 

22.96%  died  less  than  2  hours  after  the  bite, 
24.53%  died  between  2  and  6  hours  after  the  bite, 
23.05%  died  between  6  and  12  hours  after  the  bite, 
9.39%  died  between  12  and  24  liours  after  the  bite, 
"21.10%  died  after  24  hours. 

The  bite  of  the  famous  Laehesis  lanceolatus  of  St.  Martinique  causes 
death  generally  after  one  or  two  days,  and  very  seldom  earlier  than  six 
hours  after  the  bite.  With  the  venom  of  Trigonocephalus,  death  may 
come  after  two  to  five,  or  even  as  late  as  ten  days.  Death  after  sixteen 
days  from  the  Ijite  of  a  Crotalus  has  also  been  reported.  The  viperine 
bites  are  not  quickly  fatal,  but  cause  marked  local  and  general  disturb- 
ances, which  cause  death  after  days,  weeks,  or  months;  but  when  the 
venom  gets  into  the  circulatory  system  death  may  occur  more  quickly, 
with  sudden  loss  of  consciousness,  delirium,  tetanus,  and  trismus. 

In  fatal  cases,  when  death  follows  after  a  long  period,  anatomical 
changes,  such  as  hemorrhage  and  local  necrosis,  are  always  pronounced. 
Even  in  the  patients  that  recover,  local  paralysis  of  the  most  diverse 
parts  of  the  body  may  persist  for  a  long  time,  together  with  various 
local  manifestations  on  the  bitten  side.  The  sequeUie  are  paresthesias 
of  various  kinds,  ])emphigoid  eruptions,  and  pain. 

Treatment  of  Snake  Poisoning.— The  treatment  of  snake  bites  can 
be  divided  into  non-specific  and  specific  therapy. 

The  non-specific  treatment  consists  in  (1)  retarding  absorption  and 
(2)  the  removal  or  destruction  of  the  free  venom  as  far  as  possible.  The 
retarding  of  the  absorption  is  accomplished  by  the  application  of  a 
ligature  above  the  bitten  part,  but  the  ligature  must  be  removed  not 
longer  than  thirty  minutes  after,  because  of  the  danger  of  necrosis.  A 
simultaneous  opening  of  the  fang  wounds  and  cupping  or  sucking  with 
the  mouth  will  remove  the  venom  mechanically.  But  the  injection  of 
certain  chemical  agents  into  or  around  the  bitten  spot  can  be  made 
with  great  advantage,  as  definite  concentration  of  certain  chemicals 
can  destroy  the  free  venom  without  causing  any  serious  injury  to  the 
tissue  itself.  Below  is  given  a  brief  list  of  the  chemicals  which  have  been 
recommended  by  many  eminent  investigators  and  employed  for  the  same 
purposes:  potassium  permanganate  1  to  100  (Weir  Mitchell,  Fayrer, 
Lacerda),  chloride  of  calcium  or  hypochlorite  of  calcium  1  to  GO  or  1  to  72 
(Calmette),  chloride  of  gold  1  to  100  (Calmette),  chromic  acid  1  to  100 
(Kauffmann).  These  chemicals  have  no  neutralizing  action  when  they 
are  injected  into  the  vein  or  parts  distant  from  the  wound.  They 
must  always  be  injected  into  or  around  the  bitten  part. 

As  to  the  general  or  symptomatic  treatment  it  is  recommended  to 
administer  stimulants  in  various  ways.  Halford  recommended  the  injec- 
tion of  10  to  20  drops  of  ammonia  in  equal  parts  of  water  into  a  vein. 
It  has  a  stimulating  action  for  some  time,  but  if  the  amount  of  venom 
inoculated  reaches  a  minimal  fatal  dose  it  fails  to  save  the  life  of  the 
victim.     Experimentally  it  has  no  antidotal  property  whatsoever. 

Miiller  recommended  the  injection  of  strychnine,  but  the  statistics 
obtained  by  Huxtable  show  that  of  426  cases  of  snake  bites,  113  were 
treated  with  strychnine,  and  15  of  these  died,  equalling  13.2  per  cent, 
mortality.  The  remaining  313  had  no  strychnine  and  13  of  them  died, 
making  only  4 . 1  per  cent,  mortality.  In  animal  experimentation  the 
injection  of  small  amounts  of  strychnine,  morphia,  nicotine  and  curare 


SNAKE  VENOMS  263 

not  only  had  no  preventive  action,  but  made  the  results  v^orse  than  the 
control.  Alcohol,  coffee,  and  tea,  seem  to  be  of  some  use  when  used  in 
adequate  quantities.  It  is  often  said  that  alcohol,  when  taken  in  quan- 
tities sufficient  to  cause  profound  intoxication,  will  avert  or  weaken  the 
paralytic  symptoms.  But  such  an  excessive  use  of  alcohol  must  be 
avoided,  as  it  is  proved  in  animal  experimentation  that  this  exerts  a 
decidedly  unfavorable  effect. 

Artificial  respiration  even  for  one  hour  must  be  tried,  and  an  intra- 
venous injection  of  saline  solution  impregnated  with  oxygen  is  also 
recommended. 

Specific  Treatment, — Sewall  found  that  the  pigeon  can  be  gradually 
rendered  resistant  to  increasing  doses  of  Crotalus  venom  by  injecting 
small  sublethal  doses  repeatedly.  He  finally  succeeded  in  bringing  a 
pigeon  to  withstand  ten  times  a  fatal  dose.  Calmette,  in  his  first  work  on 
venom  immunity,  showed  that  an  animal  inoculated  with  sublethal  doses 
of  heated  solution  of  cobra  venom  attains  a  certain  degree  of  immunity 
which  enables  it  to  resist  a  certain  fatal  dose  of  the  venom.  A  similar 
result  was  obtained  by  Phisalix  and  Bertrand  with  viperine  venom.  Cal- 
mette pursued  this  subject  further  and  could  finally  show  that  guinea-pigs 
and  rabbits  acquire  an  immunity  against  the  venoms  of  cobra  after  re- 
peated inoculations  of  small  amounts  of  the  same,  and  that  not  only 
against  cobra,  but  also  against  certain  quantities  of  the  viperine  or  other 
venom.  He  found  also  that  the  serum  of  such  immunized  animals  has  the 
power  to  counteract  the  poisonous  effects  of  venom  in  a  second  animal,  if 
the  serum  has  been  inoculated  into  the  latter  previous  to  the  injection  of 
the  venom. 

According  to  Phisalix  and  Bertrand,  who  worked  with  viperine  venom, 
an  injection  of  0.4  mg.,  heated  to  75°  C.  for  five  minutes,  into  a  guinea-pig 
will  enable  the  latter  to  withstand  the  same  amount  of  the  unheated  poison 
after  two  days.  Fraser  later  confirmed  Calmette 's  results,  while  Calmette 
carried  on  his  immunization  work  still  further  and  finally  prepared  an 
antivenomous  serum,  by  immunizing  large  animals  like  horses  and  asses, 
which  he  used  for  human  cases. 

Calmette  recommended,  for  the  production  of  an  antivenin  for  cobra 
venom,  primary  injections  of  small  animals  with  venom  mixed  with 
1  per  cent,  calcium  chloride;  after  four  injections  of  this  modified  venom, 
gradually  increasing  doses  of  pure  venom  are  injected,  always  carefully 
watching  the  weight  of  the  animal.  He  also  recommends  the  modification 
of  the  venoms  to  be  employed  by  heating  to  75°  C.  for  30  minutes.  The 
antivenin  which  is  issvied  from  his  institute  is  obtained  from  horses  immun- 
ized against  about  2  grams  of  unmodified  venom  (1  m.  1.  d.  for  a  horse  is 
0.01  of  cobra  venom). 

The  immune  serum  is  collected  under  ordinary  aseptic  precautions,  and 
placed  in  small  bottles  holding  10  Cc,  which  are  then  heated  to  58°  C.  for 
one  hour.  According  to  Calmette  such  a  serum  will  keep  for  two  years. 
A  fluid  antivenin  may  undergo  certain  external  changes  (flocculent  pre- 
cipitate) after  being  kept  for  some  time,  but  its  antivenomous  power  re- 
mains generally  unaffected.  Such  precipitate  must  be  removed  by 
filtration  through  sterile  filter  papers,  before  use.  Dried  antivenin  in  sealed 
tubes  will  last  for  an  indefinite  period;  before  using,  it  is  dissolved  in 
sterile  water.    Calmette  considers  that  an  antivenin^  of  which  2  Cc.  will 


264  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

neutralize  1  mg.  of  cobra  venom  mixed  in  tntro,  is  sufficiently  strong  for 
practical  purposes,  and  the  injection  of  20  Cc.  of  this  antivenin  is  recom- 
mended by  him  in  case  of  snake  bite;  in  other  words,  an  amount  sufficient 
to  neutralize  10  mg.  of  cobra  venom. 

The  amount  of  venom  injected  by  a  cobra  at  one  bite  is  estimated  by 
Lamb  to  be  0.231,  Cunningham  o'.25G,  and  Rogers  0.249  gm.  If  we 
accept  these  figures  there  would  still  be  over  200  mg.  of  unneutralized 
venom,  after  the  injection  of  20  Cc.  of  antivenin.  The  minimal  lethal 
dose  of  cobra  venom  for  a  man  of  120  to  140  pounds  is  estimated  to  be 
0 . 01  gm.  (Calmette),  0 .  031  (Fraser),  0 .  015  to  0 .  0175  gm.  (Lamb).  Fraser 
who  once  prepared  a  fairly  active  antivenin,  finally  expressed  his  belief 
that  more  than  350  Cc.  of  the  antivenin,  injected  intravenously,  would  be 
necessary  to  save  a  man  from  the  effects  of  the  bite  of  a  cobra.  Both  the 
mode  of  administration  of  the  antivenin  and  the  length  of  time  elapsing 
since  the  injection  of  the  poison  make  the  therapeutic  value  of  the  anti- 
serum very  different. 

If  the  antivenin  is  injected  directly  into  the  vein  its  action  will  be  much 
quicker  than  when  it  is  given  subcutaneously.  The  longer  the  delay  of  the 
injection  of  the  antivenin,  the  greater  is  the  amount  of  the  serum  required, 
until  a  point  is  reached  when  the  antivenin  will  no  longer  save  the  animal. 
In  a  series  of  therapeutic  experiments  Noguchi  has  proved  that  the  affinity 
between  venoms  and  antivenins  is  very  great,  and  the  use  of  an  antivenin 
in  human  cases  has  a  most  encouraging  prospect. 

A  further  question  of  great  importance  is  that  of  the  specificity  of  an 
antivenin.  C.  J.  INIartin  first  pointed  out  that  the  antivenin  prepared  by 
Calmette,  by  injecting  cobra  venom,  had  almost  no  protective  property 
against  the  venoms  of  the  Australian  snakes.  Lamb's  later  systematic 
investigations  on  this  particular  point  have  led  him  to  believe  that  an  anti- 
venin prepared  by  injecting  a  particular  poison  is  antitoxic  only  for  the 
venom  used  for  the  immunization,  and  has  almost  no  action  upon  other 
venoms.  Kanthack  was  also  convinced  that  the  action  of  an  antivenin  is 
limited  to  the  venom  employed  for  its  production.  Noguchi  has  found 
that  the  action  of  an  antivenin  is  highly,  if  not  absolutely,  specific  both  m 
vitro  and  in  vivo.  It  is  of  great  interest  and  importance  that  the  hsemolytic 
and  neurotoxic  principles  of  difi^erent  venoms  are  not  identical  in  regard  to 
their  behaviors  toward  the  anti-bodies ;  in  other  words,  the  antihsemolytic 
or  the  antineurotoxic  constituents  of  a  given  antivenin  will  neutralize 
respectively  the  htemolytic  or  the  neurotoxic  principles  of  the  venom 
employed  for  its  production,  but  has  no,  or  very  slight,  action  upon  the 
same  named  principles  of  alien  venoms. 

Antivenins  for  cobra,  daboia,  Bungarus,  Crotalus,  w^ater  moccasin, 
Hoplocephalus  curtus,  and  Trimeresurus,  have  been  prepared  by  different 
workers,  but  their  antitoxic  value  has  never  been  high,  as  compared  with 
that  of  diphtheria  antitoxin.  An  antivenin  for  the  cobra  lecithid,  or  for  the 
cobra  venom  from  which  the  lecithid  is  removed,  can  readily  be  produced 
in  animals,  and  their  action  is  specific. 

A  polyvalent  antivenin, — one  prepared  by  treating  animals  with  several 
venoms, — might  prove  of  practical  value,  but  little  work  has  been  done  on 
this  line.  Calmette 's  antivenin  is  prepared  by  a  mixture  of  several  venoms 
in  different  proportions,  still  the  amounts  of  other  venoms  than  that  of 


SNAKE  VENOMS  265 

cobra  are  so  small  that  the  result  is  that  his  antivenin  is  only  of  some  value 
against  the  action  of  cobra  venom. 

The  therapeutic  value  of  antivenin  depends  upon  the  possibility  of  pre- 
paring an  antivenin  of  greater  potency  than  hitherto  has  been  accom- 
plished, and  v^'hen  such  an  object  is  reached  our  specific  treatment  of  snake 
bite  will  be  perfect.  For  the  present,  beside  the  use  of  a  specific  antivenin, 
the  local  treatment  with  any  of  the  above  mentioned  substances,  com- 
bined with  a  general  stimulant,  such  as  tea,  coffee,  or  alcohol,  is  in- 
dispensable. 


CHAPTER  XIII. 

AUTO  -INTOXICATIONS. 
By  ALONZO  ENGLEBERT  TAYLOR,  M,  D. 

Under  the  term  intoxication  we  understand  a  state  of  perversion  of 
physiological  function  induced  by  the  presence  in  the  body  of  abnormal 
substances  or  by  an  excess  or  deficiency  of  normal  metabolic  constituents. 
Under  the  term  constihicnt  is  understood  not  only  materials  of  nutrition 
and  metabolism,  but  also  the  physiological  fluids  and  secretions  asso- 
ciated with  the  different  functions.  It  has  been  long  apparent  that  the 
pharmacological  definitions  of  intoxication  are  too  narrow  to  compre- 
hend the  acts  of  morbid  physiology;  a  definition  from  the  point  |of  view 
of  general  and  experimental  pathology  must  be  made  as  broad  as  here 
stated.  The  mere  presence  of  a  known  poisonous  agent,  the  presence  of 
an  excess,  or  the  absence  of  the  adequate  amount  of  a  normal  substance, 
need  not  lead  to  any  intoxication  demonstrable  under  the  circumstances 
of  the  occurrence  or  experiment;  the  reason  for  this  lies  in  the  singular 
adaptability  of  the  metabolism  and  in  the  enormous  toleration  of  the 
organism.  To  establish  an  intoxication  there  must  be  some  disturbance 
in  the  function  of  the  body.  The  definition  must  not  be  made  so  rigid  as 
to  exclude  the  morphological  results  of  nutritional  and  metabolic  abnor- 
malities. We  cannot  afford  to  exclude  from  their  bearings  on  intoxica- 
tions the  inflammations  and  degeneration  produced  in  morphological 
structures  by  poisons,  even  at  the  risk  of  an  apparently  absurdly  broad 
expansion  of  the  terra  intoxication.  A  close  consideration  of  the  modes 
of  action  of  poisons  will  justify  this  standpoint. 

A  general  classification  of  endogenous  intoxications,  useful  solely  as 
a  working  scheme,  is  contained  on  page  267.  It  is  apparent  that  the 
point  of  view  is  not  consistently  maintained,  in  that  the  classification  is 
in  part  based  on  the  chemical  etiology  and  in  part  upon  the  function  or 
organ  involved. 

Under  auto-intoxications  we  group  the  intoxications  of  endogenous 
metabolic  order.  The  endogenous  parasitic  intoxications  exhibit  rela- 
tions that  are  often  very  intimate.  Indeed,  it  may  be  assumed  that  in 
the  majority  of  infectious  diseases  a  part  of  the  deleterious  result  is 
due  to  auto-intoxications  secondary  to  the  metabolism  of  the  bacteiia, 
but  these  have  necessarily  no  relations  to  the  specific  poison  of  the  par- 
ticular microorganism.  Since  in  some  instances  no  other  intoxications 
are  induced,  we  may  infer  that  some  microorganisms  are  harmful  solely 
through  the  excitation  of  an  auto-intoxication.  These  auto-intoxications 
are  of  the  nature  of  accelerations  and  exaggerations  of  normal  processes — 
catabolism,  oxidation,  and  cytolysis. 

Exaggerations  of  catabolism  and  oxidation  are  common  in  the  infec- 
tious diseases.     Individuals  with  infections  are  not  upon  a  metabolic 

266 


A  UTO-INTOXICA  TIONS 


267 


balance;  when  no  food  is  taken,  the  output  is  greater  than  a  starvation 
output;  and  it  often  exceeds  the  input  by  more  than  a  starvation  output 
when  the  digestion  is  sufficient  to  maintain  an  ordinary  balance.  This 
exaggerated  catabolism  may  affect  both  the  carbohydrate  and  nitrog- 
enous metabolism.  The  patient  wastes,  owing  to  the  excessive  com- 
bustion of  fat  and  muscle,  and  the  end-products  of  the  excessive  protein 
metabolism  are  found  in  the  urine. 


Endogenous 
Intoxications. 


Parasitic. 


Metabolic. 


Retention 
intoxications 


/  Due  to  bacterial  processes, 
r  Alimentary.      \  Due  to  higher  parasites,  as  vermeB 
\  Systemic.    The  infectious  diseases. 

iSuboxidation. 
Superoxidation. 
Insufficiency  of  oxygen. 
Distoxication. 
Overexertion. 

'  Retention  of  bile. 

Retention  of  perspiration. 
■  Retention  of  carbon  dioxide. 

Retention  of  fseces. 
[  Suppression  of  urine. 
Salts,  acids,  alkalies;  acidosis. 
Fever. 
Infections. 
Neoplasms. 

Metabolism      f  S?'","*- ■ 
of  protein.  I  §SS™- 

Metabolism  of  nuclein.      Gout     Oxaluria. 
Metabolism  of  /  Glycosuria, 
carbohydrate  \  Diabetes. 
Metabolism  of  fats.    Acetone  complex. 
Diseases  of       f  Thyroid,  adrenal, 

special  or-    \       pituitary  bodies. 

gans.  [  Pancreas,  liver,  etc. 

An  acceleration  of  cytolysis  is  commonly  observed  in  infectious  dis- 
eases. An  excellent  illustration  is  afforded  by  the  red  corpuscles.  The 
life  of  the  erythrocyte  is  limited.  There  is  a  regulatory  mechanism 
wheieby  the  formation  of  new  cells  is  proportioned  to  the  destruction  of 
circulating  cells;  and  there  is  a  great  reserve  power  of  compensatory 
over-production.  A  prolonged  excessive  destruction  of  red  corpuscles, 
however,  usually  overtaxes  the  centres  of  regeneration,  and  a  reduction  of 
the  unit  of  circulating  cells  is  the  result.  An  acceleration  of  the  normal 
rate  of  destruction  of  erythrocytes  is  a  very  common  result  of  infectious 
diseases.  It  is  usually  not  to  be  attributed  to  the  specific  poison.  Some 
of  the  poisons,  as  the  venoms,  are  directly  erythrolytic  and  certain  bac- 
teria contain  similarly  active  substances;  but  of  the  known  and  isolated 
toxins,  few  are  erythrolytic,  and  the  erythrolysis  must  be  attributed  to 
other  than  the  principal  product  of  the  bacterial  metaboHsm.  In  nephri- 
tis, carcinomatous  cachexia,  scarlatina,  and  in  toluylene-diamine  poison- 
ing, for  example,  we  have  the  same  oligocythsemia,  resting,  according  to 
our  present  knowledge,  upon  an  acceleration  of  the  normal  rate  of  destruc- 
tion of  red  corpuscles.  Similar  considerations  hold  for  the  glandular 
structures  of  the  body,  especially  the  liver  and  kidney.  A  certain  number 
of  liver  cells  are  constantly  passing  through  degeneration  into  death, 
being  replaced  by  new  units  derived  from  healthy  cells.    If  the  number 


268  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

of  cells  dying  be  enormously  inultiplietl  in  the  unit  of  time,  the  organ 
will  exhibit,  a  notable  degree  of  degeneration  unless  the  jjroduction  of 
new  cells  keeps  pace  with  the  increased  destruction.  Should  the  exagger- 
ation of  cell  destruction  be  very  extensive,  reproduction  could  not  keep 
pace,  for  the  simple  reason  that  the  greater  the  cytolysis,  the  fewer  the 
ninnber  of  cells  upon  which  the  reproduction  as  well  as  the  functions 
must  devolve.  Such  cytolytic  degenerations  are  most  common  in  infec- 
tious diseases.  How  these  accelerations  of  cytolyses  are  brought  about 
we  do  not  know.  The  nearest  suggestion  is  thtit  the  process  is  one  allied 
to  fermentation,  and  this  is  supported  by  chemical  study  and  by  the 
observation  that  autolysis  is  more  rapid  in  diseased  and  degenerating 
than  in  healthy  organs.  Another  suggestion  is  that  there  is  a  chemical 
combination  between  some  poison  and  a  protoplasmic  or  nuclear  con- 
stituent, resulting  in  the  death  of  the  cell.  This  has  been  made  positive 
for  certain  cells  by  recent  researches  in  experimental  cytolysis,  but  we 
do  not  know  to  what  extent  it  occurs  in  natural  disease.  Lastly,  it  might 
be  held  to  be  the  result  of  excessive  function,  the  death  of  cells  being 
proportional  to  their  overwork.  This  might  hold  in  some  of  the  acute 
infections  with  very  excessive  catabolism,  but  it  could  scarcely  account 
for  extreme  degrees  of  degeneration  in  cases  of  chronic  course  with  little 
demonstrable  excessive  catabolism. 

However  produced,  it  is  apparent  that  the  functions  of  tissues  must 
be  disturbed  by  these  cytolyses  and  an  auto-intoxication  might  result. 
To  what  extent  this  appears  in  clinical  symptomatology  and  in  the 
course  of  these  diseases,  we  can  only  conjecture.  It  is  possible  that  the 
products  of  tissue  degeneration  may  be  in  themselves  toxic.  Thus  cholin 
is  derived  from  the  cleavage  of  lecithin,  and  recent  investigations  have 
suggested  that  possibly  to  this  or  allied  substances  may  be  attributed 
some  of  the  symptoms  observed  in  general  paralysis  and  other  degenera- 
tive diseases  of  the  central  nervous  system.  In  tetanus,  the  specific 
toxin  seems  almost  entirely  to  dominate  the  symptomatology  and  these 
additional  processes  are  not  observed;  tetanus  is  almost  as  specific  and 
localized  an  intoxication  as  strychnine  poisoning.  In  sepsis,  on  the  other 
hand,  the  exaggeration  of  catabolism  and  cytolysis  is  so  marked  as  to 
suggest  that  in  these  directions  lies  the  chief  and  specific  intoxication. 
This  is  not  the  place  for  a  discussion  of  the  nature  of  the  infectious 
processes,  but,  in  connection  with  true  metabolic  auto-intoxications,  these 
secondary  auto-intoxications  associated  with  infectious  diseases  demand 
a  brief  mention. 

To  Bouchard  belongs  the  credit  of  having  first  systematically  considered 
the  auto-intoxications  from  the  general  point  of  view  of  metabolism. 
During  recent  years  an  enormous  amount  of  work  has  been  directed  to  the 
problems  of  auto-intoxication  and  diseases  of  metabolism.  Withal,  our 
knowledge  of  auto-intoxications  and  of  the  pathology  of  metabolism  is  in  its 
earliest  infancy.  In  no  intoxication  do  we  possess  such  direct  knowledge 
as  we  have  concerning  a  large  number  of  chemical  poisons.  For  this 
the  extreme  complexity  of  the  relations  is  responsible.  Nor  can  much 
be  expected  until  general  and  chemical  physiology  rest  upon  a  broader 
basis.  Once  the  actually  toxic  substance  in  an  auto-intoxication  is  deter- 
mined, the  properties  of  that  substance  become  a  purely  pharmacological 
question.    But  before  the  pharmacological  investigation  of  such  a  sub- 


AUTO-INTOXICATIONS  269 

stance  can  hope  to  elucidate  the  relations  that  are  sure  to  be  all-important 
in  the  delineation  of  an  auto-intoxication,  this  pharmacological  investi- 
gation must  enter  upon  fields  to  which  it  is  now  almost  a  stranger.  Such 
fields  are:  The  relation  of  chemical  composition,  constitution,  aud  con- 
figuration to  the  reacting  organism;  the  reaction  between  jjrotoj)lasm  and 
poison;  the  velocity  of  toxic  action;  the  nature  of  toleration  and  immu- 
nity; the  interreaction  of  poisons  upon  the  chemical  reactions  of  metab- 
olism ;  and  the  relations  of  solubility,  co-efficient  of  distribution, 
ionization,  and  velocity  of  diffusion  to  toxic  action.  Prerequisite  to 
such  investigation,  the  future  development  of  phj^siology  and  pathol- 
ogy will  need  to  elucidate  the  relations  in  metabolism  of  four  general  fac- 
tors: The  role  of  fermentations,  the  validity  of  the  law  of  mass  action, 
the  properties  of  colloids,  and  the  relations  of  electrolytes  to  the  colloids. 
A  separation  of  auto-intoxication  from  the  general  pathology  of  metab- 
olism is  not  possible,  since  all  alterations  in  general  metabolism,  if  they 
lead  to  consequences,  thereby  become  auto-intoxications.  It  is  furthermore 
desirable  from  every  point  of  view  that  the  study  of  the  auto-intoxications 
should  be  carried  out  from  the  point  of  view  of  and  based  upon  the  phy- 
siology of  metabolism.  We  are  all  familiar  Avith  the  conception  of  the 
chemistry  of  life  as  a  series  of  processes  building  up  to  the  cells  and  dis- 
mantling from  them,  assimilation  up  to  the  plane  of  biological  dignity  and 
dissimilation  to  the  plane  of  simple  products.  The  possibility  of  a  mis- 
step in  the  various  stages  of  anabolism  or  catabolism  would  furnish  the 
occasion  for  a  perversion  of  function,  an  intoxication.  It  is  upon  these 
general  considerations  that  the  current  views  of  auto-intoxication  are  based. 
The  preachment  of  Bouchard  is  to  the  effect  that  the  body  is  constantly  on 
the  verge  of  an  intoxication,  particularly  through  a  perversion  of  the  cata- 
bolic  processes,  though  qualitative  variations  in  anabolism  could  produce 
the  same  result.  The  danger  of  this  conception  is  that  it  disregards  entirely 
two  most  prominent  attributes,— the  power  of  adaptation  to  alteration 
in  the  media  of  existence  and  the  power  of  compensation,  of  carrying  an 
overload.  We  have  many  illustrations  of  the  depletion  and  overtaxation 
of  certain  organs  and  functions  and  of  how  admirably  the  body  compen- 
sates for  them.  For  every  function,  it  is  known  that  a  heavy  overload  may 
be  well  borne  through  a  prolonged  period.  Under  these  circumstances  it 
is  absurd  to  say  that  we  are  all  on  the  verge  of  an  auto-intoxication,  liAing, 
so  to  speak,  over  a  charge  of  dynamite  that  may  each  instant  be  pro- 
voked to  explosion.  This  view  of  auto-intoxication  is  an  unwarranted  use 
of  a  physiological  concept.  The  animal  metabolism  cannot  be  compared 
to  a  light  see-saw  board,  balanced  upon  a  knife-edge,  tipping  at  the 
slightest  weight;  but  rather  to  a  heavy  see-saw  board,  balanced  upon  a 
broad  timber,  and  too  rigid  to  tip  except  upon  the  superimposition  of  a 
notable  weight.  This  conception  of  our  metabolism  and  its  leeway  of  adap- 
tation and  compensation,  is  not  only  supported  by  our  best  chemical  studies 
upon  the  subject  but  is  in  harmony  with  the  common-sense  experience  of 
mankind.  And  it  is  to  the  use  of  this  loose  and  subjective  interpretation  of 
the  facts  of  metabolism  and  their  relations  to  disease,  that  the  term 
auto-intoxication  has  become  the  limbo  into  which  untrained  practitioners 
now  consign  their  undiagnosed  cases. 


270  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

GASTRO-INTESTINAL    AUTO-INTOXICATION. 

In  no  subject  in  medicine  is  there  today  more  confusion  than  in  gastro- 
iiitestinal  auto-intoxication.  This  must  in  the  first  instance  be  separated 
from  exogenous  intoxication.  This  is  difficuU,  ])articuUirly  with  respect 
to  intoxication  from  decomposed  food.  It  is  to  be  distinguished  from  the 
gastro-intestinal  infections.  For  these  we  assume  that  they  cause  disease 
in  the  same  manner  as  systemic  infections,  by  the  ehiboration  of  specific 
toxic  substances.  That  the  gastro-intestinal  as  well  as  the  systemic 
infections  do  entrain  real  auto-intoxications  by  disturbing  the  natural 
progression  of  metabolism,  cannot  be  doubted.  Lastly,  gastro-intestinal 
auto-intoxication  ought  to  be  separated  from  indigestion,  dyspepsia, 
gastritis,  and  enteritis.  For  these  diseases,  still  more  than  for  the  specific 
infections,  is  it  certain  that  auto-intoxications  constitute  a  fraction  of  the 
morbid  consequences.  The  question  that  the  future  must  determine  con- 
cerns the  magnitudes  of  the  different  factors.  Our  jncscnt  knowledge  of 
the  diseases  of  the  alimentary  tract  indicates  that  auto-intoxication  in  the 
strict  sense  plays  a  subsidiary  role.  Future  investigations  may  demon- 
strate the  contrary. 

A  discussion  of  gastro-intestinal  auto-intoxication  in  the  strict  sense 
may,  according  to  our  present  knowledge,  be  divided  into  five  headings: 
Digestive  fluids  and  secretions;  normal  products  of  digestion;  abnormal 
products  of  digestion ;  substances  formed  normally  from  food  by  bacteria 
within  the  alimentary  tract;  and  abnormal  products  of  bacterial  disinte- 
gration. 

Intoxication  by  Resorption  of  the  Digestive  Juices. — The  digestive 
juices  have  a  certain  toxicity  independent  of  their  salts  and  reaction. 
Pepsin,  trypsin,  and  erepsin,  when  injected  into  the  circulation,  produce 
cellular  degenerations,  alterations  in  the  corpuscles  and  coagulability  of 
the  blood.  It  is  by  some  assumed  that  these  ferments  are  resorbed  in 
normal  life  and  rendered  harmless  by  some  process  of  distoxication.  This 
granted,  it  is  natural  to  assume  next  that  the  postulated  distoxication  may 
become  disturbed  and  an  auto-intoxication  result.  For  the  assumption 
that  the  ferments  are  resorbed,  there  is  no  foundation  beyond  the  fact  that 
the  tissues  and  circulating  fluids  of  the  body  contain  normally  traces  of 
proteolytic,  lipolytic,  and  glycolytic  ferments.  If  these  are  to  be  regarded 
as  derived  from  the  digestive  glands,  it  is  more  natural  to  assume  that  they 
have  passed  into  the  circulation  directly  than  to  assume  a  secondary  resorp- 
tion from  the  lumen  of  the  tract.  That  the  intestinal  tissue  behind  the 
lining  epithelium  contains  ferments  is  an  experimentally  established  fact. 
Beyond  this  there  is  not  a  single  reported  experimental  fact,  exact  obser- 
vation, or  clinical  fact,  that  is  explained  by  the  assumption  of  the  resorption 
and  non-distoxication  of  the  digestive  juices.  There  are  good  reasons  to 
question  the  resorption  of  ferments.  Ferments  are  colloids,  and,  as  such, 
unadapted  to  absorption.  The  pepsin  and  curdling  ferment  are  digested 
by  the  trypsin;  the  salivary  ferments  are  digested  by  the  pepsin;  and, 
according  to  our  present  experimental  knowledge  of  the  constitution  of 
ferments  and  their  hydrolysis,  the  products  are  amido-acids.  These  fer- 
ments, with  those  of  the  pancreas  a.nd  succus  entericus,  are  exposed  to 
putrefaction  by  bacteria,  to  which  they  are  very  sensitive.  Ferments  are 
prone  to  hydrolysis,  a  fact  capable  of  ready  test-tube  demonstration 


AUTO-INTOXICATION  271 

The  Products  of  Normal  Digestion. — Some  of  these  are  toxic.  The 
albumoses  and  peptones,  when  injected  hypoderrnieally,  produce  fever, 
leukocytosis,  alterations  in  the  coagulability  of  the  blood,  hfemolysis,  and 
cellular  degenerations  of  mild  degree, — all  conditions  not  particularly 
associated  with  so-called  gastro-intestinal  auto-intoxication.  In  the 
severe  degenerative  diseases,  as  acute  yellow  atrophy  of  the  liver,  acute 
pancreatitis  and  septic  exudations,  these  proteins  may  be  found  in  the 
blood  plasma;  there  is,  indeed,  a  probability  that  albumosfcmia  regularly 
accompanies  fever.  The  writer  is  acquainted  with  no  experimental  work 
or  clinical  investigations  tending  to  show  that  these  lower  proteins  are 
responsible  for  any  gastro-intestinal  auto-intoxication. 

The  amido-acids  are  quite  innocuous  so  far  as  they  have  been  investi- 
gated and  in  the  quantities  that  could  be  met  with.  Amido-nitrogen  is 
found  in  all  organs  and  in  the  circulation.  In  conditions  attended  with 
excesses  of  cellular  degeneration,  as  in  acute  yellow  atrophy  of  the  liver, 
large  quantities  of  these  substances  have  been  found  in  the  blood  and  the 
tissues.  There  are  no  reported  analyses  tending  to  show  that,  in  connec- 
tion with  gastro-intestinal  auto-intoxications,  the  content  of  amido-nitro- 
gen in  the  blood  or  urine  is  increased. 

Charrin  has  attempted  under  the  term  "fever  of  digestion"  to  set  up,  as 
a  clinical  entity  in  children,  a  condition  assumed  to  be  the  result  of  an 
abnormal  performance  of  the  cligestive  functions,  unassociated  with  any 
infection.  The  descriptions  lack  clearness  and  precision,  and  these  defects 
have  been  exaggerated  by  the  later  reports. 

The  products  of  the  digestion  of  fats  must  also  be  held  guiltless.  Glycer- 
ine is  somewhat  toxic;  there  is  normally  no  glycerine  in  the  urine. 
Since  the  fats  are  found  resynthesized  in  the  retroperitoneal  lymph  ves- 
sels, it  is  apparent  that  the  glycerine  split  off  during  the  digestion  has  been 
again  used  in  the  recombination.  The  fatty  acids  themselves  cannot  be  a 
factor,  because,  when  administered,  they  are  easily  absorbed  and  converted 
into  fats  by  the  addition  of  glycerine.  The  products  of  the  carbohydrate 
digestion  are  entirely  innocuous. 

Abnormal  Products  of  Digestion. — Of  qualitative  variations  in  the 
digestion  of  protein  we  know  little.  In  the  complete  hydrolysis  of  pro- 
tein a  large  number  of  amido-acids  are  formed.  Recent  investigations 
indicate  that  the  different  proteins  contain  the  same  amido-acids  but  in 
different  relative  amounts  and  probably  in  different  combinations  v\dthin 
the  molecule.  In  the  act  of  absorption,  the  products  of  the  protein  di- 
gestion are  reconverted  into  protein,  not  into  the  original  forms  present 
in  the  diet,  but  into  serum  albumin  and  serum  globulins.  In  the  act  of 
absorption  further,  the  biological  stamp  is  placed  upon  these  proteins, 
in  particular  upon  the  globuUns.  Whatever  of  these  processes  of  syn- 
thesis is  not  completed  in  the  intestinal  mucosa  is  completed  in  the 
liver.  It  is  conceivable  that  under  abnormal  conditions  the  products  of 
digestion  might  suffer  some  alteration,  either  within  the  tract  or  during 
the  process  of  absorption.  We  have  no  facts  that  indicate  that  such  is 
the  case.  There  is,  in  connection  with  the  digestion  of  fats,  one  recog- 
nized possibiHty  for  an  abnormal  de^dation, — the  formation  of  /?-oxy- 
butyric  and  diacetic  acid.  As  will  be  described  under  acidosis,  there  is 
one  group  of  cases  of  acetonuria  associated  with  gastro-intestinal  symp- 
toms which  may  be  of  gastro-intestinal  origin,  though  at  present  the 


272  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

evidence  is  against  this  direct  relationship.  In  connection  with  the  diges- 
tion of  carbohydrate,  it  must  be  borne  in  naind  that  a  gastro-intestinal 
oxahiria  is  theoretically  possible,  the  oxalic  acid  being  derived  from 
glucose.  Cystinuria  and  alkaptonuria  Avere  once  regarded  as  of  gastro- 
intestinal origin,  but  this  ])()int  of  view  cannot  now  be  maintained. 

Substances  Formed  by  Bacteria  from  Normal  Food  Within  the  Ali- 
mentary Tract.— The  normal  digestive  tract  contains  many  sapro])hytes 
•ind  not  a  few  pathogenic  bacteria.  The  temperature  is  favorable, 
nutrient  media  are  abundant,  the  products  of  their  metabolism  are  regu- 
larly removed,  and  we  have  the  best  evidence  that  fermentations  and  putre- 
factions are  constantly  in  operation.  The  material  consumed  in  these 
operations  is  not  large;  over  nine-tenths  of  the  food  is  absorbed  in 
digestion  and  the  larger  portion  of  the  remainder  is  residual  in  the  faeces. 
This  is  not  due  to  the  antise]:)tic  pro]:)erties  of  the  digestive  juices  (which 
are  not  ])ronounced),  but  rather  to  the  rapidity  of  the  processes  of  diges- 
tion and  absorption,  and  to  the  brief  residence  of  the  residue  in  the 
tract. 

Do  the  products  of  the  normal  bacterial  disintegration  of  normal  food 
give  rise  to  intoxications  ?  Under  conditions  of  increased  virulency  upon 
the  part  of  the  bacteria  normally  present,  may  not  greater  quantities  of  the 
normal  products  be  generated,  with  the  causation  of  an  intoxication  ?  One 
must  attempt  to  separate  systemic  intoxication  from  local  irritation.  The 
stools  of  children  with  acute  enterocolitis  may  present  the  acidity  of  a 
tenth-normal  acid,  due  to  acetic  and  butyric  acids.  Now  since  the 
ammonia  and  fixed  alkalies  of  the  urine  need  not  be  increased  in  these 
cases,  it  is  clear  that  the  children  are  not  suffering  from  an  acid  intoxi- 
cation by  absorption.  But  there  can  be  no  doubt  that  such  a  degree  of 
acidity  causes  irritation  and  inflammation  of  the  mucous  membrane  and 
might  be  responsible  for  colic,  diarrhoea,  and  fever.  The  products  of 
normal  fermentation  and  putrefaction  within  the  alimentary  tract  are,  so 
far  as  we  know,  the  following :  From  the  fermentation  of  carbohydrates  are 
derived  formic,  acetic,  butyric,  proprionic,  valerianic,  lactic,  succinic,  and 
traces  of  oxalic  acids.  Apart  from  oxalic  acid,  none  of  these  are  toxic 
beyond  their  acidity.  The  quantities  formed  are  not  large.  They  are  in 
large  part  absorbed,  since  normal  ffeces  contain  but  traces  of  them.  Their 
neutralization  and  oxidation  entrains,  in  all  probability,  no  metabolic 
difficulties,  and  we  may  regard  them  as  innocuous.  The  same  acids  could 
in  part,  together  with  oxy-acids,  be  derived  from  the  bacterial  disinte- 
gration of  the  fats;  this  occurs  but  to  a  slight  extent,  since  fatty  acids  are 
very  difficult  of  fermentation.  The  putrefaction  of  protein  yields  the 
derivatives  of  the  benzol  nucleus — indol,  skatol,  phenol,  and  cresol; 
amido-acids,  such  as  leucin,  tyrosin,  asparaginic  and  glutamic  acids; 
hexone  bases  and  their  derivatives;  sulphurous  bodies,  such  as  mer- 
captan,  hydrogen  disulphide,  and  other  unclassified  bodies  containing 
neutral  sulphur.  Indol,  skatol,  phenol,  and  cresol,  are,  in  the  quantities 
concerned,  quite  non-toxic.  The  amido-acids  are  quite  harmless;  they 
are  absorbed  and  either  elaborated  or  oxidized.  The  sulphur  bodies  are 
of  unknown  importance.  Hydrogen  disulphide  is  of  course  toxic,  but 
the  quantities  concerned  are  trivial.  Carbon  dioxide,  nitrogen,  acetone, 
alcohol,  methane,  and  other  hydrocarbon  gases  that  exist  in  traces,  can 
not  be  convicted  of  any  toxic  effects. 


A  UTO-INTOXICA  TIONS  273 

Thus  the  sum  total  of  our  present  knowledge  is  that  in  the  normal 
bacterial  disintegration  of  foodstuffs  in  the  alimentary  tract  no  known 
toxic  substance  is  formed.  To  plead  that  since  some  of  the  denominated 
substances  are  toxic  in  overwhelming  doses,  they  must  lie  therefore  in 
every  dose  poisonous  to  some  degree,  and  that  consequently  we  are  all 
constantly  intoxicated  to  a  slight  extent  but  are  able  to  nullify  the  effects, 
is  not  a  proper  toxicological  argument.  This  is  indeed  the  position  of 
the  Bouchard  school,  well  exemplified  in  the  expression  "Auto-intoxica- 
tion a  I'etat  normal."  This  theory  is  lacking  in  objectivity  and  in  its 
concrete  interpretation  incapable  of  control.  A  normal  life  cannot  be 
termed  an  auto-intoxication  if  this  term  is  to  retain  any  meaning. 

Are  these  bacterial  processes  sometimes  so  excessive  as  to  cause  a 
direct  intoxication?  In  infantile  enterocolitis  the  organic  acids  may  be 
produced  in  excessive  quantities  and  possibly  these  are  responsible  for 
some  of  the  acid  intoxications;  we  do  not  know  whether  these  fatty 
acids  cause  acidosis  or  whether  it  is  always  due  to  the  acids  of  the  acetone 
group.  Intoxication  with  hydrogen  disulphide  occurs  certainly,  though 
rarely.  When  so  much  hydrogen  disulphide  is  absorbed  as  to  appear 
unoxidized  in  the  urine,  it  is  proper  to  attribute  to  it  the  suggestive  toxic 
symptoms  that  are  present.  Large  quantities  of  lactic  acid  are  some- 
times found  in  the  stomach;  indeed,  there  are  paroxysmal  attacks  ac- 
companied by  excessive  formation  of  this  acid.  There  is  no  evidence 
that  it  is  absorbed,  since  the  lactic  acid  met  with  in  the  urine  is  optically 
active,  while  that  obtained  from  the  stomach  is  inactive. 

In  many  conditions  of  the  alimentary  tract  the  benzol  derivatives  are 
increased  in  the  urine.  While  this  should  be  interpreted  to  mean 
nothing  more  than  that  the  bacterial  processes  in  the  intestine  are  in- 
creased, it  is  usually  interpreted  as  a  sign  of  auto-intoxication.  If  the 
pancreatic  duct  be  ligated,  the  conjugated  sulphates  will  sink  to  almost 
nothing;  the  bacteria  act  not  on  the  protein  but  most  energetically  upon 
the  products  of  pancreatic  digestion.  Indol  and  skatol  are  products  of 
the  action  of  bacteria  on  tryptophane,  an  end-product  of  tryptic  diges- 
tion. They  are  for  the  most  part  absorbed,  eliminated  paired  w4th  sul- 
phuric and  to  some  extent  with  glycuronic  acid,  and  in  small  part  as 
oxyacids.  Skatol-carboxylic  acid  is  in  part  eliminated  as  a  salt,  in  part 
oxidized.  The  phenol  and  cresol  are  derived  from  tyrosin.  They  are 
absorbed,  in  large  part  oxidized  to  hydrochinon  and  pyrocatechin  (which 
pair  with  sulphuric  acid);  the  rest  is  eliminated  paired  w4th  sulphuric 
and  glycuronic  acid.  Paraoxyphenyl-acetic  and  -proprionic  acids,  inter- 
mediary products  in  the  derivation  of  phenol  from  tyrosin,  appear  as 
salts  in  the  urine,  but  bear  no  constant  relation  to  either  the  tyrosin  or 
the  phenol.  Hippuric  acid,  apart  from  that  obtained  from  the  vegetable 
diet,  is  probably  derived  from  phenyl- alanine.  Normally  the  absorption 
of  these  substances  is  very  good,  but  that  cannot  be  assumed  and  should 
be  controlled  by  examination  of  the  stools.  The  conjugation  of  the  aro- 
matic bodies  occurs  largely  in  the  liver,  to  some  extent  in  the  lungs  and 
kidneys;   the  oxidations  occur  in  large  part  in  the  liver. 

There  is  normally  little  putrefaction  but  much  fermentation  in  the 
small  intestine.  Obstruction  of  the  colon  leads  to  little  increase  in  putre- 
faction, obstruction  of  the  small  intestine  leads  to  a  morbid  increase; 
nevertheless  in  a  few  reported  cases  there  was  no  increase  in  the  urinary 

IS 


274  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

aromatic  sulphates.  Diarrhoea  usually  leads  to  a  diminution  of  putre- 
faction, but  in  typhoid  fever,  dysentery,  and  intestinal  tuberculosis,  we 
often  observe  an  increase.  There  is  no  relation  between  gastric  acidity 
and  intestinal  putrefaction:  the  hydrochloric  acid  is  too  distant  from 
the  colon.  There  is  no  constant  relation  between  intestinal  {)utrefaction 
and  the  biliary  secretion;  there  is  an  antiseptic  tendency  in  the  bile,  but 
it  is  not  pronounced.  Intestinal  putrefaction  is  dependent  to  some  ex- 
tent upon  the  diet.  With  an  excess  of  protein,  an  abundant  substrate 
is  afforded  the  bacteria.  In  the  qualitative  sense  the  products  of  intes- 
tinal putrefaction  will  depend  to  some  extent  upon  the  particular  pro- 
teins contained  in  the  diet.  Proteins  that  yield  nuich  tryptophane  on 
hydrolysis  will  yield  much  indol,  skatol  and  their  derivati\es;  proteins 
that  yield  much  tyrosin  on  hydrolysis  A\ill  yield  much  phenol  and  cresol 
and  their  derivatives.  Thus  serum  albumin  and  globulin,  fibrin,  casein 
and  histone  yield  large  amounts  of  tyrosin  and  but  little  tryptophane, 
while  gelatine,  elastine  and  egg-albumin  yield  much  tryptophane. 

Intestinal  putrefaction  is  dependent  on  the  diet  apart  from  protein. 
The  ingestion  of  carbohydrate  tends  to  reduce  the  putrefactive  processes, 
presumably  by  virtue  of  the  acids  of  fermentation.  In  starvation  the 
putrefaction  is  low.  The  flora  of  the  alimentary  tract  is  of  great  impor- 
tance, though  as  yet  little  studied  in  detail.  Certain  of  the  actively 
putrefying  anaerobic  bacteria  produce  no  indol  or  skatol  but  much  phenol; 
the  colon  bacillus  is  an  active  producer  of  indol.  Variations  in  the  flora 
may  be  of  determining  influence  in  the  quantitative  relations  of  the  dif- 
ferent aromatic  substances. 

There  is  no  constant  relation  between  the  protein  ration  and  the  output 
of  aromatic  substances.  No  one  single  aromatic  substance  bears  a  con- 
stant relation  to  the  total  conjugated  sulphates;  this  is  to  be  emphasized 
for  indican.  One  cannot  judge  of  the  total  paired  sulphates  from  the 
indican;  one  may  see  high  indicanuria  with  a  low  total,  or  high  values 
for  the  total  with  but  traces  of  indican.  There  is  no  constant  relation 
between  the  aromatic  substances  and  the  bacterial  count  of  the  faeces. 
The  least  faulty  method  of  determining  the  extent  of  intestinal  putre- 
faction is  by  the  estimation  of  the  conjugated  sulphates.  Nevertheless 
this  may  yield  a  totally  false  interpretation.  One  sees  individuals  in 
perfect  health  who  eliminate  large  quantities  of  aromatic  substances. 

What  is  then  the  exact  meaning  of  an  increase  in  benzol  derivatives 
in  the  urine?  A  normal  output  need  not  indicate  a  normal  state  of  in- 
testinal putrefaction;  an  excessive  output  indicates  that  more  protein 
than  usual  is  undergoing  putrefaction  in  the  alimentary  tract.  (We  are 
not  here  concerned  with  tissue  putrefaction,  which  of  course  gives  rise 
to  an  excess  of  aromatic  bodies  in  the  urine.)  This  may  be  due  simply 
to  some  individual  idiosyncrasy,  to  peculiarities  in  the  diet,  to  a  height- 
ened virulence  of  the  bacterial  flora,  to  the  presence  of  a  particular  bac- 
terium, or  to  the  retention  of  the  food  in  the  tract.  Does  it  necessarily 
indicate  an  intoxication  ?  By  no  means.  A  certain  amount  of  intestinal 
putrefaction  is  normal;  an  increase  may  be  entirely  innocuous.  A  con- 
stant relation  between  putrefaction  and  intoxication  could  hold  only  if 
the  aromatic  bodies  were  in  themselves  toxic,  if  the  process  of  oxidation 
and  pairing  were  deleterious  to  the  body,  or  if  the  formation  of  the  aro- 
matic substances  bore  a  constant  relation  to  the  elaboration  of  some 


A  UTO-INTOXICA  TIONS 


275 


unknown  poison  and  to  the  symptoms.  There  is  no  evidence  that  the 
substances  are  themselves  toxic  to  any  degree,  or  that  the  conjugation 
places  any  burden  upon  the  body.  The  amount  of  sulphuric  acid  avail- 
able for  conjugation  with  the  aromatic  bodies  is  limited  by  the  extent 
of  protein  catabolism;  and  the  actual  availability  of  it  will  be  determined, 
in  part  at  least,  by  the  excess  of  cations  in  the  diet.  It  is  possible  that 
the  conjugation  with  glycuronic  acid  may  be  in  part  reciprocal  to  the 
conjugation  with  sulphuric  acid.  We  have  no  method  of  estimating  the 
quantity  of  aromatic  bodies  that  are  eliminated  with  glycuronic  acid. 
We  have  no  feasible  method  of  estimating  the  oxidized  aromatic 
substances.  There  is  no  clinical  parallelism  between  symptoms  and 
conjugated  sulphates  in  the  urine,  either  in  degree  or  in  the  onset  and 
disappearance.  What  is  all  along  actually  assumed  is  that  other  sub- 
stances, poisons,  are  produced  by  the  putrefaction;  and  as  the  degree  of 
putrefaction  may  be  often  approximately  measured  by  the  aromatic  sub- 
stances, the  degree  of  the  hypothetical  poisoning  is  also  so  measured. 

Table  of  Aromatic  Urinary  Products  of  Intestinal  Putrefaction. 


Tryptophane- 


Skatol-acetic 
acid—* 


p-Oxy-phenyl- 
acetic  acid— » 


Tyrosin. 


r  Indican.  + 
-Indol— >    "I  Indoxyl-glycuronic  acid. 
[  Oxidation  products. 


Skatol-sulphuric  acid.  + 
-Skatol— >      Skatol-glycuronic  acid. 

Oxidation  products. 

Skatol-carboxylic  acid. 
As  salt. 
With  sulphuric  acid. 

Phenol-sulphuric  acid.  + 

Phenol-glycuronic  acid. 
->Phenol— »  \  Hydrochinon-sulphuric  acid.  + 

Pyrocatechin-sulphuric  acid.  + 

Benzoic  acid— ^Hippuric  acid. 


p-Oxy-phenyl- 
proprionic  acid- 


-^Cresol- 


f  Cresol-sulphuric  acid.  + 

\  Cresol-glycuronic  acid.  + 

[  Benzoic  acid^  Hippuric  acid. 


I  As  salt. 

[  With  sulphuric  acid.  + 
->  Benzoic  acid  — >  Hippuric  acid. 


Phenyl-alanine  — >  x  — >  x 

The  crosses  indicate  the  substances  that  are  included  in  the  method  for  the 
total  setherial  sulphates.  Since  we  are  not  able  at  the  present  time  to  estimate 
or  control  the  amounts  of  aromatic  derivatives  eliminated  in  other  form  that 
paired  with  sulphuric  acid,  it  is  obvious,  not  only  that  the  estimation  of  indican 
must  often  be  of  no  value,  but  also  that  the  estimation  of  the  conjugated  sul- 
phates must  often  yield  an  uninterpretable  result,  and  one  that  will  permit  of 
no  inference  as  to  the  degree  of  intestinal  putrefaction. 

Abnormal  Products. — When  proteins  are  subjected  to  putrefaction, 
a  large  number  of  alkaloid-like  substances  are  formed,  commonly  termed 
ptomains.  They  include  a  large  number  of  substances  of  the  fatty 
series,  amines,  and  members  of  the  pyridin  and  the  chinolin  series.  In 
addition  there  are  a  number  of  bases,  some  belonging  to  the  pyridin 
group,  others  yielding  reactions  of  chinolin,  while  still  others  resemble 
muscarin.    Most  of  these  ptomains  are  innocuous.    None  of  them  except 


276  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

the  simple  amines  have  ever  been  found  in  the  urine  or  faeces  of  normal 
individuals  or  of  those  sufi'ering  from  any  diseases  except  cholera,  idio- 
pathic cystinuria  (occasionally  dysentery,  enteritis,  and  obstruction),  and 
true  ptomain  poisoning  due  to  the  ingestion  of  decomposed  protein. 
Several  years  ago  the  writer  made  a  systematic  search  for  ptomains  in  the 
urine  and  faeces  of  patients  with  pernicious  anaemia,  gastric  carcinoma, 
chronic  gastro-intestinal  disease,  and  subacute  partial  obstruction  of  the 
intestine,  always  with  negative  results.  It  is  known  from  experimental 
work  that  time  is  required  for  the  elaboration  of  ptomains,  particularly 
the  toxic  ones;  in  general  no  poisonous  bases  are  formed  in  less  than 
ten  days.  That  these  relations  are,  however,  only  relative  is  shown  by 
the  fact  that  in  some  of  the  well-studied  cases  of  ptomain  poisoning  due 
to  the  ingestion  of  decomposed  food,  the  analytically  incriminated  foods 
have  been  but  a  few  days  old.  We  possess  no  information  that  in  the 
so-called  gastro-intestinal  auto-intoxications  (the  ingestion  of  decomposed 
foods  must  be  excluded)  ptomains  have  ever  been  found.  Since  a  cer- 
tain decomposition  of  food  occurs  within  the  alimentary  tract  and  the 
degree  of  this  decomposition  may  be  increased  under  certain  conditions, 
we  are  driven  to  the  conclusion  (a)  that  there  is  not  time  for  these 
changes  to  proceed  to  the  stage  of  ptomain  formation,  (b)  the  ptomains 
are  decomposed  in  the  system,  or  (c)  the  decomposition  of  protein  in 
the  intestine  is  different  from  that  outside  the  body.  The  last  conjecture 
may  be  dismissed.  We  are  left  to  choose  between  the  other  possibilities: 
Either  ptomains  are  not  formed  in  the  alimentary  tract  (apart  from  the 
known  instances  already  mentioned)  or  they  are  formed  and  distoxi- 
cated.  What  evidence  is  there  that  ptomains  are  distoxicated  ?  In 
experimental  work,  ptomains  are  eliminated  in  the  urine  just  as  in  idio- 
pathic cystinuria.  The  general  concensus  of  opinion  is  that  for  the 
diagnosis  of  ptomain  poisoning,  the  presence  of  the  poison  must  be 
demonstrated.  Such  chemical  demonstration  has  never  been  accom- 
plished for  the  class  of  cases  under  discussion.  Of  experirnental  demon- 
stration, w'e  have  largely  the  measurement  of  the  urotoxic  co-efficient. 
But  since  the  normal  urotoxic  co-efficient  is  valueless,  deviations  are  of 
little  import.  The  strict  conclusion  to  be  drawn  from  our  present  know- 
ledge is  that  the  term  "ptomain  poisoning"  should  be  confined  to 
instances  of  intoxication  due  to  the  ingestion  of  decomposed  food  and 
accompanied  by  the  elimination  of  the  poison,  and  to  instances  of  decom- 
position within  the  tract  in  which  toxic  ptomains  may  be  isolated.  All 
other  usage  is  guess-work.  The  presence  of  cadaverin  and  putrescin 
would  mean  little,  for,  apart  from  their  harmless  roles  in  cystinuria, 
they  are  to  be  found  in  old  digestion  experiments,  where  they  are 
derived  by  fermentation  of  lysinandornithin,  and  thus  they  do  not  neces- 
sarily indicate  an  abnormal  bacterial  decomposition.  The  neurinc  group 
has  been  considered  responsible  for  some  of  the  symptoms  of  Addison's 
disease,  though  without  chemical  demonstration. 

There  are  several  clinical  symptom-complexes  in  which,  though  the 
term  ptomain  poisoning  is  improper,  there  are  reasons  of  fact  and  anal- 
ogy that  furnish  some  warrant  for  the  use  of  the  term  gastro-intestinal 
auto-intoxication.  What  is  needed  in  these  domains  is  exact  investiga- 
tions,— accurate  clinical  observation  and  objective  chemical  research. 
While  there  is  a  large  element  of  an  art  in  practical  medicine,  diagnosis 


AUTO-INTOXICATIONS  111 

ought  to  be  an  objective  science.  There  is  an  element  of  fashion,  per- 
sonal or  collective,  in  the  manner  in  which  the  obscure  conditions  of 
disease  are  interpreted.  The  progress  of  the  auto-intoxication  propa- 
ganda, like  that  of  every  other  uncontrolled  movement  in  practical  medi- 
cine, is  like  the  development  of  gossip  in  common  life:  The  first  person 
suggests  that  it  might  be  so,  the  second  states  that  it  is  so.  The  serious 
aspect  of  the  situation,  which,  if  we  may  judge  by  the  history  of  medicine, 
is  ephemeral  and  in  a  sense  self-corrective  (a  good  illustration  is  afforded 
in  the  history  of  the  diagnosis  of  malaria),  lies  in  the  fact  that  positive 
diagnosis,  however  fictitious,  inhibits  investigation. 

Tetany. — Under  tetany  we  understand  the  full  complex,  excluding  the 
atypical  instances  of  peripheral  or  carpopedal  spasm.  The  tetanies 
associated  with  extirpation  of  the  thyroid,  intestinal  parasites,  pregnancy 
and  lactation,  acute  infections,  exogenous  intoxications,  rachitis,  and  the 
so-called  epidemic  or  occupational  variety,  can  have  no  dependence  upon 
the  digestive  tract. 

Typical  tetany  of  the  severe  form  occurring  in  adults  in  association  with 
gastric  dilatation  is  rare  and  very  fatal.  The  dilated  obstructed  stomach 
furnishes  a  most  favorable  opportunity  for  the  decomposition  of  food. 
To  determine  whether  these  processes  have  gone  to  the  stage  of  the  pro- 
duction of  poisons,  the  gastric  contents  and  urine  have  been  investigated. 
Hyperchlorhydria  cannot  be  incriminated.  In  a  few  instances  unchar- 
acterized  substances  have  been  obtained  from  the  gastric  contents 
(method  of  Brieger)  that  were  somewhat  toxic  to  rabbits;  in  other  cases 
the  substances  were  innocuous.  From  the  urine  in  a  few  cases,  substances 
have  been  isolated  that  gave  group  reactions  of  ptomains  but  were  not 
toxic  on  intravenous  injection  into  rabbits.  Up  to  the  present,  therefore,  a 
ptomain  poisoning  has  not  been  demonstrated  for  tetany.  Tetanic  seiz- 
ures are  observed  in  dogs  in  whom  the  duodenum  is  cut  across  and  the 
ends  brought  into  external  fistulae,  so  that  the  gastric  contents  leave  the 
body;  the  results  might  be  explained  by  the  assumption  that  there  is  in 
the  gastric  secretion  some  substance,  a  constituent  necessary  to  the  inter- 
mediary metabolism,  that  should  return  to  the  circulation  by  intestinal 
resorption. 

The  tetany  of  children,  associated  with  gastro-intestinal  symptoms  and 
diseases,  is  often  accompanied  by  acidosis,  and  an  excess  of  ammonia  and 
of  aromatic  bodies  in  the  urine.  The  toxicity  of  properly  prepared 
extracts  from  the  urine  or  digestive  contents  has  not  been  studied.  The 
association  with  the  acidosis  is  of  slight  moment,  since  this  is  very  com- 
mon in  children  in  subnutrition. 

The  Alimentary  Tract. — Commonly  regarded  as  intoxications  are 
certain  gastro-intestinal  attacks  associated  with  cutaneous  symptoms. 
The  symptoms  are  pain,  vomiting,  often  diarrhoea,  fever,  followed  by  a 
general  erythema,  urticaria,  or  possibly  by  other  exanthemata.  Desqua- 
mation may  follow.  The  symptoms  in  many  cases  resemble  closely 
intoxication  with  shell-fish  in  susceptible  individuals,  less  closely  the  drug- 
exanthemata.  These  attacks  tend  to  recur  periodically.  Recovery  usually 
follows  promptly  after  gastric  lavage,  irrigation  of  the  colon,  and  free 
purgation.  Ptomains  have  never  been  reported  in  the  contents  of  the 
tract  or  urine.  The  writer  is  acquainted  with  one  case  in  which  a  care- 
ful search  was  made  with  negative  results. 


278  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

Not  infrequently  instances  of  severe  violent  disturbances  of  the  alimentary 
tract  are  observed  that  bear  all  the  external  marks  of  an  auto-uitoxication. 
Usually  no  adequate  cause  is  to  be  determined,  particularly  no  gross 
dietary  indiscretion.  The  attacks  consist  of  sudden  vomiting,  that  may  be 
uncontrollable,  extreme  pain,  profuse  diarrhoea  in  some  cases,  and  in 
others  spasms  of  the  intestine,  with  mcteorism,  vertigo,  vasomotor  dilata- 
tion, shock,  local  spasms,  even  convulsions  and  coma.  It  does  not  seem 
possible  to  consider  these  as  indigestions  or  infections.  If  it  is  possible  to 
exclude  exogenous  intoxication,  the  assum])tion  of  a  gastro-intestinal 
auto-intoxication  is  justified,  even  though  a  chemical  investigation  (which 
has  apparently  never  been  attemjited)  should  fail  to  isolate  any  known 
poison.  This  reasoning  does  not  hold  for  the  marasmus  of  enterocolitis. 
One  must  here  choose  between  a  gastro-intestinal  and  a  metabolic  auto- 
intoxication, and  there  has  been  so  little  work  done  that  a  definite  opinion 
is  not  now  possible.  The  recurrent  vomiting  of  children  will  be  discussed 
under  acetone  acidosis. 

In  connection  with  subacute,  complete,  or  partial  obstruction  of  the 
stomach  or  intestine,  symptoms  suggesting  gastro-intestinal  auto-intoxica- 
tion are  usually  noticed.  There  is  fever,  albuminuria,  headache,  insom- 
nia, a  marked  increase  in  the  aromatic  substances  in  the  urine,  sometimes 
exanthematous  rashes,  possibly  severe  nervous  symptoms,  \Ahich  sub- 
side when  the  obstruction  is  relieved.  The  difference  in  the  appearance 
of  patients  with  gastric  carcinoma,  before  and  after  gastro-enterostomy, 
is  usually  so  striking  that  one  is  driven  to  question  whether  this  can  be 
explained  by  the  conditions  of  nutrition,  and  is  not  due  in  part  to  the  re- 
moval of  conditions  of  decomposition  in  the  stomach.  Nevertheless  the 
definite  demonstration  is  wanting.  In  not  a  few  instances  of  chronic  ap- 
pendicitis, nervous  symptoms  have  been  prominent  (even  epileptic  seiz- 
ures), which  disappeared  with  the  removal  of  the  appendix.  Admitting  the 
facts,  the  assumption  of  agastro-intestinal  auto-intoxication  is  hypothetical. 

Constipation. — The  diagnosis  of  auto-intoxication  rests  largely  upon  an 
excess  of  indican  or  conjugated  sulphates  in  the  urine.  The  elimination 
of  indican  and  of  the  aromatic  sulphates  bears,  however,  no  constant  re- 
lation to  the  presence  or  absence  of  constipation;  nor  does  the  degree  of 
increase  in  the  aromatic  substances  in  the  urine  bear  any  relation  to  the 
intensity  of  the  symptoms.  As  previously  stated,  indicanuria  is  not  a  sign 
of  auto-intoxication,  nor  does  it  afford  any  index  of  the  elimination  of  other 
and  toxic  substances.  The  urine  and  fseces  of  patients  with  constipation 
have  been  analyzed  "v\'ithout  success  for  ptomains.  An  illustration  of  the 
fictitious  value  of  the  ir.terpretation  of  the  symptoms  of  constipation  is 
afforded  by  the  fact  that  they  are  at  all  times  more  pronounced  in  Avomen 
than  in  men,  and  particularly  marked  during  the  menstrual  period,  which 
is,  in  all  probability,  to  beexplained  as  a  mechanical  result  of  thedistension 
on  the  pelvic  organs.  It  is  also  noteworthy  that  many  of  the  symptoms  of 
constipation  are  to  be  observed  in  association  with  abdominal  and  pelvic 
diseases  unaccompanied  by  constipation.  A  recent  suggestion  is  that  the 
evil  results  of  constipation  may  be  due  to  the  non-secretion,  by  the  intes- 
tinal mucosa,  of  toxic  substances,  whose  elimination  is  assumed  to  be  a 
function  of  the  intestine.    For  this  hypothesis  there  is  no  evidence. 

Nervous  Dyspepsia. — This  has  been  classed  as  a  gastro-intestinal  auto- 
intoxication.   The  absence  of  inflammatory  lesions  and  abnormalities  of 


AUTO-INTOXICATIONS  .       279 

digestion,  apart  from  variations  in  the  secretion  of  hydrochloric  acid, 
makes  a  conception  of  the  etiology  of  nervous  dyspepsia  obscure  but  there 
is  no  good  evidence  that  an  auto-intoxication  is  present.  It  will  not  do  to 
say  that,  since  we  know  of  nothing  else,  it  must  be  an  auto-intoxication; 
if  we  do  not  know  of  anything  else  and  there  is  no  exact  evidence  of  an 
intoxication,  we  simply  do  not  know  the  cause  at  all. 

Nervous  System. — For  the  etiology  of  a  large  number  of  diseases  of  the 
nervous  system,  (migraine,  neuritis,  epilepsy,  myasthenia,  melancholia, 
dementia  paralytica,  psychoses,  and  even  periodic  family  paralysis) 
gastro-intestinal  auto-intoxication  has  been  invoked.  The  evidence  com- 
prises analogies  between  these  diseases  and  conditions  in  the  nervous 
system  due  to  known  poisons,  the  occurrence  of  constipation  and  often 
of  an  excessive  ehmination  of  aromatic  substances,  the  occasional  occur- 
rence of  acetonuria,  the  apparent  relation  of  attacks  to  dietetic  errors,  the 
finding  in  nerve  cells  of  lesions  resembling  those  produced  by  experi- 
mental intoxications,  and  in  the  results  of  the  measurement  of  the  toxicity 
of  the  urine  and,  in  some  cases,  of  the  perspiration.  A  perusal  of  the  liter- 
ature bearing  upon  the  subject  suggests  that  it  is  not  the  validity  or  natural 
probability  of  the  findings  above  summarized  that  leads  to  the  diagnosis, 
but  rather  a  conviction  of  the  insufficiency  of  the  previously  offered  hypoth- 
esis.   Of  exact  investigations  there  are  none. 

The  Anaemias. — These  have  long  been  regarded  as  diseases  of  intoxi- 
cation. The  earlier  theory  of  the  gastro-intestinal  origin  of  chlorosis  is 
now  generally  recognized  as  disproved.  For  pernicious  anaemia,  however, 
a  good  case  has  been  made  out.  The  reasoning  does  not  rest  upon  such 
indefinite  facts  as  constipation  or  diarrhoea,  Indicanuria,  acetonuria.  That 
a  persistent  haemolysis  is  at  the  bottom  of  pernicious  anaemia  is  shown  and 
this  is  one  of  our  best  studied  effects  of  poisons,  and,  wuth  the  demonstra- 
tion of  the  occurrence  of  a  severe  and  persistent  haemolysis  as  the  cardinal 
feature  of  the  disease,  a  reasonable  etiology  is  established.  Earlier  w^ork 
made  it  probable  that  the  poison  was  absorbed  from  the  alimentary  tract; 
this  has  been  supported  by  the  experiments  with  toluylene-diamine,  and  the 
analogy  with  the  anchylostoma  anaemia.  It  is  supported  by  the  histological 
findings,  which  indicate  that  the  haemolysis  occurs  in  the  portal  system, 
and  by  the  atrophy  of  the  mucosa  of  the  stomach  and  intestine,  so  often 
observed.  Concerning  the  nature  of  the  haemolytic  agent  we  know 
nothing.  A  ptomain  it  certainly  is  not.  Years  ago,  the  writer  searched 
the  faeces  and  urine  of  a  series  of  cases  systematically  for  ptomains,  w'ith 
negative  results.    For  leukaemia,  we  have  no  exact  knowledge. 

Asthma  Dyspepticum. — Is  there  a  dyspnoea  of  toxic  gastro-intestinal 
origin?  The  experimental  foundation  for  such  a  conception  is  to  be 
found  in  the  observation  that  in  dogs  with  an  Eck's  fistula  the  ingestion  of 
bouillon  or  meat  is  followed  by  acute  dyspnoea.  Children  exhibit  attacks 
of  acute  dyspnoea  associated  with  alimentary  disturbances  and  unaccom- 
panied by  any  lesions  in  the  thoracic  organs  or  kidneys.  The  condition, 
not  confined  to  children,  has  not  been  extensively  studied.  A  close  con- 
nection exists  between  the  diet  and  exacerbations  in  the  attacks.  No  poi- 
sons have  been  isolated. 

Gastro-intestinal  Albuminuria. — The  kidneys  are  sensitive  to  poisons. 
In  not  a  few  instances  of  gastro-intestinal  disturbances,  albuminuria  is 
observed,  and  it  is  common  in  poisoning  by  shell-fish  and  decomposed 


280  DISEASES  CAUSED  BY  ORGAXIC  AGEXTS 

foods.  There  can  be  no  strong  objection  to  this  chissification  of  the  in- 
stances of  albuminuria  that  occur  in  well-defined  cases  of  gastro-intestinal 
diseases.  But  to  go  to  the  extent  of  the  assunij)tion,\vithout  exact  evidence, 
that  the  so-called  idiopathic,  cyclic,  and  recurrent  albuminuria  rest  upon 
an  otherwise  unmanifestcd  gastro-intestinal  auto-intoxication  is  surely 
unjustified. 

ABNORMALITIES  IN  THE  PROCESSES  OF  OXIDATION. 

The  relations  of  the  existence,  extent,  and  nature,  of  sub-  and  super- 
oxidation  are  intricate  and,  in  part,  undetermined.  Upon  a  normal  mixed 
diet,  the  body  heat  is  largely  maintained  by  the  carbonous  metabolism; 
on  a  protein  diet,  the  protein  metabolism  will  be  so  exaggerated  as  to 
supply  the  entire  heat.  The  minimum  is  determined  by  the  amount 
required  to  sustain  the  body  temperature  under  proper  conditions  of 
control  Avithout  food  and  at  complete  rest  of  voluntary  movements.  Since 
the  body  is  sparse  in  its  metabolism  when  deprived  of  food,  the  figures 
under  these  circumstances  will  be  below  the  real  normal;  but  it  is  the 
nearest  approximation  we  can  secure,  since  otherwise  the  heat  of  digestion 
introduces  a  factor  of  disturbance.  For  normal  adults  the  minimum  heat 
values  may  be  given  as  14  calories  per  lb.  (30  cal.  per  kilo)  per  day. 
Elderly  individuals  may  require  less,  children  will  require  more,  emaciated 
convalescents  may  maintain  a  balance  upon  as  little  as  10  cal.  per  lb.  (22 
cal.  per  kilo).  The  average  is  probably  higher,  and  there  are  notable 
individual  variations.  Less  than  10  per  cent,  of  this  heat  is  derived  from 
the  combustion  of  body  protein  utilized  in  the  daily  metabolism.  To 
produce  the  rest,  nearly  17  oz.  (500  gm.)  of  sugar  or  8  oz.  (225  gm.)  of 
fat  are  burned. 

Under  less  experimental  conditions  of  life  than  a  fasting  repose  in  a 
respiration  chamber  at  constant  temperature,  these  figures  will  be  in- 
creased. On  a  usual  diet,  nearly  twice  as  much  protein  would  be  dis- 
assimilated,  so  that  a  couple  of  hundred  of  calories  a  day  would  be  there 
added.  The  heat  dissipation  will  be  somewhat  increased  under  ordinary 
conditions.  An  increase  in  oxidation  is  observed  following  the  ingestion 
of  food,  which  is  marked  for  protein,  much  less  for  carbohydrates  and  fats. 
This  increase  is  notslight  sincetheO-inputand  theCOo-output  afterameal 
may  exceed  the  fasting  figures  by  30  per  cent.,  and  with  forced  protein 
feeding  equal  the  entire  fasting  oxidation.  The  reasons  for  this  fact,  which 
has  clinical  bearings,  are  not  entirely  clear.  Digestion  is  an  exothermic 
process;  but  since  the  products  must  be  reconverted,  heat  will  be  again 
absorbed.  Peristalsis  and  the  secretion  of  the  digestive  juices  represent  a 
certain  slight  heat  production.  The  older  idea,  that  this  increase  in  oxi- 
dation represents  an  extravagance  of  luxury  (in  the  sense  that,  like  a  spend- 
thrift, the  body  increases  its  outlay  with  its  income),  has  been  shown  not  to 
hold  good.  The  cleavage,  after  resorption  of  the  protein,  into  the  nitrog- 
enous and  the  non-nitrogenous  moieties,  is  held  to  account,  in  large  part, 
for  this  increased  oxidation.  Apart  from  the  obscurity  of  this  explanation, 
it  is  not  in  harmony  with  the  fact  that  the  degree  of  this  digestive  increment 
of  oxidation  is  apparently  quite  constant  in  percentage  for  a  particular 
substance,  and  not  dependent  upon  the  quantity.    This  digestion-oxidation 


AUTO-INTOXICATIONS  281 

is  greater  in  the  child  than  in  the  aged,  low  in  the  obese,  and  high  in  the 
convalescent. 

Muscular  exercise  produces  a  great  increase  in  the  processes  of  oxi- 
dation. In  the  respiration  experiment,  this  is  limited  to  the  movements  of 
respiration,  circulation,  and  peristalsis.  The  respiratory  movements  fur- 
nish a  considerable  percentage  of  the  heat  production.  Ordinary  work 
increases  the  oxidation  processes  by  50  per  cent.,  heavy  work  may  double 
the  oxidation  of  the  resting,  fnsting  individual.  Marked  individual 
variations  occur.  Exercise  of  the  untrained  muscle  increases  oxidation 
more  than  in  the  trained  muscle;  exercise  of  the  exhausted  muscle  espe- 
cially is  accompanied  by  superoxidation.  The  velocity  of  contractions  in 
the  unit  of  time  increases  the  oxidation  disproportionately.  The  weight 
of  the  individual  is,  for  obvious  reasons,  of  great  influence.  Lastly,  there  is 
the  factor  of  temperament  and  facility.  Two  men  of  the  same  stature  and 
weight  will  not  do  the  same  muscular  task  with  the  same  expenditure  of 
energy.  This  is  not  entirely  a  matter  of  training ;  some  are,  by  nature  and 
construction,  economical  of  motion,  others  extravagant.  Restlessness  is 
a  factor  of  influence.  These  considerations  are  of  great  importance; 
unless  constant  conditions  can  be  secured,  fair  comparison  between  the 
sick  and  the  well  cannot  be  made. 

Under  the  incidental  oxidations  are  classed  those  associated  with  func- 
tions that  have  a  raison  d'etre  independent  of  the  heat  production,  such 
as  the  protein  and  nuclein  metabolisms.  These  are  increased  but  slightly 
by  exercise  and  to  some  extent  by  conditions  in  the  diet.  So  long  as  the 
diet  contains  the  normal  quota  of  fat  and  carbohydrate,  less  than  a  sixth 
of  the  heat  required  for  the  body  is  derived  from  these  incidental  sources. 
There  is  a  regulatory  mechanism  in  the  carbonous  metabolism.  When  the 
other  sources  of  heat  are  prominent  the  combustion  of  sugar  and  fat  is 
reduced;  that  this  is  a  limited  adaptation  is  shown  by  the  fact  that  the- 
heat  production,  apart  from  the  incidental  combustions,  is  not  reduced  to 
nil  when  the  individual  is  placed  in  an  atmosphere  of  the  temperature  of 
the  body,  and  by  the  continuation  of  sugar  combustion  when,  to  a  mixed 
diet,  protein  is  added  in  quantities  sufficient  to  supply  the  body  heat. 
Under  these  circumstances  sugar  is  still  burned  and  the  needless  heat  dis- 
sipated by  physical  means.  There  is  evidence  that  at  higher  tempera- 
tures, as  in  the  Russian  bath,  the  processes  of  oxidation  in  the  body  are 
actually  increased.  In  considering  the  relations  of  oxidation  in  disease, 
we  are  concerned  with  the  total  alone;  it  is  not  necessary  to  state  that  a 
particular  oxidation  may  be  increased  or  decreased  in  health  and  disease. 

Suboxidation. — Have  we  evidence  of  the  existence  of  a  state  of  general 
suboxidation?  The  metabolic  heat  production  is  derived  from  the  move- 
ments of  circulation,  respiration  and  peristalsis,  secretion,  and  the  reac- 
tions of  catabolism.  The  hypothesis  of  a  retardation  of  metabolism 
means  that  these  reactions  would  be  accomplished  with  less  consumption 
of  material  and  production  of  heat  than  in  the  normal;  and  since  the  cir- 
culation and  respiration  act  in  part  reciprocally  to  these,  they  would  be 
reduced.  The  hypothesis  of  a  retardation  of  metabolism  means  that  the 
unit  of  protoplasm  would  have  a  lower  level  of  metabohsm.  The  unit  of 
protoplasm  in  the  cold-blooded  animals  has  a  very  low  level  of  metabolism, 
and  in  the  hibernating  animal  a  much  lower  level  than  during  the  summer. 
The  hypothesis  of  a  retardation  of  metabolism  is  therefore  tantamount  to 


282  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

the  predication  that,  as  a  diseased  condition,  the  unit  of  human  protopLasm 
can  suffer  a  reduction  in  the  plane  of  its  metabohsm.  That  this  is  true  to 
a  certain  extent  is  ilhistrated  by  the  economy  in  metabohsm  dispUayed  in 
the  chronica Uy  underfed.  The  real  question  is  whether  such  a  reduction 
as  is  assumed  in  the  hypothetical  retardation  of  metabolism  is  compatible 
with  the  relations  of  heat  dissipation  and  body  temperature.  A  moderate 
suboxidation  could  occur  without  reduction  in  the  body  temperature. 
There  are  four  directions  of  heat  dissipation:  Radiation  from  the  skin, 
evaporation  of  persjjiration,  respiration,  and  the  heating  of  food  and  drink 
to  the  temperature  of  the  body„  The  respiratory  loss  cannot  be  reduced 
below  the  values  for  the  resting  individual.  The  cutaneous  radiation  and 
perspiration  are  subject  to  a  greater  degree  of  regulation,  and,  with  these 
physical  regidations  enforced  to  the  maximum,  the  body  temperature  of 
the  resting  individual  could  be  maintained  upon  less  than  the  minimum 
values  given.  On  how  much  less  we  do  not  know.  Since,  however,  tlip 
body  temperature  is  normal  in  individuals  suspected  of  having  suboxi- 
dation, the  argument  is  concerned  with  just  this  rubric.  A  reduction  of 
the  body  temperature  would  not  in  itself  indicate  suboxidation. 

That  such  a  state  of  suboxidation  exists  as  an  acute  condition  may  be 
assumed,  though  no  accurate  studies  of  appropriate  cases  exist.  In  pro- 
longed surgical  anaesthesia  and  drug  narcosis,  following  extreme  hemor- 
rhage, in  shock,  in  asthenic  infections,  in  terminal  diabetic  and  cholsemic 
coma,  such  a  condition  probably  exists.  In  these  states  the  body  tem- 
perature is  low.  This  may  be  due  in  part  to  excessive  heat  dissipation, 
since  many  have  extreme  vasomotor  dilatation.  The  renal  functions  are 
nearly  abolished  and  analyses  of  the  urine  indicate  a  very  low  protein 
catabolism,  far  below  that  of  starvation.  The  whole  picture  suggests 
prostration  of  all  the  vital  functions,  including  that  of  systemic  oxidation. 
The  state  is  one  adjacent  to  death  and  can  be  tolerated  but  a  few  hours. 

In  connection  with  chronic  diseases,  the  use  of  the  expression  may  be 
controlled  by  investigations,  and,  though  these  are  very  onerous,  enough 
cases  have  been  carefully  studied  to  enable  us  to  form  a  tentative  judg- 
ment in  the  matter.  Nowadays  we  read  and  hear  much  of  suboxidation. 
It  is  particularly  unfortunate  to  mix  magnitudes  of  undetermined  defi- 
nition with  purely  fictitious  terms.  Suboxidation  is  the  name  of  an 
objective  condition,  and  subject  to  control  as  such. 

There  are  four  groups  of  chronic  diseases  in  which  suboxidation  has 
been  considered ;  obesity,  the  ana?mias,  myxoedema  and  cachexia  strum- 
ipriva,  and  the  cachexia  of  malignant  diseases.  The  facts  to  be  deter- 
mined are:  What  is  the  condition  of  the  nitrogenous  and  carbonous 
metabolism,  how  is  the  O-input  and  C02-output? 

Obesity. — Is  there  suboxidation  in  obesity?  Prehminary  to  this 
question  a  consideration  of  the  relations  of  the  sexual  functions  to  metab- 
olism is  important.  Castrated  animals  are  more  easily  fattened  than 
their  normal  fellows.  In  young  animals  this  growth  comprises  a  flesh-  as 
well  as  a  fat-mast.  The  question  whether  this  rests  upon  a  reduction  in 
the  oxidation  processes  is  of  great  importance,  because  if  it  should  be 
demonstrated  that  the  plane  of  oxidation  may  be  shifted  by  castration, 
the  sexual  glands  would  acquire  a  metabolic  function  allied  to  that  of  the 
thyroid.  Castration  in  animals  converts  a  nervous  into  a  phlegmatic 
temperament,  and  we  know  as  an  experimental  fact  that  the  nervous 


AUTO-INTOXICATIONS  283 

temperament  is  wasteful  in  movements,  metabolism,  and  combustion. 
There  is  an  actual  loss  of  material  attending  the  functions  of  the  organs  of 
reproduction,  though  we  have  no  way  of  estimating  it.  The  sum  total  of 
these  influences  is  sufficient  to  account  for  changes  of  notable  degree, 
though  a  measurement  is  impossible.  In  the  end,  therefore,  the  decision 
must  be  left  to  the  metabolic  experiment. 

Years  ago  investigations  were  believed  to  have  shown  that  the  oxygen 
consumed  by  castrated  animals  was  nearly  20  per  cent,  less  than  the 
amount  consumed  by  the  controlled  animals.  The  methods  were  faulty,  the 
experiments  brief  and  the  results  excessive;  such  a  degree  of  suboxidation 
would  lead  to  the  development  of  the  highest  degree  of  obesity  within  a 
very  short  time.  Recently  the  work  has  been  repeated  with  longer  periods 
of  observation;  a  positive  evidence  of  suboxidation  has  not  been  obtained. 
Castrated  dogs  of  both  sexes  (and  unsexed  women)  exhibit  the  same  car- 
bonous  and  nitrogenous  metabolism  as  the  properly  managed  controls. 
In  the  current  literature  there  is  a  general  confusion  of  the  indirect  and  the 
direct  effects  of  castration  on  nutrition,  metabolism,  and  combustion. 

Coming  to  the  question  of  obesity,  there  are  two  groups  of  fat  peoplethat 
present  symptoms  suggesting  an  abnormal  metabolism:  The  excessively 
fat  children,  and  those  adults  who  leading  active  muscular  lives,  and,  not 
being  addicted  to  excesses  in  eating  and  drinking,  become  pathologically 
obese.  There  are  two  ways  of  investigating  these  cases:  The  method  of 
metabolic  and  combustion  experiment,  and  the  method  of  prolonged 
observation  on  a  known  and  controlled  diet,  with  careful  observation  of  the 
body  weight.  In  the  use  of  the  method  of  metabolic  experimentation,  one 
must  realize  that  much  lower  values  will  be  secured  than  in  thin  indi- 
viduals, without  affording  any  basis  for  induction.  The  unit  of  substance 
necessary  for  a  body  is  related  only  to  the  mass  of  the  metabolic  tissues. 
The  bones,  apart  from  the  marrow,  are  practically  of  no  metabolic 
moment;  but,  since  they  remain  constant  with  respect  to  obesity,  need  not 
be  considered.  Little  energy  is  required  for  fatty  tissue.  When  an  indi- 
vidual weighing  160  lbs.  (70  kilos),  in  good  nutrition,  adds  fat  up  to  220 
lbs.  (100  kilos),  his  metabolic  transformations  will  not  increase  in  the  ratio 
of  16  to  22;  the  stout  man  will  have  about  the  same  metabolism  that 
he  had  when  thin,  and  the  unit  of  calories  of  0-input  and  C02-output 
per  kilo  weight  will  have  decreased.  To  be  of  positive  value  the  varia- 
tions must  exceed  these  relations.  There  have  been  some  twenty  inves- 
tigations of  the  combustion-metabohsm  of  cases  of  obesity.  The  results 
of  these  have  been  negative, — no  evidence  has  been  obtained  that  there 
is  any  reduction  in  the  processes  of  oxidation.  The  error  in  the  method 
of  prolonged  observation  is  the  difficulty  of  determining  the  relations  of 
water  to  solids,  and  of  excluding  dropsy.  There  are  a  few  reported 
cases  in  which  obese  subjects  have  maintained  their  weight  on  a  diet  of 
very  low  caloric  value  (as  low  as  1,000  cal.).  It  is  unfortunate  that  such 
an  individual  has  not  been  placed  on  a  respiration  experiment.  Inves- 
tigations therefore  tend  to  show  that  no  such  thing  as  suboxidation  occurs 
in  obesity. 

Myxoedema  and  Cachexia  Strumipriva. — The  evidence  bearing  upon 
suboxidation  in  these  diseases  may  be  grouped  under  four  headings:  (o). 
The  direct  combustion  experiment.  In  one  case  of  sporadic  cretinism  the 
values,  though  low,  were  within  the  normal,    {b)  The  clinical  symptoms. 


284  DISEASES  CAUSED  BY  ORGAXIC  AGEXTS 

These  suo;gest  suboxidation.  The  patients  incline  to  low  body  tempera- 
ture despite  the  faettliat,  on  account  of  the  almost  comi)lete  abolition  of 
perspiration,  the  heat  dissi})ation  seems  below  the  normal.  These  facts, 
while  sugg-estive,  do  not  directly  indicate  the  existence  of  suboxidation; 
they  indicate  that  the  subjects  have  lost  in  part  the  power  of  suddenly 
increasing  their  combustion  to  meet  the  demands  imposed  upon  it.  (c) 
The  results  of  thyroid  medication.  These  are  striking,  but  they  bear  only 
in  part  upon  this  question.  The  administration  of  thyroid  preparations 
in  the  healthy,  and  to  a  greater  extent  in  the  m}ocoedematous,  results  in  a 
marked  increase  in  the  protein  catabolism  and  to  some  increase  in 
O-input  and  COj-output.  The  increase  of  the  combustion  may  be  as 
high  as  15  or  20  per  cent,  {d )  The  contrast  between  myxoedema  and 
cachexia  strumipriva,  and  exophthalmic  goitre.  Increase  in  the  nitrog- 
enous and  carbonous  metabolism  is  the  striking  metabolic  symptom  of 
Graves's  disease;  it  is  relieved  by  extirpation  of  the  thyroid.  Myxoedema 
associated  with  atrophy  of  the  thjToid  and  cachexia  strumipriva  due  to 
total  extirpation  of  the  thyroid  are  relieved  by  thyroid  medication.  The 
inference  is  tempting,  nevertheless  the  facts  do  not  establish  a  suboxidation. 
The  nitrogenous  and  not  the  carbonous  metabolism  is  the  prominent 
feature.  It  is  possible  that  the  influence  upon  the  carbonous  combustion 
may  be  entirely  secondary  to  the  disturbances  in  the  protein  metabolism. 
The  fact  that  "on  administration  of  thyroid  preparations  a  certain  exag- 
geration in  combustion  occurs,  is  not  proof  that,  with  the  atrophy  of  that 
organ,  the  combustion  would  fall  below  the  normal. 

The  Anaemias. — The  essential  antemias  were  long  held  to  be  associated 
with  suboxidation.  It  seemed  natural  to  question  whether  an  adequate 
quantity  of  oxygen  could  be  transported  by  such  small  quantities  of 
hsemogiobin.  The  experimental  studies  have  given  the  answer  in  the 
negative.  Under  proper  conditions  of  control,  subjects  with  chlorosis 
exhibit  a  normal  protein  and  carbonous  metabolism,  while  cases  of 
pernicious  antemia  and  leukaemia  display  excesses  in  the  protein  metab- 
olism and  normal,  or  supernormal,  oxidation.  The  work  of  circulation 
and  respiration  is  notably  increased  in  these  subjects. 

Cachexia  and  Marasmus. — One  not  infrequently  meets  with  instances 
of  these  conditions  that  suggest  suboxidation.  The  patients  become 
emaciated  to  the  last  degree,  the  condition  seems  to  become  stationary  and, 
for  weeks,  the  patients  remain  in  a  scarcely  more  than  hibernating  exist- 
ence. The  body  temperature  is  low,  the  skin  dry,  the  extremities  cold, 
there  is  scarcely  any  digestion,  and  yet  life  is  prolonged  in  a  most  remark- 
able manner.  That  their  metabolism  and  combustions  are  low  is  not  to 
be  doubted,  but  it  is  questionable  whether  they  are  lower  than  in  simple 
chronic  subnutrition.  It  is  established  that  individuals  subjected  to  pro- 
longed subnutrition  become,  in  a  sense,  inured  thereto  and  exhibit  a 
nitrogenous  and  carbonous  metabolism  notably  lower  than  in  acute 
starvation.  There  is  nothing  to  indicate  that  in  the  conditions  of  ma- 
rasmus and  cachexia  the  relations  are  different  or  more  extreme 
than  in  simple  chronic  subnutrition,  and,  although  the  body  under  these 
circumstances  operates  very  economically,  we  cannot  speak  of  subox- 
idation. 

The  hypothesis  that  diabetes,  gout,  the  so-called  lithfemic  diathesis,  the 
chronic  arthritides,  asthma,  migraine,  eczema  and  other  diseases  of  un- 


A  UTO-INTOXICA  TIONS  285 

known  etiology  are  manifestations  of  a  retardation  of  metabolism  is  devoid 
of  foundation. 

Superoxidation, — ^Under  this  term  we  understand  an  increase  in  com- 
bustion in  excess  of  the  caloric  demands  of  the  body.  Since  the  body 
habitually  burns  something  more  than  is  needed  to  supply  heat  on  the 
minimal  physical  heat-dissipation,  it  is  apparent  that  there  is  a  physio- 
logical superoxidation  that  serves  as  a  compensatory  arrangement, 
superoxidation  occurs  in  many  diseases.  There  are  oxidations  in  the  pro- 
tein metaboUsm,  but  the  chief  reaction  is  hydrolytic  cleavage;  and  oxi- 
dation of  the  products  of  the  hydrolytic  cleavage  of  protein  can  scarcely 
be  conceived  to  be  susceptible  of  an  exaggeration  in  the  direct  sense. 
Thus,  oxidation  is  a  secondary  process  in  the  metabolism  of  protein,  and 
as  such  is  not  susceptible  of  a  primary  exaggeration,  though  it  might  be 
subject  to  a  primary  retardation.  Superoxidation  affects  directly  the 
sugar  metabolism.  If  the  carbohydrate  input  be  not  sufficient,  the  fat 
combustion  will  become  exaggerated  so  soon  as  the  body  glycogen  has 
run  low.  If  the  fat  ingestion  be  not  sufficient  to  the  oxidation,  the  body 
fat  will  be  burned.  Since  we  regard  these  combustions  as  of  the  nature 
of  ferment  reactions,  the  pathological  exaggerations  are  naturally  and 
logically  to  be  ascribed  either  to  an  increased  concentration  of  the  sub- 
strate, or  to  an  excess  of  the  ferments.  An  important  practical  con- 
comitant to  the  superoxidation  of  sugar  and  fat  is  the  more  or  less 
complete  loss  of  the  saving  power  of  sugar  and  fat  for  the  protein  me- 
tabolism. 

Deficiency  of  Oxygen. — Asphyxiation  is  the  result  of  lack  of  oxygen. 
Many  exogenous  intoxications  act  in  part  by  preventing  the  utilization  of 
oxygen;  such  are  the  nitrites,  morphine,  arsenious  acid,  carbon  monoxide, 
cyanides,  chloral,  paraldehyde,  veratrine.  A  marked  degree  of  deficiency 
in  oxygen  cannot  be  borne  for  more  than  a  short  time.  One  hears  a  great 
deal  of  the  deficiency  of  oxygen  in  the  production  of  disease,  but  when  the 
evidence  is  analyzed  it  is  seen  to  be  very  scanty.  In  order  to  establish  a 
lack  of  oxygen,  one  ought  to  possess  gas  analyses  of  the  respiration  or 
blood.  Breathing  an  atmosphere  low  in  oxygen  is  accompanied  by  a  high 
respiratory  quotient.  In  acute  pneumothorax  and  cardiac  dilatation, the 
body  suffers  from  lack  of  oxygen ;  the  blood  content  of  oxygen  and  carbon 
dioxide  falls.  This  situation  cannot  be  long  maintained;  if  compensation 
be  not  rapidly  established  death  occurs.  In  acute  and  massive  hemor- 
rhage a  deficiency  occurs ;  this  cannot,  however,  be  due  to  the  reduction 
in  the  red  corpuscles,  for  it  is  not  possible  to  bleed  an  animal  over  40  per 
cent,  of  its  blood  even  if  the  fluid  be  replaced,  and  there  is  no  deficiency 
of  oxygenation  in  such  a  degree  of  ansemia  per  se. 

As  a  subacute  condition,  there  is  evidence  that  a  certain  degree  of 
deficiency  in  oxygen  occurs  in  severe  cardiac  and  pulmonary  diseases.  In 
these  diseases  the  efforts  at  compensation  usually  are  practically  success- 
ful; what  so  often  kills  is  the  exhaustion  produced.  In  these  one  may 
observe  an  excess  of  protein  catabolism  and  the  appearance  of  lactic  acid 
in  the  urine.  In  some  instances  of  heart  disease  the  blood  contains  more 
CO2  and  less  O  than  normal.  A  favorable  tension  of  O  and  CO2  can  be 
shown  to  exist  in  the  alveoli  of  the  lung,  despite  v\^hich  the  blood  does  not 
seem  able  to  cast  out  the  normal  amount  of  CO2  or  absorb  the  normal 
amount  of  O.    Whether  the  fault  lies  in  an  alveolar  induration  or  in  a 


286  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

slowing  of  the  circulation  is  not  known.    It  does  not  lie  in  a  deficiency  of 
the  respiratory  movements. 

Just  how  the  partial  lack  of  oxygen  affects  the  organism  is  not  well 
known.  The  loss  falls  first  on  the  protein  metabolism,  the  intermediary 
products  of  which  appear  unoxidized  in  the  urine.  The  protein  catab- 
olism  is  exaggerated.  The  body  attempts  to  make  up  for  the  deficiency 
by  the  utilization  of  intramolecular  oxygen;  to  what  extent  this  can  com- 
pensate is  not  known.  In  animals  under  carefully  selected  conditions  of 
experimentation ,  an  acidosis  may  be  produced.  In  the  anannias,  cachexia, 
and  tuberculosis,  in  which  a  deficiency  of  oxygenation  has  been  popularly 
supposed  to  exist,  the  consumptionof  oxygen  is  either  normal  or  excessive. 
It  is  possible  that  exercise  would  lead  to  a  temporary  relative  deficiency 
of  oxygen,  but  under  conditions  of  rest  there  is  no  such  deficiency. 


DISTOXIOATION. 

Under  distoxication  are  grouped  those  acts  of  metabolism  by  means  of 
which  endogenous  toxic  substances  are  rendered  innocuous.  The  known 
reactions  of  distoxication  include  conjugation,  oxidation,  and  reduction. 
In  the  intestinal  putrefaction  of  the  products  of  protein  digestion,  a  num- 
ber of  aromatic  bodies  are  formed.  In  the  act  of  absorption  they  are 
subjected  to  alterations  that  render  their  slight,  though  undetermined, 
toxicity  inert.  Some  of  the  products  of  the  digestion  of  protein  are  quite 
toxic,  yet  in  the  liver  this  is  nullified.  If  in  the  dog  the  portal  blood  be 
conducted  directly  to  the  vena  cava,  a  severe  intoxication  is  the  result. 
The  general  application  of  the  theory  of  distoxication  lies  in  the  propo- 
sition that  the  intermediary  products  of  metabolism  are  more  or  less  toxic 
and  that  in  the  completion  of  the  processes  of  metabolism  to  end-products 
we  have  what  in  effect  has  the  value  of  a  distoxication.  When  also  abnor- 
mal intermediary  products  of  metabolism  appear,  they  may  be  distoxi- 
cated.  Thus  cations  are  withdrawn  from  the  tissues  to  combine  with  the 
anions  in  experimental  acid  poisoning,  in  the  acetone  acidosis,  and  in 
connection  with  an  ash-free  diet.  When  glycuronic  acid  is  derived  from 
glucose  it  is  paired  in  the  body.  If  leucin  and  tyrosin  are  formed  by  an 
abnormal  intermediary  protein  metabolism,  they  will  be  oxidized  to 
phenyl-oxy-acids;  should  the  amount  of  the  amido-acids  be  large,  a  certain 
rest  will  be  eliminated  unchanged.  In  an  analogous  sense  we  may  speak 
of  cystinuria  and  alkaptonuria  as  abnormalities  of  distoxication.  Phar- 
macology is  filled  with  references  to  chemical  processes  of  distoxication. 
EUmination  is  obviously  an  indispensable  adjunct  to  distoxication.  Some 
substances  that  cannot  be  chemically  distoxicated  are  harmless  if  promptly 
eliminated.  The  general  tendency  has  been  to  concede  the  relative  in- 
nocuousness  of  the  end-products  of  metabolism  and  to  refer  auto-intoxi- 
cations rather  to  deviations  in,  or  the  non-completion  of,  the  intermediary 
processes  of  metabolism.  Under  the  different  headings  specific  references 
will,  whenever  possible,  be  made  to  the  chemical  reactions  concerned;  we 
here  merely  state  the  point  of  view. 

A  hypothesis  is  now  current  to  some  extent,  by  which  distoxication  is 
assumed  to  be  a  function  of  the  thyroid,  adrenal,  and  pituitary  bodies. 
This  is  not  assumed  to  the  exclusion  of  an  internal  secretion  but  in  , 


AUTO-INTOXICATIONS  287 

addition  thereto.  In  particular  the  thyroid  body  is  held  to  distoxicatc 
the  products  of  renal  insufficiency.  The  hypothesis  is  not  yet  upon  an 
exact  basis,  and,  while  it  may  in  the  future  develop  into  a  recognized 
theory,  it  does  not  occupy  that  plane  to-day. 

RETENTION  INTOXICATIONS. 

Under  this  we  understand  the  retention  of  the  normal  end  products 
through  insufficient  excretion.  This  leads  to  accumulation  of  these  sub- 
stances, and  the  intoxications  are  due  to  their  influence  upon  various 
tissues  and  functions.  We  ought  to  distinguish  the  retention  of  an  excess 
of  a  normal  substance  from  the  accumulation  of  an  abnormal  substance. 
The  demonstration  of  the  etiological  relations  will  be  obviously  much 
more  easy  in  the  second  than  in  the  first  group. 

Jaundice. — It  may  be  accepted  that,  with  the  exception  of  cholesterine, 
no  specific  organic  constituent  of  bile  is  normally  present  in  the  tissues. 
The  biliary  constituents  that  may  be  held  responsible  for  the  toxic  action 
of  bile  are  the  salts  of  the  glyco-  and  tauro-cholic  acids  and  the  pigments. 
Glycocoll  and  taurin  are  products  of  protein  hydrolysis ;  the  derivation,  as 
well  as  the  chemical  nature,  of  cholic  acid  is  not  known.  Since  the  liver  is 
the  seat  of  the  final  disintegration  of  haemoglobin,  it  has  been  assumed 
that  the  glycocoll  and  taurin  are  derived  in  part  from  the  hydrolysis  of 
the  protein  moiety  in  hsemoglobin.  The  pigments  are  derived  from  the 
haemoglobin.  Following  biliary  obstruction,  the  formation  of  the  acids 
seems  to  suffer  a  reduction,  but  the  pigments  continue  to  be  formed  in 
the  usual  quantities. 

The  toxicity  of  bile  lies  largely  in  the  biliary  salts,  although  the  pig- 
ments possess  a  certain  toxicity,  especially  evident  in  the  depression  of  the 
body  temperature.  Bile  acts  as  a  tissue  poison,  particularly  to  the  renal, 
hepatic,  and  muscle-cells.  There  is  further  evidence  that  it  exerts  a 
hsemolytic  action.  Possibly  this  may  be  related  to  the  hemorrhagic 
tendency  so  frequently  noted  in  jaundice.  The  body  temperature  is 
reduced,  the  pulse  and  respiration  retarded, — apparently  on  account  of 
peripheral  influences,  since  the  effects  occur  following  the  local  appli- 
cation of  bile  to  the  surface  of  the  heart  after  section  of  the  vagus  in  the 
curarized  frog.  There  is  dilatation  of  the  peripheral  capillaries.  Large 
doses  cause  coma,  convulsions,  and  paralyses.  In  jaundice  we  observe 
clinically,  retardation  of  the  pulse,  somnolence,  albuminuria,  sometimes 
emaciation  and  cutaneous  disturbances,  occasionally  hemorrhages, — 
directly  corresponding  to  the  experimental  findings.  In  simple  instances 
of  jaundice  the  digestion  is  little  impaired.  The  temperature  of  the  body 
may  be  normal  or  slightly  reduced.  Usually  there  is  little  disturbance  in 
the  nitrogen  metabohsm,  nutrition,  or  body  weight.  In  prolonged  cases 
the  functions  of  the  liver  may  be  greatly  impaired,  the  glycogen  of  the 
muscles,  as  well  as  of  the  liver,  may  be  practically  absent,  and  the  epithelial 
cells  extensively  degenerated.  The  exceptionally  deleterious  effects  of 
disturbances  of  digestion  in  jaundiced  indi"sdduals  have  led  several  authors 
to  assume  a  reduction  in  the  activity  of  the  distoxication  functions  of  the 
liver. 

Quite  inconclusive  is  the  relationship  of  hepatic  coma  to  jaundice. 
Symptomatically  the  so-called  cholsemia  resembles  experimental  bihary 


288  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

intoxication,  but  the  same  symptoms  are  as  frequently  seen  in  hepatic 
cirrhosis  without  jaundice.  It  is  difficult  to  understand  how  many  indi- 
viduals bear  jaundice  without  marked  toxic  sym})toms.  The  common 
explanation  that  in  one  case  the  renal  elimination  of  the  bile  is  sufficient, 
in  another  insufficient,  is  not  borne  out  by  urinary  observations.  In  all 
likelihood  the  cause,  of  hepatic  coma  is  to  be  sought  less  in  the  toxic  effects 
of  the  circulating  bile  than  in  a  disturbance  of  the  metabolic  functions  of 
the  liver,  just  as  in  acute  yellow  atrophy,  phosphorus  poisoning,  experi- 
mental ablation  of  the  liver,  and  anastomosis  of  the  portal  vein  and  in- 
ferior cava.  Under  this  interpretation  the  prolonged  jaundice  could  lead 
to  grave  auto-intoxication  through  abolition  of  hepatic  function.  Auto 
intoxications  by  retention  do  not  remain  pure  but  tend  to  entrain  second- 
ary metabolic  auto-intoxication. 

Retention  of  Carbon  Dioxide. — Is  there  an  intoxication  with  meta- 
bolic carbon  dioxide,  connected  with  disturbances  of  the  circulation  and 
respiration  ?  There  is  the  greatest  discrepancy  between  the  apparent  sim- 
plicity and  the  actual  complexity  of  the  problem.  The  actual  problem  must 
be  first  defined,  (a)  The  gas-exchange  of  the  body  has  no  necessary  rela- 
tions to  dyspnoea.  Dyspnoea  appears  when  the  gas-exchange  is  decreased 
or  exaggerated,  but  often  exists  independent  of  any  alterations  of  the  gas 
metabolism.  The  increased  res])irations  following  muscular  exertion  are 
not  due  to  the  accumulation  in  the  venous  system  of  an  excess  of  carbon 
dioxide,  but  to  a  stimulation  of  the  respiratory  centre  by  substances 
derived  from  the  muscular  metabolism.  Not  a  few  chemical  substances 
cause  dyspnoea.  Many  forms  of  auto-intoxication,  in  which  the  gas- 
exchange  is  not  in  the  least  concerned,  give  rise  to  dyspnoea;  such  are 
diabetic  coma,  uraemia,  hepatic  coma.  Lastly,  bacterial  toxins  cause 
dyspnoea,  as  seen  in  pneumonia,  (b)  Intoxication  with  carbon  dioxide  is 
not  necessarily  associated  with  cyanosis,  since  the  fault  may  lie  entirely 
within  the  internal  respiration,  (c)  There  is  no  necessary  association 
between  the  gas-exchange  and  the  carbon-dioxide  content  of  the  blood. 
It  is  possible  for  the  O-input  and  the  COa-output,  the  heat  metabolism, 
to  be  normal,  while  the  blood  is  surcharged  with  carbon  dioxide  and  the 
cyanosis  pronounced,  (d)  Lastly,  deficiency  of  oxygen  must  be  separated 
from  an  excess  of  carbon  dioxide.    This  is  often  extremely  difficult. 

In  what  diseases  and  under  what  circumstances  is  there  an  excess  of 
carbon  dioxide  in  the  blood  and  tissues,  and  what  degree  of  such  excess 
may  be  properly  said  to  cause  auto-intoxication?  Oxygen  is  carried  in  the 
blood  in  chemical  combination  with  haemoglobin,  in  small  part  by 
physical  absorption  in  the  cells  and  plasma.  The  arterial  plasma  is 
saturated  with  oxygen.  Arterial  blood  contains  about  20  vol.  per  cent,  of 
oxygen,  venous  blood  some  8  to  10  vol.  per  cent.  In  death  by  suffocation 
the  oxygen  is  decreased  before  the  death  of  the  animal  to  less  than  1  vol. 
per  cent. 

The  relations  of  the  carbon  dioxide  are  less  certain.  It  is  present  in 
arterial  blood  to  the  extent  of  30  to  40  vol.  per  cent.,  in  venous  blood  about 
10  vol.  per  cent.  more.  Five-sixths  of  the  gas  is  in  the  plasma.  In  asphyx- 
iated animals  the  concentration  of  CO2  in  the  venous  blood  rises  but  little 
above  the  maximum  normal  of  50  vol.  percent.;  this  is  comprehensible 
when  we  realize  that  most  of  the  oxygen  contained  in  the  body  is  held  in 
the  tissues.   The  mode  by  which  the  COg  is  removed  from  the  tissues  and 


AUTO-INTOXICATIONS  289 

transported  in  the  blood  to  the  lung  is  obscure.  The  most  difficult  ques- 
tion concerns  the  nature  of  the  substances  with  which  the  CO2  is  held 
combined  in  the  plasma.  Since  the  stay  of  the  blood  in  the  tissues  and 
lungs  is  so  very  brief,  association  and  dissociation  must  occur  with  great 
rapidity.  Since  the  reaction  of  the  blood  is  neutral,  no  process  can  be 
assumed  that  is  chemically  incompatable  with  this  neutrality.^  The  gas 
has  been  held  to  circulate  as  a  bicarbonate,  this  being  formed  in  the 
peripheral  venous  blood,  and  then  during  the  passage  through  the  lungs 
reduced  to  the  carbonate,  in  which  form  it  would  circulate  to  the  arterial 
periphery,  there  to  combine  with  a  fresh  quantum  of  the  gas  to  again 
form  the  bicarbonate.  This  conception  cannot  be  maintained.  When  a 
weak  solution  of  sodium  bicarbonate,  exposed  to  the  atmosphere,  attains 
an  equilibrium,  it  contains  about  93  per  cent,  of  the  bicarbonate  and  about 
7  per  cent,  of  the  carbonate;  it  requires  but  slight  partial  pressure  of  CO2, 
as  low  a  pressure  as  10  mm.  of  Hg,  to  check  the  dissociation  entirely. 
Now  the  CO2  in  the  arterial  blood  never  falls  below  25  mm.  of  Hg  and  the 
absorbed  gas  is  equal  in  the  arterial  and  venous  bloods.  In  addition,  a 
reduction  of  bicarbonate  to  carbonate  would  result  in  a  pronounced 
alkaline  reaction.  The  inadequacy  of  the  carbonate  hypothesis  is  further 
illustrated  by  the  fact  that,  in  grave  condition  of  acidosis,  the  only  cation 
available  in  the  circulation  would  be  ammonia.  The  role  of  carrier  has 
also  been  ascribed  to  the  phosphates.  This  is  impossible,  from  the  fact 
that  the  plasma  contains  but  a  trace  of  phosphate.  The  most  recent  view 
allies  the  CO2  with  alkali-globulin  combinations.  It  is  known  that  the 
proteins  combine  with  acids  or  alkalies  to  form  bodies  subject  to  hydroly- 
tic  dissociation.  The  weakest  acids  and  alkalies,  however,  are  able  to  dis- 
place the  proteins  and  CO2  is  able  to  do  so.  The  conception  is  that  the 
proteins  of  the  blood  plasma  are  combined  with  cations  and  in  the  venous 
blood  the  CO2  drives  out  the  protein,  which  then  circulates  alone  until 
the  removal  of  the  CO2  in  the  lungs,  when  it  reassociates  with  the 
cations.  The  existence  of  combinations  of  protein  with  hydrogen-  and 
hydroxyl-ions  has  been  experimentally  demonstrated.  If  the  so-called 
alkali-globulin  be  considered  to  be  an  ion-protein,  it  must  be  remarked  that 
no  one  has  been  able  to  determine  the  existence  of  such  combinations  in 
the  case  of  the  proteins  of  blood  plasma;  and,  although  considerations  in 
general  physiology  have  made  it  possible  to  postulate  the  existence  of  such 
combinations,  the  present  data  will  not  permit  us  to  assume  them  for  the 
blood  plasma.  Such  a  cation-globulin  would  be  subject  to  a  high  degree 
of  hydrolytic  dissociation,  with  the  production  of  an  alkaline  reaction.  In 
short,  though  the  general  relations  indicate  that  factors  of  association  and 
dissociation  control  the  transportation  and  discharge  of  the  CO2,  the  actual 
definition  of  these  factors  is  not  now  possible. 

In  asphyxiation  the  blood-content  of  CO2  is  increased  from  one-fourth 
to  one-third,  the  oxygen -content  falls  to  a  trace.    Death  is  due  to  lack  of 

^  There  is  a  confusing  difference  in  terminology  regarding  the  reaction  of  the 
blood.  "Some  use  the  term  alkalinity  in  the  sense  of  titration  alkalinity  to 
indicate  that  the  blood  will  neutralize  a  certain  amount  of  weak  acid.  Others 
employ  the  term  in  its  strict  sense,  as  developed  by  modern  physical  chemistry, 
to  indicate  an  excess  of  hydroxyl  ions  (OH — )^"  (Howell).  The  latter  view  re- 
gards the  blood  as  neutral  but  there  seems  little  doubt  that  the  amount  of  alkali 
in  the  blood  as  determined  by  titration  is  of  much  importance  in  regard  to  the 
neutralization  of  acid  products. — Editor, 
19 


290  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

oxygen  and  not  to  the  excess  of  CO2.  If  an  animal  be  placed  in  an 
atmosphere  containing  20  percent,  or  more  of  O,  76  percent,  of  N,  and 
4  per  cent,  of  CO2  (the  quantity  in  expired  air),  death  will  occur  after  a 
period  of  narcosis  and  this  represents  true  CO2  poisoning.  If  an  animal 
be  placed  in  an  atmosphere  too  low  in  oxygen,  death  ^^•ill  result  after  a 
lapse  of  time  and  the  blood  will  contain  less  CO2,  as  well  as  less  O,  than 
normal. 

Do  disturbances  exist  in  disease  which  act  to  reduce  the  exj^iration  of 
CO2  more  than  the  inspiration  of  O,  to  the  end  of  CO2  congestion  in  the 
blood  ?  What  is  the  extent  of  such  CO2  congestion  ?  The  conditions  are 
divided  into  two  groups:  those  in  which  the  respiratory  surface  is  dimin- 
ished and  those  in  which  the  action  of  the  heart  is  disturbed.  Recent 
studies  in  the  physiology  of  combustion  have  taught  us  the  extent  of  the 
powers  of  ada))tation  and  comjDcnsation  residing  in  the  organs  of  circu- 
lation and  respiration.  In  all  probability,  until  these  limits  are  reached, 
until  the  unit  of  blood  is  not  aerated  in  the  unit  of  time,  an  auto-intoxica- 
tion is  not  to  be  apprehended. 

Of  gas  analyses,  either  experimental  or  clinical,  we  have  few,  but  it  is 
fairly  certain  that  five  conditions  may  be  met  with:  (a)  The  O-input  and 
C02-output  and  the  content  of  the  blood  in  the  two  gases  are  normal.  This 
has  been  found  in  several  cases  of  emphysema  and  of  heart  disease,  and 
indicates  a  complete  sufficiency  of  the  efforts  at  compensation,  (b)  The 
O-input  and  C02-output  are  normal,  but  the  CO2  content  of  the  venous 
blood  is  excessive.  This  has  been  noted  in  experimental  disturbances  of 
respiration,  and  indicates  that  the  efforts  at  compensation  were  successful 
only  when  the  level  of  CO2  in  the  venous  blood  was  raised,  (c)  The  O- 
input  is  normal,  the  C02-output  reduced,  the  CO2  in  the  venous  blood 
not  increased.  This  has  been  found  in  some  experimental  pneumonias. 
(d)  The  O-input  and  C02-output  are  reduced.  The  CO2  is  increased 
and  the  O  reduced  in  the  blood.  This  has  been  found  in  several  cases  of 
heart  disease,  (e)  The  O-input  is  much  reduced,  the  C02-output  re- 
duced, the  O  in  the  blood  much  reduced,  the  CO2  not  increased.  This 
has  been  found  in  some  instances  of  experimental  pneumothorax.  CO2 
intoxication  could  appear  in  (6)  and  (d)  alone;  intoxication  from  deficiency 
in  O  could  occur  in  (<:/)  and  (e).  Cyanosis  is  a  sign  of  lack  of  O  rather  than 
of  congestion  with  CO2.  Considering  the  marked  powers  of  adaptation 
and  compensation,  what  we  most  need  are  repeated  gas  analyses  to  show 
what  degrees  of  reduction  in  O-input  and  COg-retention  in  the  blood  exist, 
and  with  what  symptoms  and  signs  they  are  associated. 

In  the  ordinary  cases  of  the  types  under  consideration,  the  combustions 
of  the  body  are  normal.  This  does  not  indicate  that  there  is  no  CO2  con- 
gestion— the  over-flow  of  a  stream  will  be  the  same  over  a  high  as  over  a 
low  dam.  It  docs,  however,  indicate  that  the  input  of  O  is  adequate  and 
the  total  combustion  normal;  if  these  subjects  are  intoxicated  it  must  be 
from  simple  COj-rctention.  In  acute  experimental  dyspnoea  the  protein 
metabolism  is  abnormally  increased,  the  result  of  deficient  oxygenation. 
The  urine  contains  glucose  and  lactic  acid,  the  results  of  lack  of  oxygen. 

In  all  these  there  is  less  to  suggest  that  the  subjects  are  in  a  direct  sense 
suffering  from  intoxication  with  CO2  than  to  indicate  lack  of  O.  CO2- 
retention  is  accompanied  by  an  increase  in  the  molecular  and  ionic  con- 
centration of  the  blood  serum — a  fact  that  is  not  yet  understood.    It  is  not 


A  UTO-INTOXIC'A  TIONS  291 

to  be  denied  that  there  is  an  intoxication  with  CO2  in  these  diseases,  but 
we  should  realize  how  scant  is  our  information  of  the  actual  conditions 
and  how  indefinitely  it  points  to  such  an  intoxication.  The  data  certainly 
furnish  no  warrant  for  such  generalizations  as  those  contained  in  the 
statement  of  von  Jaksch,  that  to  C02-i'etention  is  to  be  ascribed  the  cellular 
degenerations  sometimes  seen  in  this  class  of  cases.  That  there  is  a 
possibility  of  serious  disturbance  of  metabolism  in  an  organism  whose 
venous  blood  is  overloaded  with  CO2  is  made  obvious  by  the  following 
consideration.  The  combustions  of  the  body  are  acts  of  fermentation. 
Accumulation  of  the  reaction  products  retards  the  velocity  of  fermen- 
tation. If  now  the  venous  blood  be  so  charged  with  CO  2  as  to  take  up  no 
further  gas  from  the  tissues,  an  excess  of  the  gas  would  accumulate  and 
exert  a  retarding  influence  upon  the  reactions  of  combustion.  The  COg- 
content  of  the  tissues  is  known  to  be  much  higher  than  in  blood.  We  do 
not  know  that  in  any  circulatory  or  respiratory  diseases  the  blood-content 
rises  to  the  height  of  the  tissue-content,  or  that  the  latter  is  increased. 

Whether  the  retention  of  the  products  of  the  respiratory  metabolism 
can  be  considered  toxic  apart  from  the  CO2  is  not  known.  Our  present 
knowledge  is  negative;  other  toxic  substances  have  never  been  demon- 
strated in  expired  air. 

Retention  of  Perspiration. — The  natural  interpretation  of  the  cause 
of  death  from  extensive  superficial  injury  to  the  skin,  as  in  burns, rests  upon 
the  abolition  of  the  cutaneous  function.  The  chief  symptoms  are  quite 
like  shock.  They  are  not  due  to  the  retention  of  the  normal  perspiration, 
as  the  sweat  is  almost  free  of  toxic  action.  There  is  a  widespread  notion 
that  toxic  volatile  substances  exist  in  the  perspiration,  but  this  is  unsup- 
ported by  data.  The  amount  of  gas-exchange  that  occurs  in  the  cutaneous 
functions  of  higher  animals  is  almost  nil.  The  retention  of  water  could 
not  account  for  the  symptoms  nor  the  salts  and  organic  substances  known 
to  be  eliminated  through  the  skin  in  the  quantities  and  time  concerned. 
That  the  simple  retention  of  perspiration  cannot  be  the  factor  is  shown  b,^- 
the  experiments  in  which  nearly  the  entire  bodies  of  men  were  covered  for 
days  with  rubber  plaster  and  collodion,  without  producing  any  symptoms 
or  signs  of  illness  whatever.  That  rabbits  die  after  being  coated  with 
varnish  has  been  explained  as  the  consequence  of  the  paralysis  of  the  vaso- 
motor system,  whereby  the  heat  dissipation  is  exaggerated  beyond  the 
power  of  compensation. 

We  are  thus  driven  to  the  assumption  that  widespread  lesions  of  the 
skin  cause  disturbances  in  metaboHsm,  which,  acting  with  the  disturbances 
in  the  vasomotor  system,  lead  to  the  rapid  collapse.  We  have  no  idea  of 
the  nature  of  these  assumed  disturbances  in  metabolism.  That  toxic 
substances  are  at  work  is  shown  by  the  widespread  heemolyses,  the  acute 
degenerations  of  parenchymatous  and  muscular  cells,  and  the  rapid  onset 
of  these  lesions  and  of  the  clinical  symptoms.  The  hypothesis  that  the 
coagulations  occurring  in  different  parts  of  the  body  are  due  to  an  excess 
of  fibrin  ferment  has  not  been  proved.  A  burn  must  have  a  certain  super- 
ficial extent  in  order  to  be  fatal,  but  this  cannot  be  related  to  a  similar 
fractional  destruction  or  alteration  of  erythrocytes.  A  much  more  rational 
explanation  would  be  that  the  erythrocytes  are  affected  while  circulating 
through  the  burned  areas.  Thromboses  are  prominent  in  the  pulmonary 
vessels,  and  these  have  been  held  to  lead  to  an  acute  venous  congestion  and 


292  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

arterial  anremia.  Acute  venous  congestion  and  arterial  anremia  due  to 
other  causes,  however,  do  not  produce  the  symptom-complex  observed  in 
burns. 

Retention  Intoxication  of  Intestinal  Origin. — Under  a  strict  inter- 
pretation of  the  term,  we  have  no  evidence  that  such  a  thing  as  a  retention 
of  the  intestinal  excretions  exists.  The  fa?ces  contain  the  undigested  and 
unabsorbed  residue  of  the  food;  the  alimentary  juices;  bacteria  and  the 
products  of  their  metabolism;  the  unabsorbed  gases  of  the  atmosphere, 
mostly  nitrogen,  and  the  gases  of  fermentation  and  putrefaction;  the 
unabsorbed  salts  of  the  diet,  and  the  salts  eliminated  from  the  tract  and 
glands;  and  a  small,  though  undetermined,  quantity  of  metabolic  products. 
The  bulk  of  the  fa?ces  is  water  and  bacteria.  Of  the  nitrogen  of  normal 
fseces,  that  of  the  digestive  juices  may  comprise  as  much  as  one-sixth. 
Now  the  alimentary  tract  is,  from  the  metabolic  point  of  view,  outside  the 
body.  The  only  true  retention  intoxication  would  therefore  be  such  as 
results  from  the  non-secretion  of  salt  and  the  juices  of  the  tract  and  the 
oifferent  glands.  Non-secretion  of  the  gastric  juice  occurs  as  a  nervous 
abnormality,  independent  of  any  lesion;  it  is  not  accompanied  by  signs 
of  auto-intoxication.  Of  the  non-secretion  of  the  succus  entericus  we  know 
nothing.  In  all  probability,  however,  it  would  result  simply  in  starvation. 
Eliminations  of  excretions  stand  obviously  upon  a  totally  different  footing 
as  regards  their  relations  to  auto-intoxications  than  the  eliminations  of 
secretions  of  physiological  function.  Abolition  of  the  one  results  in  a 
damming  back;  abolition  of  the  other  simply  in  the  cessation  of  the 
particular  function  associated  with  it,  though  this  may  entrain  a  secondary 
auto-intoxication.  The  digestive  juices  in  the  lower  intestines,  after  their 
functions  are  completed,  are  themselves  the  prey  of  putrefactive  bacteria, 
and  from  this  time  are  apparently  to  be  ranked  with  the  unabsorbed  pro- 
tein. A  retention  intoxication  from  non-elimination  of  salts,  particularly 
of  iron  and  lime,  is  inconceivable.  Of  an  intoxication  resting  upon  the 
non-elimination  of  metabolic  products  we  have  no  knowledge. 

All  of  the  so-called  retention  intoxications  of  the  alimentary  tract  are, 
so  far  as  we  have  reliable  evidence,  due  to  the  action  of  bacteria.  Some 
foods  are  primarily  toxic,  others  are  directly  indigestible.  These  and  the 
bacterial  decompositions  should  not  be  classed  as  retention  intoxications. 

Suppression  of  Urine. — Under  this  term  we  understand  the  non-secre- 
tion of  urine.  The  hypothesis  that  ursemia  is  simply  a  retention  intoxica- 
tion, the  result  of  the  non-secretion  of  the  urine,  is  incompatable  with  a 
number  of  well-determined  facts.  The  anuria  of  hysteria  probably  repre- 
sents a  pure  non-secretion  of  urine  without  notable  qualitative  changes. 
There  is  no  reason  to  believe  that  the  functions  of  metabolism  are  repressed 
or  altered ;  we  are  simply  dealing  with  a  total  inactivity  of  a  healthy  kid- 
ney, an  inhibition  doubtless  of  nervous  origin.  The  suppression  may  be 
complete;  there  are  many  carefvilly  controlled  cases  in  which  the  anuria 
persisted  for  a  number  of  days,  in  a  few  cases  for  over  a  week.  In  this 
type  there  are  no  symptoms  of  intoxication,  and  when  secretion  is  re- 
established the  urine  is  normal  and  the  organs  exhibit  no  signs  of  disease. 
Attacks  of  anuria  may  be  of  reflex  origin ;  the  presence  of  a  calculus  in  one 
kidney  or  ureter  may  for  days  inhibit  secretion  by  the  other  kidney.  Here, 
too,  no  signs  of  intoxication  are  present.  Another  form  of  non-secretion 
without  intoxication  is  seen  in  acute  cardiac  dropsy,  in  which  there  may 


AUTO-INTOXICATIONS  293 

be  almost  complete  suppression  of  urine.  Naturally  the  kidneys  will 
become  diseased  from  the  passive  congestion,  but  for  some  time  they 
remain  practically  intact,  and  the  slight  amount  of  urine  secreted  may 
present  no  pathological  changes  but  a  trace  of  albumin  and  a  few  casts. 
This  may  persist  for  weeks  without  any  indication  of  ura-mia,  and,  when 
later  cardiac  compensation  is  reestablished,  the  kidneys  will  often  be 
found  practically  free  of  disease.  Following  the  defervescence  of  fever 
in  the  infectious  diseases,  a  marked  output  of  urine  often  occurs,  result- 
ing in  the  elimination  of  enormous  amounts  of  organic  constituents, 
whose  retention  has  caused  no  signs  of  uraemia.  Thus  we  must  concede, 
that,  with  healthy  kidneys,  complete  suppression  is  usually  without  any 
signs  or  symptoms  of  intoxication. 

In  renal  disease  there  is  no  parallelism  between  urgemia  and  retention. 
There  are  periods  of  almost  complete  anuria  in  subacute  nephritis  without 
symptoms  of  uraemia.  Often  in  subacute  nephritis  anuria  and  uraemia  go 
together,  but  many  exceptions  occur.  A  nephritic  or  cardio-nephlritic 
patient,  dropsical  to  the  last  degree  but  free  of  uraemia,  may  be  freed  of  his 
dropsy  only  to  develop  uraemia.  The  hypothesis  is  advanced  that  the 
diuresis,  purgation,  or  diaphoresis,  have  brought  into  the  circulation  the 
poisons  that  lay  concentrated  in  the  tissues.  This  explanation  will  not 
hold,  for  unless  it  be  shown  that  there  is  some  co-efficient  of  distribution  to 
account  for  such  localization  of  the  urinary  constituents,  we  cannot  with 
our  knowledge  of  the  circulation  and  of  the  laws  of  diffusion  believe  in  it. 
Certainly  if  that  explanation  be  true,  the  treatment  of  the  uraemic  attack 
by  purging  and  sweating  is  dangerous. 

One  reads  a  great  deal  of  the  retention  of  particular  constituents  with 
elimination  of  the  water.  Obviously  such  a  condition  could  be  but 
transient  for  the  electrolytes,  because  it  would  lead  soon  to  a  condition  of 
hyperisotonicity  that  we  know  to  be  impossible  The  organic  constituents 
could  be  much  longer  retained  without  disturbing  the  osmotic  conditions 
to  a  notable  degree.  But  such  retention  must  be  analytically  demon- 
strated by  investigations  under  controlled  conditions.  The  present  data 
fail  to  substantiate  the  claim. 

A  general  consideration  against  the  theory  of  simple  retention  is  that  it 
lays  upon  the  kidneys  no  blame  but  that  of  a  stoppage  of  the  elimination; 
it  reduces  nephritis  simply  to  a  plugging  of  a  filtering  membrane.  Exper- 
ience with  nephritis  surely  suggests  that  the  disturbances  are  more  than 
a  simple  reduction  in  the  power  of  elimination.  Our  knowledge  of  the 
toxicity  of  the  normal  urine  does  not  support  the  idea  that  a  simple 
retention  would  lead  to  an  intoxication.  The  toxicity  of  the  urine  depends 
upon  the  fact  that  the  urine  is  a  hyperisotonic  solution  rich  in  potassium 
salts.  Even  this  toxicity  will  practically  disappear  if  the  rate  of  injection 
be  so  slow  that  the  cells  have  an  opportunity  to  accommodate  themselves 
to  the  new  conditions.  As  a  matter  of  fact,  the  whole  line  of  reasoning  on 
the  urotoxic  co-efficient  presupposes  a  function  of  distoxication  on  the 
part  of  the  kidney, — which  is  inadmissible  in  the  theory  of  retention 
intoxication.  It  must  be  insisted  that  the  urotoxic  co-efficient  of  Bou- 
chard, as  determined  by  the  intravenous  injection  of  urine  into  animals, 
is  worthless;  not  over  ten  per  cent,  of  the  toxicity  thus  developed  is  due 
to  the  organic  constituents;  the  main  toxicity  of  the  urine  is  that  of  a 
hypertonic  solution  rich  in  potassium  salts. 


294  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

From  the  wider  theoretical  ]ioint  of  view,  one  can  understand  how  a 
retention  of  urine  could  lead  to  tlisturbances  in  metabolism.  If  the  organic 
constituents  were  retained  to  a  g-veater  degree  than  the  water,  the  result 
would  be  to.  increase  the  concentration  of  those  substances  in  the  body. 
Now  the  processes  leading  to  the  formation  of  these  urinary  constituents 
may  be  assumed  to  be  of  the  nature  of  ferment  reactions.  The  obvious 
result  of  an  increase  in  the  concentration  of  the  products  of  the  reaction 
would  be  to  retard  the  reaction,  that  is,  to  retard  the  rapidity  of  catab- 
olism,  and,  in  addition,  to  afford  opportunities  for  qualitative  variations. 
This  is,  of  course,  a  pure  speculation,  but  it  is  one  based  upon  sound 
theory. 

SALTS.  ACIDS,  AND  ALKALIES. 

The  proper  study  of  the  relations  of  acids,  alkalies,  ions,  and  salts,  by 
physico-chemical  methods  is  quite  recent.  That  they  must  possess  re- 
lations of  the  greatest  importance  in  disease  may  be  confidently  assumed. 
Of  direct  data  almost  none  are  available.  Indeed,  little  of  our  present 
knowledge  has  been  derived  from  studies  on  higher  organisms.  In  the 
investigation  on  the  actions  of  ions  and  salts  on  even  lower  organisms 
there  is  much  confusion  and  not  a  little  contradiction.  The  time  has  not 
yet  arrived  to  attempt  a  discussion  of  the  relations  of  these  factors  to  dis- 
ease. At  present,  our  knowledge  of  the  relations  of  salts,  alkalies,  and 
acids  in  endogenous  intoxications  is  limited  to  acidosis. 

Acidosis. — Under  this  term  we  group  the  disturbances  in  metabolism 
that  result  from  the  predominance  of  acids  in  catabolism.  There  is  in  the 
carnivorous  organism  always  some  such  predominance,  but  one  easily 
compensated  for.  The  chief  sources  of  acid  are  the  following:  (a)  The 
acids  of  carbohydrate  fermentation  in  the  alimentary  tract,  {b)  The 
sulphuric  and  phosphoric  acids  derived  from  the  catabolism  of  common 
protein  and  nuclein  respectively,  (c)  Lactic  acid,  (d)  The  members  of 
the  acetone  group,  diacetic  and  beta-oxybutyric  acids,  derived  from  the 
fats,  (e)  Other  acids  formed  in  the  body — glycuronic,  oxalic,  uric,  aro- 
matic oxy-acids,  carbamic  acid,  and  carbon  dioxide — are  apparently  never 
concerned  in  the  production  of  an  acidosis.  For  the  neutralization  of 
these  acids  we  have  the  excess  of  alkali  contained  in  the  mixed  diet  and  in 
drinking-water;  when  these  are  insufficient,  the  fixed  cations  of  the  body 
and  the  ammonia  of  the  metabolism.  Obviously  an  acidosis  may  be 
inaugurated  either  by  a  deficiency  in  alkali  or  an  excess  in  acids.  The 
result  will  be  the  same  whether  acid  be  ingested  or  formed  within  the  body. 

Experimentally  an  acidosis  may  be  produced  by  the  use  of  an  ash-  and 
alkali-free  diet.  Under  these  circumstances  the  sulphuric  and  phosphoric 
acids  must  combine  with  fixed  cations  withdrawn  from  the  tissues,  and 
ammonia  withdrawn  from  the  urea  metabolism.  After  a  certain  number 
of  days,  no  matter  how  normal  the  diet  in  other  respects,  severe  symptoms 
appear  in  the  peripheral  neuro-muscular  and  central  nervous  systems, 
followed  by  death.  In  simple  starvation  the  degree  of  acidosis  is  not 
marked,  since  the  protein  catabolism  is  low.  Acidosis  could  occur  only 
very  late  in  a  protein-free  diet,  since  here  too  the  protein  catabolism  is  low. 
The  human  body  cannot  maintain  the  daily  catabolism  of  a  hundred 


A  V  TO-IN  TOXICA  riONS  295 

grams  of  protein  in  the  absence  of  ingested  cations,  without  the 
development  of  an  acidosis  within  a  fortnight.  In  a  similar  manner,  if  a 
mineral  acid  be  administered  in  quantity  equal  to  that  daily  formed  in  the 
average  metabolism,  an  acid  intoxication  will  develop  after  a  few  days. 

The  acids  of  carbohydrate  fermentation  arc  ran^ly  of  pathological 
importance;  they  are  easily  oxidized  and  are  rarely  formed  in  (quantities 
so  large  as  to  constitute  a  menace.  There  is,  however,  a  possibility  that 
these  acids  may  be  responsible  for  some  of  the  attacks  of  acidosis  seen  in 
childhood.  Lactic  acid  may  be  derived  either  from  protein  or  carbohy- 
drate; its  constitution  is  very  similar  to  that  of  alanine,  a  derivative  of 
protein  hydrolysis.  Lactic  acid  is  an  intermediary  product  in  the  oxida- 
tion of  glucose.  It  may  theoretically  be  derived  from  the  oxy-acids  of 
the  fatty  acid  series.  In  disease,  it  seems  usually  to  have  been  derived  from 
protein  and  sugar.  The  lactic  acid  formed  within  the  alimentary  tract 
is,  apparently  not  a  cause  of  acidosis.  Most  important  are  the  members 
of  the  acetone  group,  which  are  most  often  concerned  in  the  production 
of  an  acidosis. 

The  ill  effects  of  acidosis  are  not  clearly  understood.  There  are  several 
chemical  possibilities,  (a)  Acidosis  may  act  simply  by  virtue  of  acidity. 
Difficult  as  it  is  to  explain  how  large  quantities  of  acids  may  be  held  com- 
bined in  the  blood  after  .a  prolonged  period  of  cation  withdrawal,  the 
postulated  acidity  of  the  blood  must  be  first  proven,  and  this  cannot  be 
done  by  determining  that  the  carbon  dioxide  is  reduced.  That  the  blood 
may  become  acid  shortly  before  the  death  of  an  animal  with  sulphuric 
acid  poisoning,  has  been  demonstrated.  In  any  event,  an  acid  reaction  of 
the  blood  could  be  only  a  terminal  phenomenon. 

(6)  Acidosis  may  act  through  cation  withdrawal.  The  reserve  of 
cations  in  the  body  is  limited.  It  is  a  postulate  of  physiology  that  there 
are  cation -protein  complexes  in  protoplasm.  To  .wdiat  extent  these 
might  be  assumed  to  be  broken  up  cannot  be  conjectured.  Very  soon  the 
supply  of  fixed  cations  is  greatly  reduced  or  fails,  and  from  thence 
ammonia  alone  remains  to  combine  with  the  acids.  Ammonia  does  from 
the  very  beginning  combine  with  a  portion  of  the  acid.  What  we  do  not 
understand  are  the  relations  of  the  ammonia  to  the  fixed  cations  in  the 
neutralization  of  the  anions;  no  regularity  is  apparent  in  the  fluctuations 
clinically  observed.  How  the  cation  "withdrawal  results  in  symptoms  is 
totally  obscure.  It  may  be  said  that  the  withdrawal  of  fixed  cations  leads 
to  protoplasmic  disintegrations,  to  the  suspensions  of  functions,  and  that 
the  withdrawal  of  the  ammonia  from  the  urea  metabolism  gives  rise  to 
disturbances  in  the  protein  catabolism;  but  from  such  statements  we 
obtain  no  exact  or  definite  ideas.  If  the  withdrawal  of  the  cations  be  the 
condition  underlying  the  symptoms  of  intoxication,  one  does  not  under- 
stand those  cases  in  which  the  symptoms  appear  suddenly  without  having 
been  preceded  by  a  period  of  cation  withdrawal.  That  the  adminis- 
tration of  alkalies  does  not  always  result  in  amelioration  is  no  argument 
for  or  against  this  factor. 

(c)  The  acids  may  possess  a  toxicity  'per  se.  A  certain  toxicity  has  been 
made  probable  for  the  salts  of  /?-oxybutyric  and  diacetic  acids.  Normally 
the  body  possesses  the  power  of  oxidizing  large  quantities  of  these  acids. 
We  do  not  know  whether  we  are  dealing  with  such  an  overflooding  that 
even  the  normal  powers  of  oxidation  are  insufficient,  or  whether  the  body 


290  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

has   lost,  in   part,   its   power  of  oxidation;    weighty  reasons   favor  the 

hitter.  11,, 

(d)  It  is  theoretically  possible  that  the  internal  gas-exchange  should  be 
disturbed,  at  least  in  the  severe  intoxications;  and  investigations  have 
shown  that  under  these  circumstances  the  oxidations  of  the  body  may  fall 
to  less  than  one-half.  Nevertheless,  it  is  doubtful  if  this  be  an  essential 
feature  of  the  situation. 


CHAPTER   XIV. 

AUTO-INTOXICATIONS  ASSOCIATED  WITH  PROTEIN,  PU- 
RIN,  CARBOHYDRATE  AND  FAT  METABOLISM. 

By  ALONZO  ENGLEBERT  TAYLOR,  M.  D. 

The  digestion  of  protein  is  an  act  of  hydrolysis;  the  end-products  are 
amido-acids.  It  has  been  shown  that  animals  may  be  maintained  in 
nitrogen  balance  on  a  diet  whose  sole  nitrogen  is  present  in  the  form  of 
amido-acids.  Under  exceptional  circumstances,  native  protein  may  pass 
through  the  intestinal  mucosa  into  the  circulations  (for  example,  gelatine, 
egg  albumin,  and  foreign  serum),  and  be  eliminated  by  the  urine.  The 
higher  albumoses  are  absorbable;  secondary  albuminoses  and  peptones 
are  readily  absorbed.  In  the  dog's  stomach  ligated  at  the  pylorus,  protein 
will  be  absorbed  without  the  appearance  of  more  than  traces  of  amido- 
acids.  If  such  a  stomach  be  deprived  of  its  return-circulation,  amido- 
acids  will  accumulate  in  large  quantities.  From  nutrose  the  human 
stomach  will  form  amido-acids  within  two  hours. 

The  processes  of  protein  catabolism  may  be  discussed  under  the  four 
end-products,  urea,  ammonia,  purin  bases,  and  kreatinin.  The  purin 
metabolism  is  really  separate  from  the  common  protein  metabolism  and 
will  be  considered  by  itself. 

Urea. — Protein  catabolism  is  chemically  very  similar  to  protein  diges- 
tion; qualitatively  we  know  of  few  distinctions.  In  metabolism,  as  in 
digestion,  the  end-products  of  the  hydrolysis  are  amido-acids,  simple  and 
complex.  In  the  aseptic  autolysis  of  organs  and  in  the  rapid  degenerations 
of  tissue,  amido-acids  are  found  in  large  quantities.  It  must  be  further 
assumed  that  the  dynamic  factor  is  a  ferment  accelerating  a  slow  hydroly- 
sis that  can  be  demonstrated  to  occur  whenever  cells  (protein)  and  water 
are  mixed.  The  products  of  protein  hydrolysis  are  subject  to  a  variety  of 
reactions, — disamidation,  oxidation,  anhydration,  and  reduction.  It  is 
obviously  possible  that  these  secondary  reactions  might  be  disturbed  or 
insufficient,  but  our  knowledge  of  these,  in  so  far  as  they  concern  the 
elaboration  of  the  nitrogen,  is  confined  to  the  steps  by  which  urea  is 
formed  from  amido-acids. 

The  liver  is  the  chief  seat  of  urea  formation.  Perfusion  of  the  liver  with 
the  vegetable  salts  of  ammonia,  in  particular  the  lactate,  carbamate  and 
carbonate,  with  the  monamido-acids  that  are  formed  in  the  hydrolysis  of 
protein,  or  with  the  poly-amido-acids  like  arginine,  will  result  in  the 
formation  of  urea.  Liver  pulp  is  able  to  convert  these  several  substances 
into  urea.  There  can  be  little  doubt  that  these  reactions  are  fermenta- 
tive, and  consist  of  disamiclation  and  oxidation.  In  connection  with  the 
Eck  fistula  and  extirpations  of  the  liver,  the  elimination  of  urea  sinks  to  a 
trace,  while  the  blood  becomes  flooded  with  ammonium  salts.  We  do  not 
know  experimentally  where  the  quantities  of  ammonia  (some  12  gm.) 

297 


298  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

could  be  secured  to  furnish  the  material  for  the  entire  urea  output;  of 
amido-acid  the  necessary  (juantitv  is  easily  ayailable.  Some  ammonia 
comes  to  the  liver  through  the  ])ortal  vein,  some  is  formed  in  the  liver,  and 
a  certain  amount  of  amido-substance  is  withdrawn  from  the  muscles  by 
the  venous  blood.  On  purely  theoretical  grounds  it  would  seem  that  most 
of  the  material  should  come  to  the  liver  from  the  general  system  through 
the  arterial  blood  and  that  it  should  come  rather  in  the  form  of  amido- 
acids  than  as  salts  of  ammonia. 

The  liver  is  not  the  sole  seat  of  urea  formation;  the  excretion  of  urea 
never  disappears  entirely  after  the  extirpation  of  the  liver  or  its  exclusion 
from  the  portal  circulation.  We  have,  in  the  different  tissues,  hydrolytic 
and  oxidizing  ferments,  and  to  a  certain  extent  the  reactions  probably 
occur  in  all  tissues.  That  the  kidneys  are  prominent  in  the  synthesis  of 
urea  is  not  demonstrated. 

Ammonia. — The  ammonia  of  the  urine  was  once  supposed  to  bear  a 
reciprocal  relation  to  the  urea.  According  to  this  idea,  if  the  diet  were  rich 
in  vegetable  salts  of  the  fixed  alkalies  or  in  ingested  fixed  alkali,  the  urine 
would  contain  little  or  no  ammonia;  if  the  diet  were  poor  in  fixed  alkalies 
or  their  vegetable  salts,  the  urine  would  contain  a  large  amount  of  ammonia, 
this  being  withdrawn  from  the  urea  metabolism  to  combine  with  the 
sulphuric  and  phosphoric  acids  derived  from  the  oxidation  of  protein  and 
nuclein,  respectively.  When  herbivora,  whose  natural  urine  is  very  poor 
in  ammonia,  are  starved,  their  urine  contains  notable  amounts  of  ammonia 
in  combination  with  the  sulphuric  and  phosphoric  acids  derived  from 
their  own  flesh.  Of  the  importance  of  this  factor  there  is  no  doubt,  but  it  is 
■not  even  the  sole  factor.  The  formation  of  diacetic  and  /?-oxybvityric  acids 
in  the  intermediary  metabolism  is  associated  with  an  excess  of  ammo- 
nuria  and  may,  indeed,  except  in  so  far  as  the  acids  are  reduced  to 
acetone,  be  measured  by  it.  Normal  urine  contains  a  trace  of  acetone  but 
neither  of  the  acids.  The  absorption  from  the  alimentary  tract  of  the 
acid  products  of  fermentation  is  accompanied  by  the  binding  of  ammonia, 
of  small  moment  normally.  It  is  furthermore  certain  that  if  the  forma- 
tion of  urea  is  to  be  regarded  as  the  conversion  of  ammonium  salts  into 
urea  under  the  influence  of  enzymic  acceleration,  a  certain  amount  of 
ammonia  must  remain  in  the  circulation  for  the  simple  reason  that  the 
reaction  is  an  incomplete  and  reversible  one.  This  ammonia  circulating 
in  the  blood-plasma  would  naturally  be  eliminated  by  the  kidneys.  The 
elimination  of  ammonia  is  subject  to  rather  marked  fluctuations,  even 
■when  the  subjects  are  upon  a  constant  diet.  INIasked  pathological  aug- 
mentations are  in  all  probability  connected  always  with  acetone  acidosis. 

Kreatinin. — Blood  and  muscles  contain  small  quantities  of  kreatinin 
and  larger  quantities  of  the  parent  substance,  kreatin;  the  urine  contains 
kreatinin  alone;  kreatinin  of  urine  is  identical  with  that  of  muscle. 
Kreatin  on  administration  is  eliminated  in  part  unchanged,  in  part  as 
kreatinin;  a  fraction  however  is  lost  in  the  metabolism.  It  is  possible 
that  it  has  been  converted  either  into  purin  or  into  urea.  The  natural 
interpretation  of  these  relations  would  be  that  kreatin  is  formed  from  some 
protein  of  muscle  and  then  elsewhere  converted  into  kreatinin.  The 
amount  of  kreatin  and  kreatinin  is  greater  in  the  exhausted  than  in  the 
resting  muscle,  but  this  does  not  appear  to  show  itself  in  the  total  nitrogen 
or  kreatinin  output.     Kreatinin,  on  hydrolysis  in  an  alkaline  reaction,  is 


INTOXICATIONS  IN  GENERAL  299 

split  into  urea  and  methyl-glycocoU,  and  this  has  been  regarded  as  one  of 
the  possible  sources  of  urea.  I'ossibly  the  amounts  concerned  are  too 
small  to  be  noted  under  the  conditions  of  the  experiments. 

Disturbances  in  the  Protein  Metabolism  Dependent  on  the  In- 
put.— A  diet  devoid  of  protein  means  nitrogen  starvation.  If  carbohydrate 
and  fat  be  present  in  excess  of  the  quota  required  for  the  maintenance  of 
the  body  heat,  the  nitrogen  output  (urea)  will  sink  far  below  the  output 
in  starvation.  Insufficiency  of  protein  is  unfortunately  of  frequent  occur- 
rence. Whether  any  people  live  for  any  length  of  time  upon  a  ration  con- 
taining less  than  1  oz.  (30  gm.)  for  a  body  weight  of  150  lbs.  (05  kilos) — 
the  lowest  known  experimental  figures — is  not  known.  The  results  lead, 
so  far  as  we  know,  to  no  auto-intoxication.  Subnutrition  is  of  grave  con- 
sequences to  children,  less  harmful  to  the  aged.  The  most  prominent 
result  is  the  lowering  of  the  resistance,  particularly  to  the  infections 
(starvation  may  be  shown  in  animals  to  be  accompanied  by  a  reduction  in 
the  antibacterial  properties  of  the  blood) ;  i.  e.,  the  full  employment  of  the 
powers  of  compensation  with  respect  to  the  diet  diminishes  the  further 
available  powers  of  compensation.  Pronounced  weakness  attends  such 
a  diet,  but  prompt  recovery  follows  on  return  to  a  normal  diet.  Important 
is  one  metabolic  sign  which  those  underfed  in  protein  share  with  the  con- 
valescent,— the  retention  of  nitrogen  on  a  ration  that  would  not  be  suffi- 
cient to  maintain  a  balance  in  the  same  individual  in  health  and  good 
nutrition. 

The  results  of  an  excess  of  protein  have  not  been  fully  investigated.  A 
man  of  160  lbs.  (70  kilos)  can  digest  probably  not  over  2.2  lbs.  (1  kilo)  of 
protein  per  day.  When  an  individual  in  good  nutrition  is  placed  upon  a 
heavy  protein  diet,  the  usual  result  is  that  catabolism  is  exaggerated,  so 
that  the  output  equals  the  input  and  the  body  is  upon  a  nitrogen  balance. 
In  an  individual  of  superior  powers  of  digestion,  under  forced  feeding 
with  carbonous  as  well  as  nitrogenous  food,  an  appreciable  retention  of 
nitrogen  may  occur.  This  is  not  permanent  for  the  healthy  adult ;  it  dis- 
appears after  the  forced  feeding  is  suspended,  the  products  being  elimi- 
nated by  the  urine.  Such  a  retention  of  nitrogen  is  very  easy  to  attain  in 
children,  but  here  it  is  largely  permanent,  represents  a  true  flesh-mast,  and 
is  proportional  to  the  growth  and  not  to  the  input.  The  same  thing  is  true 
to  some  extent  of  convalescents;  until  they  have  regained  their  normal 
musculature  and  body  weight,  the  retention  is  likely  to  be  permanent.  In 
the  aged  such  a  retention  is  scarcely  attainable. 

This  retention  is  in  the  form  of  protein.  It  is  in  part  carried  in  the  blood 
plasma,  the  protein  content  being  increased  over  the  normal.  (No  in- 
crease in  plasma  protein  leads  to  albuminuria.)  The  protein  of  the  blood 
plasma  is  not  a  constant  but  a  fluctuating  quantity,  being  lowered  in 
sickness  and  subnutrition  and  raised  in  supernutrition.  In  part,  however, 
the  excess  of  protein  is  carried  in  the  tissues,  especially  in  the  muscles, 
which  seem  to  possess  powers  of  compensation.  The  muscle  cells  shrink 
in  sickness,  as  has  been  shown  by  measurements ;  and  chemical  analyses 
have  shown,  under  these  circumstances,  a  reduction  in  the  nitrogen  and  an 
increase  in  the  water.  Supernutrition  will  result  in  aii  increase  in  the  size 
of  the  muscle  fiber,  and  an  increase  in  the  nitrogen  and  a  reduction  in  the 
water.  We  have  no  knowledge  that  the  retained  nitrogen  is  carried  in  any 
other  form  than  as  protein.    This  retention  simply  indicates  an  excess  in 


300  DISEASES  CAUSED  DY  ORGANIC  AGENTS 

the  individual's  powers  of  digestion  and  absorption  over  the  power  of 
disassiniihition;  when  the  input  falls  holow  the  level  of  catabolism,  the 
excess  will  be  gradually  removed  until  the  individual  is  restored  to  the 
natural  balance. 

Does  the  excessive  ingestion  of  protein  lead  to  abnormalities  in  the 
metabolism,  to  auto-intoxication  ?  There  is  now  current  in  the  laity,  and 
also  among  many  physicians,  the  idea  that  the  heavy  consumption  of  pro- 
tein is  harmful,  indeed  the  cause  of  widespread  disease.  It  is  supposed 
to  be  responsible  for  gout,  innumerable  ill-defined  diatheses,  arterio- 
sclerosis, nephritis,  a  large  number  of  skin  diseases,  and,  by  extreme 
vegetarians,  for  an  intoxication  sui  generis.  For  all  these  claims  there  is 
no  adequate  basis.  The  excess  of  protein  is  hydrolyzed,  the  body  dis- 
plays the  greatest  vigilance  in  keeping  the  system  in  a  nitrogen  balance; 
to  accomplish  this  means  an  expenditure  of  energy,  which  might  be 
conceived  to  lead  to  some  disturbance  of  function.  With  an  increased 
protein  ration  the  protein  residue  in  the  intestine  is  increased,  affording  a 
greater  substratum  for  putrefactive  processes.  The  products  of  the 
excessive  protein  metabolism  have  all  to  be  eliminated,  and  this  imposes 
an  increased  task  upon  the  kidneys.  If  the  products  of  protein  metabolism 
be  toxic,  this  toxicity  must  be  exaggerated  under  an  excessive  protein  diet. 
These  considerations  make  it  apparent  that  the  excessive  ingestion  of 
protein  might  tend  to  alterations  in  metabolism  and  elimination  that 
would  constitute  auto-intoxication.  The  question  is  again  one  of  fact. 
Large  classes  have,  since  time  immemorial,  been  accustomed  to  an  excess 
of  protein  food.  We  have  little  exact  information  that  this  has  produced 
disease.  We  have  no  exact  evidence  that  a  moderate  excess  of  protein  is 
the  sole  and  direct  cause  of  any  known  disease.  There  are,  however, 
individuals  who  under  such  conditions  are  not  well,  suffer  from  headache 
and  insomnia,  have  little  spontaneity  and  initiative,  are  sluggish  and 
uncomfortable,  possibly  morose,  and  who  are  relieved  by  reduction  in 
the  protein  of  the  diet.  There  is,  apparently,  for  each  person  a  certain 
excess  of  protein  that  cannot  be  tolerated  without  disturbances  m  the  sen- 
sations of  health.  Excesses  of  protein  are  borne  badly  by  infants.  What 
is  commonly  regarded  as  auto-intoxication  following  the  excessive  use  of 
meat  is  usually  indigestion  and  not  a  disturbed  metabolism.  The 
limits  of  digestion  of  protein  are  often  more  narrow  than  those  for  starch 
or  fats. 

Disturbances  of  Protein  Metabolism  Independent  of  the  Input. 
- — The  retention  of  protein  is  seen  only  under  few  conditions.  In  youth  this 
is  of  obvious  purpose  and  is  proportional  to  the  growth.  Following  illness, 
subnutrition,  and  starvation,  the  body  retains  protein  until  it  has  returned 
to  the  normal.  Under  forced  feeding,  the  body  retains  protein  so  long  as 
the  forced  feeding  is  maintained.  There  is  a  current  idea  that  the  metabo- 
lism of  the  protein  is  often  incomplete.  Following  the  cessation  of  fever 
in  the  infectious  diseases,  an  increased  elimination  of  urea  may  be 
observed.  It  is  believed  that  during  the  fever  the  catabolic  processes  were 
incomplete  and  that  following  the  defervescence  they  are  completed  and 
the  excess  of  urea  eliminated.  This  explanation,  like  the  one  defining  the 
condition  as  simply  a  retention  due  to  renal  insufficiency,  is  not  supported 
by  experimental  work.  The  phenomenon  is  probably  to  be  explained  by 
the  breaking  down  of  the  excessive  number  of  leukocytes  and  other  cells, 


INTOXICATIONS  IN  GENERAL  301 

thus  corresponding  to  the  observed  increased  output  of  purin  bodies  and 
phosphoric  acid. 

Excess  of  Protein  Metabolism. — This  is  seen  particularly  in  six 
groups  of  sickness:  fevers,  infections,  neoplasms,  the  essential  anaemias, 
exophthalmic  goitre,  and  intoxications.  As  a  rule  in  exaggerated  protein 
catabolism,  the  secondary  reactions  are  sufficient,  and  the  nitrogen  ap- 
pears the  form  of  the  normal  end-products.  Sometimes,  however,  the  in- 
termediary products,  amido-acids,  appear  in  the  urine.  In  some  cases  of 
acute  atrophy  of  the  liver,  the  nitrogen  output  in  the  urine  will  be  very 
low  at  a  time  when  the  circulation  is  flooded  with  amido-acids;  under 
these  circumstances,  these,  as  well  as  the  end-products,  fail  of  elimination. 

Fever,  per  se,  increases  the  disintegration  of  protein.  The  high  tem- 
perature increases  the  cellular  disintegration  and  causes  some  cellular 
degeneration,  the  products  of  which  are  thrown  into  the  circulation  and 
there  act  to  produce  an  increase  in  the  nitrogen  output.  All  fermentative 
reactions  are  accelerated  by  increase  of  temperature  within  certain  limits, 
and  it  is  theoretically  possible  that  the  increased  combustions  in  simple 
fever  are  the  direct  result  of  this.  To  the  possible  objection  that  an  in- 
crease in  the  temperature  over  the  normal  could  not  be  supposed  to 
accelerate  a  physiological  function,  it  must  be  replied  that  for  every  fer- 
ment in  the  human  body  the  optimum  temperature  is  a  number  of  degrees 
higher  than  that  of  the  body. 

The  febrile  infectious  diseases,  especially  of  acute  type,  are  accompanied 
by  very  marked  increases  in  the  protein  catabolism.  The  relations  vary 
for  different  days  and  periods;  but  if  the  input  and  output  for  the  entire 
course  of  the  disease  be  obtained,  the  fact  in  most  instances  is  striking. 
Individuals  of  lean  constitution  are  affected  less  than  large,  well-nourished 
subjects.  The  loss  is  greatest  during  the  earlier  stages  of  the  disease. 
Rarely  there  is  no  nitrogen  deficit.  As  a  rule,  the  exaggeration  of  the  pro- 
tein catabolism  is  more  marked  in  the  fevers  than  is  the  increase  in  the 
combustion  of  sugar  and  fat ;  in  moderate  fever  the  combustion  of  fat  and 
sugar  is  often  normal.  The  deficit  may  mean  a  loss  of  protein  to  the  body, 
but  by  increasing  the  diet  the  deficit  may  be  abolished  (even  in  the  child), 
though  it  is  usually  possible  only  to  minimize  the  loss.  To  accomplish 
this,  much  greater  quantities  of  sugar  and  fat  are  necessary  than  would  be 
needed  in  the  normal  subject.  In  other  words,  the  protein-saving  power 
of  sugar  and  fat  is  reduced.  An  increase  of  the  ingested  protein  in  the 
febrile  subject  is  not  followed  by  an  increase  in  the  nitrogen  output,  at 
least  not  to  the  same  extent.  Thus,  while  sugar  has  lost  a  part  of  its  power 
of  saving  protein,  protein  in  the  diet  has  acquired  a  power  of  sparing 
protein  in  the  metabolism, — ^^vhich  is  best  explained  by  the  assumption 
that  there  is,  as  in  subnutrition,  a  protein-deficit  in  the  circulation  which 
the  excess  of  ingested  protein  simply  makes  good.  Subjects  ^^dth  moder- 
ately severe  infections  of  acute  course  will  commonly  lose  from  5  to  8  gm. 
of  nitrogen  daily;  severe  cases  from  10  to  15  gm. ;  in  extreme  cases  the  loss 
may  be  as  high  as  20  gm. 

The  afrebile  infections  have  not  been  well  studied.  In  chronic  cases  of 
tuberculosis,  malaria,  and  syphilis,  without  any  measurable  fever  and 
despite  good  feeding,  we  often  see  rapid  and  extensive  emaciation  of  the 
muscular  system,  which  must  be  accompanied  by  a  nitrogen  deficit.  In 
lesions  of  the  nervous  system,  as  transverse  myelitis,  we  often  obsen'e  a 


302  DISEASES  CAUSED  BY  ORGAXIC  AGEXTS 

rapid  and  extensive  muscuLir  wasting;  the  muscle  cells  degenerate  under 
the  absence  of  the  normal  troj)hic  influences,  and  the  protein  deriveil  from 
their  protoplasm  would  be  disintegrated  just  as. though  it  were  an  excess 
protein  ingested. 

In  exophthalmic  goitre  we  have  a  striking  illustration  of  metabolic 
exaggeration.  Associated  with  an  excessive  or  perverted  functionation 
of  the  thyroid  botlv,  the  protein  catabolism  is  exaggerated.  There  is  a 
deficit  of  nitrogen,  antl  strenuous  forced  feeding  (up  to  60  cal.  per  kilo  per 
day)  may  not  maintain  the  body  weight.  Despite  increased  heat  dissi- 
pation, the  body  tem})erature  is  normal  or  even  increased.  The  exag- 
geration of  the  protein  catabolism,  while  marked,  is  less  extreme  than  the 
increased  combustion  of  the  carbohydrates  and  fats.  The  exaggeration 
of  ])rotein  catabolism  may  represent  simply  an  attempt  at  a  compensation 
for  the  exaggerated  carbonous  metabolism,  an  aid  in  the  heat  production. 
Possibly  the  condition  may  resemble  starvation;  since  the  sugar  and  fats 
are  so  abnormally  burned,  their  sparing  power  on  the  protein  metabolism 
would  be  wanting,  just  as  in  subnutrition  with  a  low  carbohydrate  ration 
It  may  be  possible  that  the  exaggeration  of  the  protein  and  the  greater 
exaggeration  of  the  carbonous  metabolism  are  the  common  results  of  one 
cause.  The  thyroid  body  is  now  believed  to  possess  an  internal  secretion 
that  acts  as  an  accelerator  of  protoplasmic  combustions,  the  administra- 
tion of  thyroid  preparations  and  an  excessive  activity  of  the  thyroid  body 
lead  to  further  exaggerations  in  the  combustions.  In  other  words,  the 
thyroid  body  is  conceived  to  supply  a  substance  that  acts  as  a  zymo- 
excitor  to  the  fermentative  reactions  comprised  in  the  protein  and  carbon- 
ous metabolisms. 

The  exaggerations  that  are  observed  in  association  with  the  essential 
ancomias  are  not  dependent  upon  the  aneemias  per  se,  but  upon  the  con- 
ditions underlying  them.  Simply  anaemia  and  chlorosis  present  a  normal 
metabolism.  In  pernicious  anaemia  and  in  leukaemia,  the  protein  metabo- 
lism may  be  for  long  periods  notably  exaggerated  and  accompanied  by  a 
loss  of  body  protein.  All  cases  do  not  exhibit  it  at  all  times;  one  may 
obtain  normal  values,  or  indeed  a  nitrogen  retention  and  the  accumulation 
of  flesh,  during  some  periods  of  the  disease.  In  the  anaemias  the  exag- 
geration of  the  protein  metabolism  is  not  accompanied  by  a  notable  in- 
crease in  the  combustion  of  sugar  and  fat.  A  study  of  these  diseases  has 
led  to  the  assumption  that  they  are  of  toxic  origin,  and  with  this  the 
exaggeration  of  the  protein  disassimilation  is  in  good  accord. 

In  the  cachexia  of  malignant  diseases  there  is  a  notable  exaggeration  of 
the  protein  catabolism.  It  may  be  absent  during  periods  of  very  chronic 
progress,  but  during  active  groAvth  a  nitrogen  deficit  is  present,  and  this 
does  not  seem  to  be  easily  controlled  by  the  ingestion  of  a  luxurious  carbon 
ration.  These  cases  incline  also  to  an  excessive  combustion,  and  may 
indeed,  exhibit  marked  superoxidation.  The  relations  of  the  tumor  mass 
might  be  of  influence.  The  reproduction  of  neoplasmic  cells  requires 
protein  and  this,  if  extensive,  might  be  expected  to  tend  to  a  nitrogen  re- 
tention. The  neoplasmic  cells,  hoAvever,  are  short  lived  and  frequently 
degenerate  en  bloc,  and  this  would  lead  to  a  nitrogen  deficit. 

Intoxications. — Poisoning  with  exogenous  substances  (phosphorus, 
arsenic,  chloroform  and  others)  is  accompanied  by  an  exaggeration  of  the 
protein  catabolism.    As  a  rule  the  secondary  oxidations  are  sufficient  to 


INTOXICATIONS  IN  GENERAL  303 

convert  the  amido-acids  into  the  normal  end-products,  but  in  many  cases 
these  are  to  be  found  in  the  urine,  while  in  the  liver  and  blood  amido-acids 
may  be  found  in  quantities.  The  urine  contains  lar<^e  amounts  of  am- 
monia combined,  not  with  acids  of  the  acetone  group,  but  rather  with 
lactic  acid  and  mineral  acids  derived  from  the  disintegrated  protein.  The 
combustion  of  sugar  may  be  reduced  during  the  last  perio(Js  of  the  intoxi- 
cation. The  respiratory  exchange  has  been  determined  to  be  normal. 
Glycogen  disappears  from  the  liver  and  to  a  large  extent  from  the  muscles. 
The  limit  of  assimilation  for  sugars  is  reduced,  but  the  injection  of  jjhlorid- 
zin  will  not  provoke  glycosuria.  The  liver  retains  the  power  to  conjugate 
aromatic  bodies,  but  has  lost  the  power  of  oxidizing  benzol.  The  kidney 
loses  the  power  of  forming  hippuric  acid  from  benzoic  acid  and  glycocoll. 

The  brunt  of  the  intoxication  falls  upon  the  protein  metabolism.  The 
excessive  hydrolysis  of  protein  is  associated  with  exaggerated  autolysis  of 
the  cells,  particularly  of  the  liver.  That  this  postulated  exaggeration  of 
the  autolysis  of  the  liver  occurs,  is  shown  by  the  experimental  fact  that  the 
aseptic  postmortem  autolysis  of  the  liver  is  much  more  rapid  in  the  case  of 
phosphorus  poisoning  than  in  the  normal  liver.  In  a  word,  phosphorus 
poisoning  acts  like  a  fermentation.  Acute  yellow  atrophy  of  the  liver  and 
acute  pancreatitis  resemble,  in  their  chemical  details,  phosphorus  poison- 
ing, and  we  are  justified  in  the  assumption  that  the  acts  of  intoxication  are 
similar.  Whether  these  be  due  to  bacterial  or  endogenous  ferments  can- 
not be  stated. 

The  mechanisms  by  which  these  exaggerations  of  the  protein  metabo- 
lisms are  carried  out  have  not  been  investigated  for  the  various  conditions. 
The  following  considerations  deserve  mention: 

The  Fever,  Per  Se. — This  is  able  to  exaggerate  to  some  degree  the 
catabolism  of  protein. 

The  Leukocytosis. — Associated  with  this  is  an  excessive  cytolysis,  the 
products  of  which  would  enter  the  circulating  plasma  and  be  there  subject 
to  the  same  hydrolysis  as  protein  from  the  diet.  How  extensive  this  may 
be  we  do  not  know,  but  in  certain  diseases  it  should  not  be  a  negligible 
quantity. 

The  Cellular  Exudates. — These,  in  pneumonia  and  septic  collections, 
are  unquestionably  of  great  importance.  During  the  period  of  resorption, 
the  subject  of  a  croupous  pneumonia  may  resolve  and  disintegrate  a  kilo 
or  more  of  cellular  material,  and  in  such  cases  the  highest  figures  are 
obtained.  The  disintegration  of  such  exudative  collections  could  account 
for  the  protein  deficit  only  during  the  stage  of  resolution,  not  during  the 
stage  of  formation.  Noav  since  the  phenomenon  is  present  during  the 
stage  of  formation,  when  a  nitrogen  retention  might  have  been  expected, 
it  is  obvious  that  during  that  period  some  other  active  agent  was  in 
operation.  The  mechanism  of  the  exaggeration  of  protein  catabolism  is 
here  also  simply  that  of  flooding  the  circulation  with  the  protoplasmic 
protein,  which  is  then  hydrolyzed  like  any  excess  however  derived.  Closely 
allied  is  the  absorption  of  transudates,  whose  protein  is  thus  added  to  the 
circulation.  These  fluids  also  contain  urea,  so  the  figures  seem  more 
striking  than  they  really  are,  because  this  urea  only  balances  a  previous 
retention. 

An  important  factor  is  the  toxic  cellular  degenerations,  the  exaggeration 
of  the  normal  autolysis.    In  poisoning  by  phloridzin,  toluylene-diamine, 


304  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

nitro-benzol,  and  potassium  chlorate,  in  addition  to  those  previously 
mentioned,  we  find  extensive  and  very  rapid  celhilar  degenerations.  The 
writer  has  recently  seen  cases  of  extreme  degeneration  of  the  liver  occur- 
ring within  three  days  of  a  chloroform  narcosis.  Similar  conditions  are 
found  in  acute  yellow  atrophy  of  the  liver  and  in  acute  pancreatitis. 
These  degenerated  cells  become  an  excess  in  the  circidation  and  are  then 
hydrolyzed  and  burned  like  any  other  excess  of  protein.  Furthermore, 
there  exists,  particularly  in  the  muscles,  an  emaciation  of  the  cells  without 
degeneration.  That  these  cellular  emaciations  and  degenerations  exag- 
gerate the  protein  metabolism  by  casting  into  the  circulation  an  excess 
of  protein  is  shown  l^y  the  fact  that  it  is  not  possible  by  the  administration 
of  any  amount  of  carbohydrate  to  spare  the  nitrogenous  output  as  much 
as  in  health. 

Lastly,  it  is  possible  that  there  may  be  some  direct  influence  on  the 
reactions  of  the  hydrolysis  of  protein,  some  accelerating  influence  of  the 
nature  of  a  zymo-excitor.  The  hypothetical  substance  could  be  derived 
from  the  metabolism  of  the  bacteria,  or  less  probably  from  the  necrobiotic 
cells.  It  is  conceded  that  this  is  a  pure  hypothesis,  but  it  is  high  time  that 
hypotheses  derived  from  general  chemistry  and  physics  should  receive 
some  attention  in  these  matters  and  not  be  entirely  excluded  by  mechani- 
cal or  vitalistic  speculations. 

It  is  clear  that  an  exaggeration  of  the  protein  catabolism  bears  no 
constant  relation  to  any  abnormality  in  the  processes  of  carbonous  com- 
bustion, and  in  particular  one  may  not  infer  from  the  existence  of  such  an 
exaggeration  that  a  suboxidation  is  present.  The  failure  to  understand 
this  has  been  responsible  for  much  confusion. 

Cystinuria. — Cystinuria  is  a  hereditary  abnormality  of  the  protein 
metabolism.  Cystin  is  derived  from  protein ;  it  has  been  recovered  follow- 
ing the  acid  hydrolysis  of  kreatin,  hair,  serum  albumin,  and  edestin ;  it  has 
been  found  in  the  liver  and  kidney  and  among  the  products  of  the  diges- 
tion of  fibrin  with  pancreatin.  The  most  obvious  chemical  mechanism 
for  the  formation  of  cystin  in  the  body  would  be  to  assume  that  cystein  is  a 
normal  product  of  protein  disintegration,  that  it  is  oxidized  to  cysteinic 
acid,  and  this  then  converted  into  taurin  by  the  splitting  off  of  carbon 
dioxide,  probably  as  a  fermentative  reaction.  Under  the  pathological 
conditions  in  cystinuria,  the  cystein  instead  of  being  converted  into 
taurin  is  converted  into  cystin  by  the  union  of  two  molecules,  a  sort  of 
condensation.  The  administration  of  cholic  acid  to  the  cystinuric 
produces  no  increase  m  the  cystinuria. 

Cystinuria  is  usually  accom.panied  by  the  excretion  of  pentamethylen- 
diamine  and  tetramethylendiamine.  Since  these  ptomains  are  usually 
found  as  the  results  of  putrefaction,  the  first  inference  was  that  the  cys- 
tinuria was  of  intestinal  origin.  Cystinuria  has  been  observed  unaccom- 
panied by  ptomainuria;  the  ptomainuria  occurs  in  cholera  and  other 
conditions  independent  of  cystinuria.  These  diamines  may  be  recovered 
from  the  products  of  the  tryptic  or  peptic  digestion  of  protein  (due  to  the 
fermentation  of  lysin  and  ornithin)  and  there  is  no  reason  why  they  may 
not  be  of  metabolic  derivation.  Instead  of  terming  cystinuria  a  condition 
of  intestinal  origin,  it  were  better  in  these  cases  to  locate  the  origin  of  the 
diamines  in  the  tissues.  Cystinurics  are  deficient  in  the  faculty  of  oxi- 
dizing amido-acids. 


INTOXICATIONS  IN  GENERAL  305 

In  proportion  to  the  quantity  of  the  cystin,  the  neutral  sulphur  is  in- 
creased at  the  expense  of  the  sulphuric  aeia.  The  amounts  that  may  he 
eliminated  are  sometimes  quite  large,  more  than  a  gram  p(;r  day.  A 
synthetic  cystin-uramino  acid  is  known,  that  is  possibly  contained  in  the 
normal  urine.  Occasionally  calculi  form  in  the  kidneys  or  bladder.  There 
are  no  symptoms  of  auto-intoxication  and  no  known  sequelae  except  calculi. 
The  condition  is  not  affected  by  any  constituents  in  the  diet;  in  particular, 
meat  does  not  seem  to  cause  any  noteworthy  increase. 

Alkaptonuria. — Idiopathic  alkaptonuria  is  a  family  disease,  consisting 
in  the  elimination  in  the  urine  of  two  aromatic  derivatives,  trioxyphenyl- 
propionic  and  dioxyphenylacetic  acids.  It  was  first  thought  that  these 
were  formed  from  tyrosin  in  the  alimentary  tract  and  then  absorbed; 
experimental  studies  are  opposed  to  this,  as  is  also  the  occurrence  of  the 
condition  in  the  new-born  infant  in  an  alkaptonuric  family.  Tyrosin  is 
formed  in  the  intestine  as  an  end-product  of  tryptic  digestion.  From  it 
phenol  and  cresol  are  derived  by  bacterial  action  through  a  reaction  of 
disamidation.  Tyrosin  is  formed  in  the  body  as  an  intermediary  product 
of  protein  metabolism.  If  the  amount  be  excessive,  as  in  extensive  tissue 
autolyses,  tyrosin  appears  in  the  urine;  otherwise  it  is  oxidized.  A  normal 
individual  is  able  to  oxidize  notable  amounts  of  ingested  tyrosin,  and  the 
abnormality  in  alkaptonuria  consists,  then,  in  the  inability  of  the  body 
to  oxidize  the  tyrosin  derivatives  beyond  the  stage  of  dioxyphenylacetic 
acid,  which  is  eliminated  unchanged.  The  reaction  is  one  of  fermenta- 
tive order;  a  ferment  is  known  in  plants  that  converts  tyrosin  into  dioxy- 
phenylacetic acid.  The  inability  to  further  oxidize  dioxyphenylacetic 
acid  is  seen  in  occasional  cases  of  hepatic  cirrhosis,  tuberculous  peritonitis, 
and  diabetes.  The  abnormality  is  unquestionably  situated  in  the  inter- 
mediary protein  metabolism.  This  anomaly  is  usually  the  only  metabolic 
abnormality  present  and  the  subjects  are  entirely  well. 

Uraemia. — Uraemia  is  here  classed,  without  adequate  experimental  or 
chemical  evidence,  as  an  auto-intoxication  of  the  protein  metabolism, 
simply  because  this  is  the  direction  of  least  resistance.  The  carbonous 
metabolism  is  known  to  be  normal.  That  the  condition  is  an  auto-intoxi- 
cation is  provisionally  proven  by  the  resemblances  of  the  symptoms  to 
well-known  exogenous  intoxications.  As  stated,  uraemia  cannot  be 
regarded  as  a  simple  retention  intoxication;  it  is  likewise  not  possible  to 
incriminate  any  known  normal  constituent  of  the  urine. 

Urea. — That  urea  cannot  be  the  cause  of  uraemia  is  shown  by  its  com- 
parative innocuousness.  A  toxic  action  is  obtained  only  by  the  injection 
of  large  quantities,  and  the  withdrawal  of  water.  The  injection  of  urea  is 
followed  by  a  vasomotor  dilatation  of  the  vessels  of  the  kidney,  but  this 
has  no  bearing  on  the  conception  of  uraemia.  Animals  bear  such  treat- 
ment without  the  slightest  apparent  result.  A  case  has  been  reported  in 
which,  on  the  day  following  an  eight-day  anuria,  nearly  150  grams  of 
urea  were  eliminated.  There  is  no  parallelism  between  the  occurrence  of 
uraemia  and  the  urea  content  of  the  blood.  There  may  be  retention  with- 
out uraemia,  uraemia  may  set  in  without  retention.  There  is  no  relation 
between  uraemia  and  dropsy.  In  subacute  nephritis  there  is  usually  some 
retention  during  periods  of  uraemic  intoxication,  but  this  is  coincident. 

Ammonia. — The  theory  that  ammonium  salts  are  the  cause  of  uraemia  is 
disproved  by  the  simple  fact  that  no  such  amounts  of  ammonia  are  to  be 

20 


306  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

found  in  the  blood  or  urine.  If  it  were  true,  then  in  acctone-acidosis  we 
would  have  ura-mia,  since  here  we  have  the  largest  quantities  of  ammonia 
in  the  blood  and  urine,  and  it  would  be  immaterial  for  the  causation  of  an 
intoxication  whether  the  ammonia  were  withdrawn  from  the  urea  metabo- 
lism to  be  combuied  with  the  fatty  acids,  or  originated  in  a  fermentative 
decomposition  of  urea  or  in  its  non-formation.  That  the  ammonia  might 
be  sujjposed  to  circulate  as  the  hydroxide  is  out  of  the  question.  Uraemia 
cannot  be  produced  by  the  injection  of  salts  of  ammonia. 

Kreatinin  and  Kreatin. — The  extractives  are  not  responsible  for 
urirmia.  They  arc  not  retained  ])rior  to  the  attack.  In  animals  under 
ether  antesthesia,  the  ajiplication  of  kreatinin  to  the  exposed  cortex  causes 
spasms  and  convulsions,  but  since  these  may  be  provoked  by  innumerable 
substances,  the  conclusion  that  kreatinin  is  the  poison  in  uraemia  is  un- 
warranted. The  idea  that  the  extractives  bring  about  a  condition  of 
eclamptic  irritability  is  not  in  harmony  with  the  fact  that  the  electrical 
irritability  of  the  cortex  is  not  increased  after  ligation  of  the  ureters. 
Kreatinin  and  kreatin  are  not  increased  in  the  urine  or  blood  during 
uraemia. 

The  Salts, — Equally  unsatisfactory  is  the  theory  that  the  toxic  agents 
lie  in  the  salts,  particularly  of  potassium.  If  the  salts  be  injected  slowly 
and  not  in  hypertonic  solution,  the  tissues  will  accommodate  themselves  to 
very  large  quantities.  Now  in  nephritis  the  accumulation  is  slow  and 
hypertonicity  is  never  produced,  water  is  always  retained  in  proportion. 
The  more  recent  studies  of  the  actions  of  salts  have  given  no  support  to 
the  saline  theory  of  uraemia.  There  is  no  constant  retention  of  salts  in 
uraemia,  no  constant  or  notable  hypertonicity  of  the  blood,  and  the 
injections  of  hypertonic  solutions  will  not  provoke  uraemia  in  nephrectom- 
ized  animals. 

In  acute  and  subacute  nephritis  the  occurrence  of  uraemia  seems  to  run 
parallel  to  the  impermeability  of  the  kidneys;  in  chronic  interstitial 
nephritis  no  such  relation  is  observed.  We  are  entirely  ignorant  of  the 
nature  of  this  diminution  of  secretory  power.  There  is  no  constant 
relationship  between  uraemia  and  the  histological  lesions  in  the  kidneys. 

We  are  thus  led  to  the  conclusion  that  the  causation  of  uraemia  is  to  be 
sought  neither  in  the  retention  of  the  total  urinary  secretion  nor  in  the 
retention  and  toxic  action  of  any  known  constituent.  Consequently,  since 
the  end-products  of  protein  metabolism  cannot  be  held  responsible,  we 
must  look  for  the  agent  in  the  intermediary  metabolism.  Three  possi- 
bilities suggest  themselves: 

(a)  The  functions  of  the  kidney  include  an  act  of  catabolism  in  which 
some  intermediary  product  is  converted  into  an  end-product;  in  nephritis 
this  fmiction  would  be  to  a  certain  extent  non-operative  and  an  intoxi- 
cation would  result.  This  avoids  entirely  the  difficulty  of  explaining  why 
no  intoxication  is  produced  in  the  functional  anuria.  The  studies  on  the 
total  protein  metabolism  in  nephritis  have  given  very  irregular  results,  and 
it  is  possible  that  an  intoxication  from  some  intermediary  product  could 
occur  without  leading  to  a  marked  nitrogen  retention. 

(6)  A  metabolic  anomaly  lies  behind  the  kidney,  associated  with  the 
renal  lesions  as  cause,  effect,  or  correlation.  This  is  a  hypothetical  propo- 
sition; we  possess,  however,  a  suggestive  analogy.  The  intoxication  that 
follows  the  switching  of  the  liver  out  of  the  circulation  is  in  many  respects 


INTOXICATIONS  IN  GENERAL  307 

like  ursemia.  An  intoxication  may  be  due  to  the  ainrnoiiium  carbamate 
and  other  ammonium  salts,  but  the  injection  of  these  salts  will  not  yield 
the  full  symptom-complex.  The  Eck  fistula  is  well  borne  if  the  animal  be 
given  a  little  protein;  coma  and  death  occur  early  if  much  protein  be 
administered;  behind  the  known  alterations  is  some  abnormality  in  the 
intermediary  metabolism  (not  a  simple  acidosis),  and  therein  lies  the  un- 
known toxic  agent.  If  now  the  hepatic  artery  be  ligated,  death  occurs 
within  a  few  hours  under  most  excessive  acidosis  (not  the  acetone  group), 
for  which  the  available  ammonia  is  insufficient.  The  loss  of  the  hepatic 
circulation  entrains  greater  disturbance  of  metabolism  and  intoxication 
than  does  the  loss  of  the  portal  circulation,  with  its  concomitant  approxi- 
mate abolition  of  the  formation  of  urea. 

(c)  The  kidneys  possess  an  internal  secretion  necessary  for  the  inter- 
mediary protein  metabolism,  the  absence  of  which  is  followed  by  meta- 
bolic disturbances  ending  in  intoxication.  This  theory  avoids  the  difficulty 
of  explaining  the  non-occurrence  of  uraemia  following  prolonged  total 
retention;  it  is  not  irreconcilable  with  the  observations  that  in  some 
diseases,  like  pernicious  anaemia,  no  ureemic  symptoms  appear,  although 
the  kidneys  present  extensive  degenerations,  while  on  the  other  hand 
uraemia  may  appear  in  some  renal  intoxications,  as  in  cantharides  poison- 
ing, that  are  accompanied  with  trifling  lesions.  The  experimental  findings 
have,  in  general,  tended  to  speak  in  favor  of  this  hypothesis;  after  neph- 
rotomy, life  is  prolonged  and  central  symptoms  ameliorated  by  the 
injection  of  renal  extracts. 

Pertinent  in  this  connection  is  the  question  of  specific  nephrotoxication, 
and  the  facts  may  be  stated  thus:  it  is  not  possible  in  animals  to  produce 
autonephrotoxins  or  isonephrotoxins;  the  injection  of  the  blood  serum  of 
an  animal  with  nephritis  (spontaneous,  or  due  to  the  injection  of  hetero- 
nephrotoxic  serum  or  of  chromium)  into  another  animal  is  followed  by 
signs  of  transient  nephritis;  chronic  nephritis  or  uraemia  is  not  estab- 
lished. It  is  apparent  that  nothing  has  been  learned  as  yet  that  could  be 
applied  to  the  problem  of  ursemic  intoxication.  But  the  toxicity  of  the 
serum  of  animals  with  renal  lesions  for  the  kidneys  of  healthy  animals, 
warns  us  that  the  relation  of  the  kidney  to  the  circulating  blood  is  to  be 
considered  no  more  closely  than  the  relation  of  the  blood  to  the  kidney. 

Conceding  that  we  possess  as  yet  no  qualitative  demonstration  of  the 
theory  that  the  cause  of  uraemia  lies  in  the  intermediary  protein  metabo- 
lism, are  there  quantitative  variations  ?  It  is  known  that  peculiar  fluctua- 
tions in  the  nitrogen  occur  in  nephritis;  periods  of  retention  are  followed 
by  periods  of  deficit,  and  these  without  any  regular  relation  to  the  dropsy 
or  to  the  symptoms  of  uraemia.  No  one  can  work  with  the  nitrogen 
metabolism  of  nephritis  without  being  convinced  that  there  is  something 
wrong  which  is  not  expressed  in  the  end  results  except  in  an  incidental 
manner.  The  influence  of  various  diets  on  the  metabolism  of  nephritis 
is  not  known ;  we  have  only  superficial  studies  on  the  relations  of  different 
diets  to  albuminuria.  The  albuminuria  is  of  no  metabolic  consequence 
to  a  nephritic  w^ho  has  moderate  powers  of  digestion  An  excess  of  uric 
acid  is  often  found  in  the  blood  in  nephritis,  but  normal  values  are  obtained 
in  the  urine.  There  is  no  evidence  for  the  theory  that  nephritis  is  accom- 
panied by  a  retention  of  purin  base.  Acidosis  is  not  present  in  ursemia, 
nor  is  the  urinary  elimination  of  ammonia  particularly  high. 


308  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

Overexertion. — AYithin  recent  years  we  have  learned  of  the  existence 
in  human  beings  of  a  condition  termed  autotyj^hization,  apparently  of 
autotoxie  origin,  resembling  the  surmcttagr  of  animals.  It  is  seen  follow- 
ing ])rolonged  and  abnormally  heavy  exertion.  Unlike  the  surnininrjc  of 
animals,  it  seems  to  have  no  relations  to  the  diet.  The  symj)toms  are 
fever  of  irregular  type,  headache,  muscular  prostration,  albuminuria, 
sometimes  an  elimination  of  lactic  acid,  j)robably  a  slight  excess  in  the 
nitrogen  elimination,  and  often  cardiac  dilatation.  Possibly  the  conditions 
that  have  been  described  in  foot-ball  players  following  severe  games  are 
related  to  surmrnacjc.  The  theory  that  the  condition  is  due  to  an  excess 
or  abnormality  in  the  kreatinin  metabolism  has  failetl  of  confirmation  by 
urinary  analysis.  The  symptoms  and  attendant  circumstances  suggest  an 
auto-intoxication  but  we  have  no  exact  knowledge  of  it.  The  acid  intoxi- 
cation that  occurs  in  herbivora,  following  excessive  exercise,  is  a  different 
complex. 

AUTO-INTOXICATION  ASSOCIATED  WITH  THE  PURIN 
METABOLISM. 

Concerned  in  this  metabolism  are  the  substances  derived  from  the 
purih  nucleus;  uric  acid;  and  several  bases,  xanthin,  hypoxanthin,  ade- 
nine, guanin,  and  thi'ee  vegeta.ble  bases,  caffeine,  theobromine,  and 
theoj)hyllin,  all  methyl  xanthins.  The  purin  input  consists  of  the  nucleins 
and  the  preformed  purin  bodies  contained  in  the  diet,  and  the  bases  con- 
tained in  tea,  coffee,  and  cocoa.  The  purin  input  may  vary  with  the  diet, 
from  nothing  to  15  grains  (1  gm.)  per  day.  The  nuclein  is  hydrolysed  in 
the  alimentary  tract  and  split  into  purin  bases,  a  pyrimidin  complex,  a 
pentose  and  phosphoric  acid;  the  purins  thus  derived  join,  in  their 
absorption,  the  preformed  ]3urin  of  the  diet.  Whether  any  purins  are 
oxidized  or  destroyed  in  the  intestinal  tract  is  not  known.  After  absorption 
the  purin  may  be  used  in  the  synthesis  of  nuclein,  oxidized  or  eliminated 
unchanged.  Ingested  uric  acid  is  eliminated  in  part  unchanged,  in  part 
as  urea;  xanthin,  hypoxanthin,  and  adenine  are  eliminated  in  part  un- 
changed, in  part  as  uric  acid;  the  methyl-purins  (caffeine,  theobromine 
and  theophyllin)  are  eliminated  as  methyl-xanthin  and  are  not  oxidized 
to  uric  acid.  In  a  certain  sense,  therefore,  all  these  bodies  may  be 
termed  intermediary  products;  to  what  extent  conversions  occur  we  do 
not  know.  Obviously  therefore  the  purin  output  on  an  ordinary  diet 
comprises  an  exogenous  and  an  endogenous  fraction.  For  the  purposes 
of  clinical  experimentation  the  exogenous  purin  may  be  excluded  by  the 
employment  of  a  milk  diet. 

Is  the  purin  output  derived  solely  from  the  input  and  nuclein  catabolism 
or  is  uric  acid  formed  by  synthesis  ?  In  other  words,  does  the  endogenous 
purin  proceed  entirely  from  the  nucleinic  metabolism,  or  is  purin  other- 
wise formed  ?  The  hypothesis  that  uric  acid  may  be  formed  by  oxidation 
without  the  nucleinic  metabolism  is  old,  but  has  never  been  confirmed  in 
an  exact  manner.  Recent  investigations  however  have  shown  that 
hypoxanthin  is  formed  during  the  period  of  exercise  of  muscle,  an  im- 
portant observation  whose  bearing  on  the  practical  problems  is  not  yet 
definable.  Purin  may  be  derived  from  purin  and  nuclein  in  the  diet, 
from  urea  and  lactic  acid,  and  from  the  catabolism  of  nuclein;   purin 


INTOXICATIONS  IN  GENERAL  309 

bases  may  be  (;liminate(l  as  derived  from  each  of  these  three  sources; 
they  may  also  be  converted  into  uric  acid.  Uric  acid  may  be  derived 
from  the  purin  and  nuclein  input,  from  the  nuclein  catabolism,  and  by 
synthesis;  uric  acid  may  be  ehminated  as  derived  from  these  sources 
and  may  also  be  converted  into  urea 

There  is  no  parallelism  between  leukocytosis  and  uric-acid  output.  The 
circulating  leukocytes  are  but  a  fraction  of  the  total  leukocytes,  and  the 
assumption  of  a  regular  cytolysis  ])roportional  to  the  total  increase  is 
unfounded.  In  pneumonia  the  uric-acid  output  is  parallel  with  the 
resorption  of  the  exudate,  not  with  the  circulating  leukocytes.  The  excess 
of  uric  acid  to  be  seen  in  some  cases  of  nephritis  cannot  be  explained  on 
any  theory  of  leukocytosis  or  lymphatic  activity.  The  excess  of  uric  acid 
in  dogs  with  an  Eck  fistula,  following  cauterization  of  the  liver,  and  in 
acute  yellow  atrophy  of  the  liver  and  phosphorus  poisoning,  cannot  be 
reduced  to  the  lymphatic  system.  Leukocytosis  and  an  increased  output 
of  uric  acid  are  correlated  results  of  a  common  cause,  but  the  latter  can 
occur  without  the  former.  Our  knowledge  of  the  nuclein  content  of 
different  tissues  alone  renders  very  improbable  any  theory  that  rests  the 
production  of  uric  acid  upon  the  cytolysis  of  circulating  lymphatic  cells 
alone  or  even  on  the  cytolysis  of  the  whole  lymphatic  system.  The  purin 
metabolism  is  concerned  with  the  nuclein  of  the  entire  body  and  not 
specifically  with  that  of  the  lymphatic  system. 

Is  the  purin  absorbed  from  the  alimentary  tract  utilized  for  the  synthesis 
of  nuclein;  is  it  combined  with  the  pyrimidin  derivative,  pentose,  and 
phosphoric  acid,  to  form  nucleinic  acid  ?  This  is  a  crucial  question.  In 
health  the  intensity  of  the  purin  metabolism  is  quite  constant.  If  the 
ingested  purin  be  utilized  in  the  synthesis  of  nucleinic  acid,  less  would  be 
required  from  other  sources.  That  the  body  can  easily  synthesize  purin 
directly  is  shown  by  the  formation  of  nucleinic  acid  in  the  hatching  chick, 
by  the  regular  functionation  of  the  purin  output  on  a  milk  diet,  and  by 
direct  prolonged  experiments  on  growing  animals.  If  now  exogenous 
purin  be  utilized  in  the  synthesis  of  nuclein,  the  exogenous  purin  of  a 
particular  diet  cannot  be  subtracted  from  the  total  purin  output  in  order  to 
arrive  at  a  figure  for  the  purin  output  of  endogenous  origin.  Since  the 
increase  of  a  purin  input  is  followed  by  an  increase  in  the  output,  it  follows 
either  that  the  purin  metabolism  behaves  like  the  common  protein  metabo- 
lism— an  excess  of  the  substrate  results  in  an  acceleration  of  the  catabo- 
lism— or  else  the  absorbed  excess  is  simply  eliminated  directly.  This 
question  of  the  utilization  of  ingested  purin  has  not  been  definitely 
decided.  In  the  writer's  opinion  the  present  evidence  indicates  that 
exogenous  purin  is  not  utilized  in  the  synthesis  of  nuclein;  the  purin  and 
pyrimidin  rings  are  synthesized  de  novo  from  protein,  the  pentose  from 
hexose,  and  these  then  combined  with  phosphoric  acid  to  form  the 
nucleinic  acid.  In  all  probability  the  purin  metabolism,  though  it 
concerns  a  group  of  structures,  is  subject  to  exaggerations  whenever 
abnormal  excesses  of  cytolysis  occur. 

The  seat  of  the  oxidation  of  purin  bases  to  uric  acid  is  not  single, 
although  the  liver  is  particularly  active  in  this  function.  Birds  and  dogs 
when  deprived  of  liver  are  still  able  to  secrete  uric  acid.  That  the  hin- 
phatic  structures  have  the  power  of  effecting  this  oxidation  has  been 
experimentally  shown.    The  older  theory  that  the  kidneys  were  the  chief 


310 


DISEASES  CAUSED  BY  ORGAXIC  AGENTS 


seat  of  this  oxidation  is  now  entirely  discredited.  Of  the  relative  pre- 
ponderance of  the  liver  and  lymphatic  system  in  tins  function  we  know 
nothing.  This  reaction  is  to  be  regarded  as  a  fermentative  oxidation,  and 
we  are  not  surprised  that  it  shoidd  not  be  localized  in  one  organ  The 
synthesis  of  uric  acid  occurs  in  birds  only  in  the  liver,  and  the  same  has 
been  made  very  probable  for  the  mammalian  organism  The  oxidation 
of  uric  acid  to  urea  has  not  been  brought  into  definite  connection  with  any 
organ.  The  liver,  kidney,  and  muscle  of  the  dog  and  pig  have  the  power 
of  thus  oxidizing  uric  acid.  The  oxidation  of  uric  acid  to  urea  is  probably 
not  a  pronounced  })henomenon.  AYhen  a  large  single  dose  of  uric  acid  is 
ingested  it  is  converted  in  part  into  urea,  but  it  is  not  known  to  what 
extent  such  conversions  occur  in  the  course  of  metabolism.  It  is  certain 
that  the  purin  output  represents  the  larger  part  of  the  j)urin  metabolism, 
{.  e.,  an  end  rather  than  an  intermediary  product. 

Now  these  facts,  apart  from  the  light  they  may  throw  upon  this  complex 
problem,  demonstrate  one  point  of  practical  importance  in  the  inter- 
pretation of  urinary  analysis.  Without  the  purin  input  being  known  the 
estimation  of  the  uric-acid  excretion  is  worth  nothing  as  evidence  of  the 
state  of  the  purin  metabolism.  But  with  the  purin  input  known  (or  ex- 
cluded), the  estimation  of  the  ^iric  acid  alone,  or  of  the  total  purin,  cannot 
be  used  to  determine  whether  the  purin  output  be  normal,  increased,  or 
decreased,  the  purin  metabolism  normal  or  abnormal.  The  following 
diagram  illustrates  the  facts  of  the  purin  input,  metabolism,  and  output: 

Fig.  4. 


INPUT 

METABOLISM 

^1  ■Tnii.r' 

^ 

PURIN 

SYNTHESIS 

BASES 

PURIN 

- 

\(^ 

~x" 

^ 

-^ 

^ 

,('1 

NUCLEINE 

PURIN 

URIC 
ACID 

UREA 

NUCLEINE 

lBases 

— ^ 

^—"^ 

^^..'^ 

■^^ 

^^ 

MUSCLE 

URIC 

X 

ACID 

^ 

... 

When  one  realizes  that  the  output  of  uric  acid  and  nuclein  is  related 
to  respectively  three  and  four  variables,  it  is  apparent  that  by  no  simple 
estimation  of  the  output  of  uric  acid  or  the  total  purin  can  a  conclusion  be 
drawn  of  the  magnitude  of  nuclein  metabolism,  unless  we  control  the 
other  variables,  which  we  are  not  able  to  do.  We  possess  to-day  no 
analytical,  or,  for  human  organisms,  experimental  method  of  determining 
the  magnitude  of  the  purin  metabolism  or  the  relations  of  output  to 
metabolism. 

There  is  no  constant  relation  between  the  purin  and  protein  metabo- 
lisms or  between  the  purin  output  and  the  urea  or  nitrogen  output.  It  is 
possible  by  an  arbitrary  modification  of  the  diet  with  respect  to  the  in- 
gestion of  common  protein  and  nuclein ic  tissue  to  vary  the  ratio  within 
very  wide  limits;   the  urea  uric-acid  ratio  gives  no  information  of  either 


INTOXICATIONS  IN  GENERAL  311 

metabolism,  it  is  a  dietary  index  solely.  While  a  certain  amount  of  purin 
may  be  converted  into  urea  and  a  certain  amount  of  urea  may  be  utilized 
in  the  synthesis  of  uric  acid,  the  amount  of  nitrogen  concerned  is  too  small 
to  affect  the  total  nitrogen,  while  the  relations  of  these  two  processes  to  the 
purin  total  are  not  known.  The  purin  metabolism  is,  however,  not  entirely 
independent  of  the  general  metabolism,  since  a  luxurious  non-purin  diet 
will  reduce  (that  is  spare)  the  purin  output  to  a  slight  extent.  In  star- 
vation the  purin  output  is  not  reduced  corresponding  to  the  reduction  in 
the  urea.  The  nucleinic  metabolism  is  an  integral  part  of  the  daily  life  of 
the  cellular  nuclei;  it  is  not  notably  reduced  in  starvation  or  replaceable 
by  any  other  metabolism,  and  has  no  role  in  the  caloric  or  energetic  aspect 
of  general  metabolism.  In  general  language  we  may  say  that  the  cells 
that  elaborate  protein,  sugar,  and  fat,  for  the  purposes  of  the  general 
metabolism,  wear  out  in  these  efforts  a  certain  amount  of  nuclein  in  their 
own  internal  mechanisms. 

Exceedingly  important  are  the  questions  that  relate  to  the  form  in  which 
the  uric  acid  circulates  in  the  blood,  its  solubility,  and  the  influence  of  the 
reaction  of  the  blood  upon  these  relations.  We  do  not  know  in  what  form 
uric  acid  and  the  bases  circulate  in  the  blood  This  is  a  physico-chemical 
problem  and  it  has  never  been  investigated  as  such  with  proper  methods. 
It  is  difficult  to  understand  how,  in  a  complex  fluid  like  the  blood,  contain- 
ing electrolytes,  colloids,  and  many  amphoteric  substances  and  practically 
saturated  with  a  gas  of  acid  reaction,  a  substance  like  uric  acid,  which 
contains  no  carboxyl  groups  and  has  an  extremely  low  co-efficient  of  solu- 
bility and  constant  of  dissociation,  should  be  combined  with  a  cation  like 
sodium  to  form  an  electrolyte.  It  is  quite  certain  that  uric  acid  cannot 
circulate  to  any  extent  in  the  form  of  the  di-sodium  urate  (a  pronouncedly 
alkaline  salt)  or  of  the  mono-sodium  urate  (a  feebly  alkaline  salt);  the 
so-called  hemi-urate  is  a  fiction  Facts  that  have  been  demonstrated  in 
researches  on  the  purins  point  to  a  different  conception.  It  has  been  long 
known  that  no  known  method  of  direct  precipitation  will  throw  down  all 
the  uric  acid  and  purin  bases  in  an  extract  of  a  tissue  or  in  blood.  It  is  now 
known  that  some  of  the  pyrimidin  derivatives  of  nuclein  combine  to  form 
with  uric  acid  complexes  that  do  not  give  the  ion  reactions  of  uric  acid  and 
are  not  precipitable  by  the  metallic  salts,  and  of  these  substances  one, 
thymic  acid,  has  been  identified.  It  is  most  natural  to  consider  whether 
it  may  not  be  in  some  such  form  that  uric  acid  circulates.  Blood  serum 
will  dissolve  forty  times  as  much  uric  acid  as  distilled  water  (1  to  1,000  as 
against  1  to  40,000).  This  uric  acid  does  not  yield  the  ion  reactions  of 
uric  acid,  and  can  be  recovered  only  after  boiling  with  an  acid ;  obviously 
some  complex  combination  needs  to  be  split  by  hydrolysis.  The  fact  that 
uric  acid  will  crystallize  out  from  the  blood  serum  about  a  suspended 
thread  is  not  a  proof  that  the  serum  is  saturated.  It  has  been  shown 
experimentally  that  such  a  serum  will  dissolve  more  uric  acid. 

Analyses  of  uric  acid  in  the  blood  are  approximate  only.  Abnormal 
amounts  have  been  determined  to  exist  in  most  cases  of  acute  gout,  in 
many  cases  of  nephritis,  arteriosclerosis,  pneumonia  in  the  stage  of  re- 
sorption, in  conditions  associated  with  the  disintegration  of  cellular 
exudates,  following  a  meal  rich  in  nuclein,  and  most  markedlyin  leukaemia. 
Whenever  an  increased  blood-content  is  accompanied  by  an  increased 
output,  it  may  be  reasonably  inferred  that  an  exaggerated  nuclein  metabo- 


312  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

lism  or  purin  inj)iit  exists,  "Whenever  an  increased  content  is  not  accom- 
panied h\  an  increased  output,  as  in  gout  and  nephritis,  there  remain  two 
possibiHties, — if  one  assumes  tiiat  the  chemical  form  in  which  the  uric  acid 
circuh^tes  is  the  same  as  in  the  normal, — a  decreased  oxidation  of  uric  acid 
or  a  retention  throuti'h  failure  of  renal  elimination. 

As  regards  gout,  there  is  no  evidence  that  the  gouty  individual  displays 
any  abnormality  in  the  assimilation  of  purin ;  the  ingested  purin  is  quanti- 
tatively absorbed  from  the  digestive  tract,  as  shown  by  the  nitrogen 
balance  and  by  the  elimination  of  phosphoric  acid.  In  some  diet  experi- 
ments the  elimination  of  purin  following  the  ingestion  of  sweetbreads  was 
normal;  in  others  there  seemed  to  be  a  retention,  the  jihosphoric  acid  was 
eliminated  but  not  the  ])urin.  AYhether  such  a  failure  could  indicate  a  lack 
of  oxygenation  or  a  retention  cannot  be  now  decided.  We  need  to  know  in 
detail  how  the  gouty  react  in  a  c[uantitative  and  cjualitative  manner  to 
variations  in  the  j)urin  input.  The  once  current  notion  that  gout  is  the 
direct  result  of  an  excessive  purin  input  is  devoid  of  any  experimental  basis. 

Does  the  uric  acid  in  the  blood  in  gout  circulate  in  the  same  form  as 
normally  ?  This  has  been  denied  by  those  who  would  explain  the  excess 
in  the  blood  without  resting  it  upon  a  simple  retention.  We  have  no  data 
tending  to  show  that  the  solubility  of  uric  acid  in  the  blood  is  decreased  in 
gout.  The  hypothesis  of  the  dej^endence  of  this  solubility  on  the  phos- 
phates is  a  vague  speculation.  There  is  some  evidence  that  the  uric  acid 
in  the  blood  in  leukaemia  circulates  in  part  in  a  form  different  from  the 
normal. 

Is  there  a  diminished  power  of  elimination  of  uric  acid  fcr  se  in  gout  ? 
When  we  recall  that  from  the  purin  output  alone,  even  with  a  controlled 
purin  input,  the  magnitude  of  the  nuclein  metabolism  cannot  be  estimated, 
W'e  realize  that  a  retention  cannot  be  thus.determined.  Conceding  that 
many  cases  of  gout  have  renal  lesions  and  that  many  cases  of  renal  sclero- 
sis have  urate  depositions,  it  is  still  not  possible  to  maintain  that  the  excess 
of  uric  acid  in  the  blood  is  the  simple  result  of  retention  due  to  renal 
disease.  The  fact  that  the  gouty  kidney  can  eliminate  an  excess  of  uric 
acid  after  the  ingestion  of  thymus,  argues  neither  for  nor  against  the 
theory,  since  a  diseased  organ  may  respond  to  extraordinary  stimuli.  On 
the  contrary,  the  fact  that  in  chronic  nephritis  the  ingestion  of  thymus  is 
followed  by  an  increase  in  the  blood-content  as  well  as  in  the  elimination, 
does  not  prove  that  the  fault  lies  in  the  kidney.  The  renal  theory  of  gout 
can  be  assumed  only  by  postulating  an  elective  type  of  purin  nephritis.  In 
chronic  gout  and  in  the  intervals  between  the  attacks  in  acute  cases,  the 
purin  output  is  normal.  Prior  to  the  onset  of  an  acute  attack  of  gout  there 
is  a  diminution  in  the  uric-acid  output,  followed  by  an  increase;  it  has  not 
been  shown  that  this  bears  constant  relations  to  variations  in  the  blood- 
content  of  uric  acid.  It  is  scarcely  possible  to  believe  that  the  attack  is 
dependent  upon  the  diminution  in  the  output;  the  cpian titles  concerned 
are  too  small  to  be  the  direct  etiological  factor.  The  depositions  cut  no 
figure  in  the  cjuantitative  relation;  whether  the  urate  depositions  are  ever 
absorbed  with  such  rapidity  and  to  such  an  extent  as  to  show  in  the  output 
is  doubtful.  Resolution  in  acute  cases  seems  an  act  of  phagocytosis  rather 
than  of  solution. 

The  deposition  of  urates  is  not  the  direct  result  of  an  excess  of  uric  acid 
in  the  blood;   they  are  absent  in  conditions  other  than  gout,  particularly 


INTOXICATIONS  IN  GENERAL  313 

leuksemla,  in  which  an  excess  is  present  in  the  blood,  and  occur  most  often 
in  chronic  gout  in  which  there  is  no  evidence  that  the  uric  acid  in  the  blood 
is  increased.  Nor  is  the  deposition  to  be  explained  by  the  coincidental 
occurrence  of  an  excess  of  uric  acid  in  the  blood  and  a  lesion  in  the  tissues. 
Gout  would  be  very  easy  of  experimental  production  if  nothing  but  an 
excess  of  uric  acid  in  the  blood  and  a  local  lesion  were  required.  The 
formation  of  tophi  must  rest  upon  some  physico-chemical  basis  of  pre- 
cipitation and  crystallization.  That  necrosis  cannot  be  the  sole  sub- 
stratum is  certain. 

These  various  facts  compel  us  to  assume  that  the  actual  etiology  lies 
deeper  than  quantitative  variations  in  the  uric  acid;  the  determining 
moment  lies  earlier  in  the  purin  metabolism.  That  these  earlier  factors 
may  have  relations  to  retention  is  not  denied,  but  the  retention  is  a  result 
and  not  in  itself  an  etiological  factor.  In  a  certain  sense,  the  uric  acid  must 
be  considered  as  the  innocent  weapon  of  the  disease.  The  idea  that  the 
uric  acid  is  itself  the  toxic  agent,  that  it  by  a  local  action  as  uric  acid 
inaugurates  the  local  lesion,  or  that  the  local  lesion  is  simply  the  reaction 
of  the  tissue  to  a  crystallization  of  uric  acid  as  a  physico-chemical  fact 
is  contrary  to  our  best  knowledge.  That  the  purin  bases  are  devoid  of 
that  marked  toxicity  that  was  some  time  ago  ascribed  to  them  is  now 
known;   they  are  not  in  gout  increased  at  the  expense  of  the  uric  acid. 

The  hypotheses  concerning  the  morbid  physiology  of  gout  most  in 
harmony  with  our  chemical  and  experimental  data  are  two:  Gout  is  a 
disease  of  the  intermediary  purin  metabolism;  gout  is  an  auto-intoxication. 
The  first  may  be  formulated  in  several  ways.  It  may  be  assumed  that 
products  are  elaborated  in  the  purin  metabolism  which  cause  local  in- 
flammations. It  may  be  assumed  that  the  uric  acid  normally  circulates  in 
combination  in  some  pyrimidin  complex,  very  soluble  and  easy  of  elimi- 
nation, possibly  by  virtue  of  some  dissociation  in  the  kidneys;  in  gout  this 
combination  would  be  lacking  or  so  altered  that  the  uric  acid  would 
circulate  in  a  form  more  resistent  to  excretion.  Such  alterations  as  are 
postulated  in  this  theory  may  be  demonstrated.  Substances  exist,  as 
formaldehyde,  that  will  pair  with  purin s  and  thus  protect  them  from 
further  oxidation.  Thymic  acid  combines  with  uric  acid  to  form  a  large 
and  stable  complex  which  has  totally  different  chemical  relations  than 
uric  acid. 

The  disturbance  could  be  localized  either  in  the  processes  of  assimi- 
lation of  ingested  nucleins  or  in  the  cellular  purin  metabolism.  It  is  con- 
ceivable that  the  oxidation  of  the  absorbed  purin  bases  might  be  altered 
and  their  utilization  in  the  synthesis  of  nuclein  might  be  abnormal.  This 
would  reduce  gout  to  a  disturbance  within  the  realm  of  the  purin  input. 
This  is  unlikely,  since  practically  all  of  the  known  disturbances  of  metabo- 
lism have  been  shown  to  reside  in  the  intermediary  metabolism,  not  in  the 
processes  of  digestion  and  assimilation.  It  may  be  assumed  that  the  dis- 
turbance in  the  purin  metabolism  postulated  for  gout  is  resident  in  the 
cellular  nucleinic  metabolism. 

The  most  recent  theory  rests  upon  the  assumption  that  the  formation  of 
uric  acid  by  oxidation  of  the  nucleinic  purin  is  more  or  less  lowered  and 
that  instead,  uric  acid  is  formed  by  synthesis.  Since,  imder  these  circum- 
stances, the  thymic  acid  with  which  the  uric  acid  is  held  to  circulate  would 
not  be  available,  the  uric  acid  would  circulate  in  a  less  soluble  and  elimin- 


314  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

able  and  more  easily  precipitable  form.  The  abnormality  in  the  piirin 
metabolism  would  thus  be  a  sort  of  retardation;  the  meehanism  whereby 
the  synthetic  formation  of  uric  acid  would  be  increased  is  entirely  obscure. 

The  hypothesis  that  gout  is  an  auto-intoxication  other  than  in  the  purin 
metabolism  is  derived  more  from  generalization  than  from  research.  It  is 
conceivable  that  gout  may  be  associated  with  tlisturbances  in  the  common 
])rotein  metabolism.  It  has  been  established  that  there  is  during  the  acute 
attack  of  gout  a  nitrogen  deficit  that  cannot  be  explained  by  any  possible 
deviation  in  the  purin  metabolism,  and  suggests  a  toxic  exaggeration  of  the 
protein  catabolism.  Between  attacks  a  nitrogen  retention  is  often 
observed  which  may  represent  simply  the  recovery  of  protein  lost  during 
the  attack  or  a  retention  of  the  end-products  of  protein  catabolism.  Gas- 
tro-intestinal  auto-intoxication  might  be  supposed  to  produce  deviations 
in  the  assimilation  of  ingested  purin,  local  lesions  favorable  to  the  depo- 
sition of  uric  acid,  and  also  conditions  in  the  circulation  unfavorable  to 
solution  and  excretion.  It  is  obvious  that  in  the  end  any  theory  of  auto- 
intoxication extraneous  to  the  purin  metabolism  becomes  merged  into  the 
theory  of  deviations  in  the  intermediary  metabolism,  and  since  data  are  as 
yet  entirely  wanting,  it  is  more  logical  to  presume  that  the  primary  dis- 
turbance lies  not  without  but  within  the  purin  metabolism. 

Oxaluria. — Oxaluria  has  been  quite  generally  considered  to  hold  some 
relation  to  the  purin  metabolism.  There  is  no  relation  between  the 
amount  of  oxalic  acid  in  the  urine  and  the  quantity  of  crystals  of  calcium 
oxalate  in  the  urinary  sediment.  Oxalic  acid  is  formed  in  the  normal 
body  in  the  entire  absence  of  the  acid  from  the  diet.  Of  the  oxalic  acid 
contained  in  the  diet  the  larger  part  is  destroyed  in  the  alimentary  tract. 
In  all  probability  oxalic  acid  is  not  oxidized  in  the  body.  Oxaluria  is  no 
more  common  in  the  gouty  than  in  others,  and  there  is  no  clinical  evidence 
of  any  relationship  between  oxaluria  and  disturbances  of  the  purin 
metabolism. 

In  so  far  as  the  common  protein  metabolism  is  concerned,  oxalic  acid  is 
formed  from  gelatine  and  kreatin;  it  is  experimentally  not  to  be  derived 
from  any  excess  of  fat  or  carbohydrate  in  the  diet.  There  is  no  experi- 
mental evidence  that  it  is,  in  the  body,  derived  from  glycuronic  acid  or 
bears  any  relations  to  it.  Oxalic  acid  is  likewise  easily  obtained  from  the 
higher  fatty  acids,  but  there  is  no  evidence  that  it  is  in  any  way  associated 
with  the  normal  fat  metabolism  or  the  abnormal  acetone  acidosis. 
Lastly,  oxalic  acid  might  be  derived,  from  the  oxidation  of  oxy-acids 
such  as  lactic  acid.     In  this  manner  it  might  be  derived  from  sugar. 

It  is  apparent  that  these  facts  shed  no  light  upon  the  symptom-complex 
of  oxaluria.  That  this  symptom-complex  possesses  anything  but  a  definite 
objective  character  is  freely  admitted.  In  any  event  there  is  no  reason  to 
incriminate  the  oxalic  acid  In  the  quantities  concerned  it  is  innocuous 
and  the  symptoms  currently  attributed  to  the  condition  bear  no  resem- 
blance to  oxalic  acid  poisoning.  That  calculi  form  is  a  chemical  acci- 
dent. The  most  that  may  be  claimed  would  be  that  the  elimination  of 
an  excess  of  oxalic  acid  accompanies  a  symptom-complex,  and  may  be 
assumed  to  indicate  an  underlying  disturbance  in  metabolism.  In 
which  metabolism  the  assumed  abnormality  lies  is  not  conjecturable. 


INTOXICATIONS  IN  GENERAL  315 

AUTO-INTOXICATION  ASSOCIATED  WITH  THE  CARBOHYDRATE 

METABOLISM. 

The  digestion  of  the  starches  and  the  higher  sugars  is  an  act  of  hydroly- 
sis. Ordinarily  all  the  sugar  absorbed  (apart  from  pentoses)  is  in  the 
form  of  hexose.  It  is  possible  under  normal  circumstances  for  higher 
sugars  to  be  absorbed  unchanged;  the  power  of  the  alimentary  tract  to 
invert  disaccharides  is  limited;  beyond  a  certain  point  the  sugar  is 
absorbed  unchanged.  This  mellituria  is  a  strictly  alimentary  type;  the 
sugar  appears  in  the  urine  unchanged.  In  the  common  form  of  alimentary 
mellituria,  the  sugar  in  the  urine  is  glucose,  no  matter  what  sugar  was 
ingested.  Normally  no  mellituria  follows  the  ingestion  of  starch;  time  is 
the  controlling  factor  in  alimentary  mellituria;  if  absorption  be  heavy  in 
the  unit  of  time,  it  will  produce  hyperglycsemia.  The  normal  individual 
will  not  exhibit  mellituria  following  the  ingestion  of  5  ozs.  (150  gms.)  of 
glucose  or  levulose  or  nearly  double  that  amount  of  saccharose  or  maltose; 
milk  sugar  is  often  less  well  tolerated. 

The  absorbed  sugars  are  converted  into  glycogen  but  not  all  hexoses 
with  equal  readiness.  Those  sugars  that  undergo  alcoholic  fermentation, 
glucose  and  levulose,  are  easily  converted;  galactose  slowly.  The  glyco- 
lytic fermentation  takes  place  in  the  blood  and  general  tissues,  as  well  as 
in  the  liver,  and  the  ferment  and  the  conditions  of  its  activity  are  the  same 
throughout.  It  is  not  definitely  known  whether  the  different  hexoses  that 
are  formed  in  the  digestion  of  sugar  (d-glucose,  d-levulose  and  d-galac- 
tose)  are  absorbed  unchanged  or  whether  they  are  converted  into  d-glucose 
during  the  passage  through  the  intestinal  mucosa.  In  the  event  of  their 
absorption  unchanged  they  must  be  either  converted  into  d-glucose  in  the 
liver  or  the  liver  must  possess  the  faculty  of  forming  glycogen  from  the 
different  hexoses.  According  to  our  present  evidence  d-glucose  is  the 
combustion  form  of  sugar;  it  is  this  hexose  alone  that  is  formed  from 
glycogen,  and  the  body  unquestionably  possesses  the  power  directly,  and 
probably  indirectly,  of  converting  the  different  hexoses  into  d-glucose. 
This  is  of  practical  importance,  since  it  explains  why  the  use  of  galactose 
or  fructose  is  rarely  of  benefit  to  the  diabetic;  instead  of  burning  the 
sugars  directly,  the  body  converts  them  into  d-glucose.  That  the  body 
can  not  only  form  d-glucose  from  d-galactose,  but  also  form  the  latter 
from  the  former  is  shown  by  the  synthesis  of  d-galactose  in  the  central 
nervous  system  and  in  the  breast  glands. 

Following  the  conversion  of  glycogen  into  glucose,  the  latter  is  utilized 
in  combustion  for  the  maintenance  of  the  body  temperature  and  the  for- 
mation of  fat.  The  reactions  of  the  combustion  of  glucose  are  not  defin- 
itely known.  According  to  recent  work,  ferments  that  convert  glucose 
into  alcohol  are  present  in  all  tissues;  an  intermediary  stage  in  the  re- 
action is  lactic  acid.  Recent  experimental  work  has  made  it  probable 
that  the  combustion  of  sugar  in  the  body  follows  in  a  general  manner 
the  following  scheme:  glucose— ^lactic  acid -methyl  alcohol -^acetic  acid 
— ^methane— »formic  acid-^carbon  dioxide  and  water,  carbon  dioxide 
being  set  free  also  with  the  appearance  of  alcohol  and  methane,  water 
being  evolved  with  the  appearance  of  acetic  and  formic  acid.  The 
particular  importance  of  this  scheme  of  oxidation  lies  in  the  fact  that  it 
makes  ethyl  alcohol  a  normal  intermediary  product  in  the  sugar  metab- 


31G  DISEASES  CAUSED  BY  ORGAXIC  AGEXTS 

olism.  Tlic  combustion  of  sugar  is  an  act  of  fermentation.  For  the 
maximum  acceleration  of  the  reaction,  substances  derived  from  two 
sources  are  necessary, — the  muscles  and  the  pancreas.  We  may  regard 
the  muscular  enzyme  as  primary,  and  the  pancreatic  substance  (that 
seems  to  be  associated  with  the  mtegrity  of  the  islands  of  Langerhans)  as 
a  zvmo-excitor.  It  has  not  been  proven  that  this  relation  is  the  sole  one 
associated  with  the  burning  of  sugar  in  the  body,  n  )r  is  the  loss  of  the 
power  of  burning  sugar  always  associated  with  lesions  in  the  pancreas. 
Were  this  ])roven  the  })roblem  of  the  intermediate  carbohydrate  metab- 
olism would  be  greatly  simplified.  The  process  by  which  fats  are  formed 
out  of  sugar  is  not  known.  However  this  conversion  is  effected,  the 
function  is  directly  associated  with  the  catabolic  power  of  the  carbohy- 
drate metabolism,  just  as  is  the  formation  of  glycogen. 

Normally  the  body  sugar  is  derived  entirely  from  the  carbohydrates  of 
the  diet.  Tilany  ]:»roteins  contain  preformed  carbohydrate,  which  is  avail- 
able for  the  formation  of  glycogen ;  but  the  quantities  are  not  large.  It  is, 
however,  probable  that  when  the  sugar  of  the  body  is  reduced,  the  body 
can  secure  it  from  other  sources.  For  this  })urpose  the  protein  and  the 
fats  are  available  and  if  they  cover  the  caloric  needs  of  the  body  little 
sugar  need  be  derived  at  all.  That  an  animal,  fed  on  sugar  free  protein, 
may  retain  a  little  carbon  while  eliminating  all  the  nitrogen  is  true,  but 
this  retention  is  slight  and  transient.  Animals  fed  on  a  carbohydrate  free 
diet  may  display  a  glycogen  content  that  suggests  a  formation  from  the 
protein  of  the  diet,  but  the  figures  are  not  conclusive.  It  is  an  error  to 
assume  that  the  facts  and  interpretations  in  diabetes  may  be  applied  to 
the  normal  individual,  since  sugar  starvation  and  the  inability  to  oxidize 
sugar  are  totally  different  things.  While  recent  experimental  work  has 
made  it  quite  certain  that  in  the  depancreatized  dog,  sugar  can  be  formed 
from  amido-acids  derived  from  protein,  it  is  an  equally  certain  experi- 
mental fact  that  in  the  normal  dog,  sugar  is  formed  only  from  carbo- 
hydrate. 

No  known  disturbances  follow  the  absence  of  carbohydrate  from  the 
diet.  The  use  of  carbohydrate  alone  (plus  the  necessary  protein)  to 
furnish  the  heat  of  the  body  seems  equally  harmless.  When  one  recalls 
that  the  limit  of  assimilation  of  cane-sugar  is  some  200  grams,  it  is  obvious 
that  were  an  individual  to  supply  his  whole  heat  by  the  use  of  sugar,  he 
would  at  each  meal  approach  the  limit  of  assimilation.  This  may  be 
avoided  by  the  substitution  of  starch  for  sugar  and  such  a  ration  is  ade- 
quate to  the  greatest  physical  exertion.  If  more  carbohydrate  be  ingested 
than  is  necessary  for  the  maintenance  of  the  body  heat,  the  remainder  is 
converted  into  fat.  The  combustion  of  carbohydrate  is  determined  not 
by  the  input  but  by  the  demands  for  heat  and  energy;  to  a  small  extent, 
however,  the  ingestion  of  an  excess  of  carbohydrate  may  be  followed  by  an 
increase  in  combustion,  just  as  in  the  protein  metabolism. 

Important  for  the  estimation  of  the  carbohydrate  metabolism  is  a 
reduction  of  the  limit  of  assimilation.  This  may  be  lowered  to  less  than 
one-half  the  normal  whh  no  signs  of  ill-health.  This  reduction  is  usually 
confined  to  glucose  and  saccharose,  not  to  levulose  and  lactose.  An 
alimentary  mellituria  associated  with  a  starch  diet  is  always  pathological, 
indeed  probably  always  diabetic.  The  best  interpretation  of  the  reduction 
of  the  limit  of  assimilation  is  that  the  power  of  the  liver  to  convert  a  unit 


INTOXICATIONS  IN  GENERAL  317 

of  sugar  into  glycogen  in  the  unit  of  time  is  reduced.  Whether  an  ab- 
sorption of  sugar  by  the  lacteal  instead  of  the  portal  system  accounts  for 
alimentary  glycosuria  is  not  known.  A  lowering  of  the  limit  of  assimi- 
lation is  regularly  seen  in  exophthalmic  goitre  and  often  in  alcoholism, 
gout,  arteriosclerosis,  lead  poisoning,  organic  diseases  of  the  liver,  obesity, 
and  in  some  of  the  psychfjses  and  organic  diseases  of  the  nervous  system. 
A  curious  susceptibility  to  levulose  has  been  observed  in  some  cases  of 
hepatic  disease.  The  condition  may  be  mild  or  pronounced  and  may  be 
associated  with  a  reduction  in  the  power  to  burn  sugar,  but  is  in  itself  not 
associated  with  hyperglycfemia,  apart  from  the  period  following  the 
ingestion  of  the  sugar. 

Superoxidation.^ — An  excessive  combustion  of  sugar  is  a  common 
phenomenon.  Most  prominent  in  Graves's  disease,  it  is  seen  also  in  infec- 
tious diseases,  in  severe  ansemia,  in  malignant  neoplasms,  and  in  cachexia 
due  to  other  causes.  It  is  usually  not  marked  in  the  febrile  infectious 
diseases;  the  supercombustion  is  less  marked  than  the  exaggeration  of 
protein  catabolism.  Though  such  a  superoxidation  of  sugar  usually 
accompanies  fever,  it  does  not  in  itself  need  to  produce  fever.  The  excess 
of  combustion  has  apparently  two  causes:  an  exaggeration  in  the  fermen- 
tative acceleration  and  the  lowering  in  the  saving  power  of  sugar  for  pro- 
tein. The  excessive  combustion  of  sugar  is  in  itself  unattended  with  any 
untoward  results,  the  body  seems  able  to  carry  the  process  to  the  end- 
products  of  water  and  carbon  dioxide;  that  the  body  may  not  be  able  to 
control  the  heat  dissipation  can  be  no  fault  of  the  carbohydrate  metabo- 
lism. 

Sub  oxidation. — A  lessened  combustion  of  sugar  as  a  quantitative 
abnormality  is,  apart  from  acute  conditions  such  as  shock,  hemorrhage, 
etc.,  probably  met  with  only  in  true  diabetes.  In  no  other  condition  is 
there  evidence  that  the  body  burns  fat  or  protein  to  maintain  the  heat  as 
the  consequence  of  an  inability  to  burn  sugar.  Since  the  combustion  of 
sugar  is  a  fermentation,  the  only  dynamic  explanation  for  the  loss  of  the 
faculty,  since  the  concentration  of  the  sugar  is  not  lowered,  is  to  assume 
the  loss  of  the  ferment  or  of  some  zymo-excitor,  or  the  presence  of  some 
condition  in  the  system  inimical  to  the  action  of  the  ferment. 

Glycosuria. — Glycosuria  may  be  associated  with  normal  or  hyper- 
glycsemia.  An  increase  of  sugar  in  the  blood  may  be  due  to  an  increased 
formation  or  a  decreased  oxidation.  Glycosuria  with  a  normal  blood- 
content  is  probably  associated  with  some  abnormality  in  the  renal 
functions.  We  have  evidence  that  all  these  forms  exist  clinically.  That  of 
the  number  of  non-diabetic  glycosurias  many  are  best  explained  as  results 
of  renal  disturbances  is  certain.  Glycosuria  due  to  an  increased  for- 
mation of  sugar  may  be  due  either  to  an  excessive  input,  to  an  inability  of 
the  body  to  convert  the  absorbed  sugar  into  glycogen,  or  to  what  might  be 
termed  an  instability  in  the  storage  of  glycogen.  Sugar  is  known  to  circu- 
late in  complex  combinations  (possibly  colloidal),  in  fact  the  least  part  of 
the  circulating  sugar  exists  in  the  simple  state.  It  is  pertinent  to  inquire 
whether  abnormalities  in  these  relations,  independent  of  hyperglycsemia, 
might  not  lead  to  renal  elimination.  Glycosuria  per  se  need  have  no 
consequence  to  the  metabolism.  W'hile  it  is  current  teaching  that  hvper- 
glycsemia  per  se  exerts  a  deleterious  action  upon  the  tissues,  many  indi- 
viduals have  persistent  glycosuria  without  signs  of  disturbance  in  the 


318  DISEASES  CAUSED  BY  ORGANIC  AGENTS 

carbohydrate  or  other  metabohsms.  It  is,  however,  possible  experi- 
nientaliy  to  show  that  cells  are  quite  sensitive  to  higher  concentrations  of 
sugar. 

Diabetes. — In  diabetes  arc  concerned  several  disturbances  of  interme- 
diary metabolism :  loss  of  the  power  of  burning  sugar;  loss  of  the  power 
in  the  liver  of  converting  sugar  into  glycogen;  loss  of  the  power  of  con- 
verting sugar  into  fat;  loss  of  the  power  of  burning  fat  completely  and  in 
the  normal  manner;  and  a  loss  of  the  normal  tendency  to  remain  upon  a 
minimum  plane  of  carbohydrate  metabolism  when  on  a  carbohydrate  free 
diet.  The  ordinary  distinction  between  diabetes  and  glycosuria, — the 
persistence  of  sugar  in  the  urine  (L  e.,  hyperglyca?mia)  following  the  with- 
drawal of  carbohydrate  from  the  diet — is  convenient  but  pathologically 
inexact,  since  cases  pass  from  one  to  the  other  side. 

The  loss  of  the  function  of  oxidizing  sugar  is  a  gradient  in  which  the 
successive  lapses  may  be  grouped  about  as  follows,  in  the  order  of  their 
severity:  The  loss  of  the  power  of  assimilating  starch — mellituria  after 
starch  ingestion;  reduction  in  the  limit  of  assimilation  of  sugar  to  the 
point  when  any  sugar  causes  a  glycosuria;  reduction  in  the  assimilation 
of  starch  to  the  point  when  any  starch  is  followed  by  glycosuria;  the 
jiartial  loss  of  the  power  of  burning  sugar;  the  loss  of  the  power  of  burning 
sugar  during  exercise;  the  loss  of  the  power  of  burning  more  sugar  during 
fever;  the  loss  of  the  saving  power  of  carbohydrates  on  the  protein  metab- 
olism; and  the  total  loss  of  all  power  of  burning  sugar.  The  last  is 
extremely  rare.  The  cases  in  which  sugar  no  longer  spares  protein  and 
supports  in  part  fever  and  muscular  exercise  are  uncommon.  The  suc- 
cession of  losses  in  function  do  not  necessarily  occur  in  the  order  given  and 
a  function  once  lost  may  be  regained.  In  proportion  to  the  loss  in  the 
power  to  burn  sugar,  the  heat  of  the  body  must  be  maintained  by  the  com- 
bustion of  protein  and  fat  in  the  diet  or  from  the  body.  The  inability  to 
convert  sugar  into  glycogen  is  rarely  lost,  the  tissues  are  not  devoid  of 
glycogen.  The  power  of  prompt  conversion  of  alimentary  sugar  is  lost. 
The  power  of  formmg  fats  from  sugar  is  reduced,  in  severe  instances 
entirely  absent. 

The  origin  of  the  excessive  glycsemia  is  a  fundamental  problem  in 
diabetes.  It  is  now  generally  held  that  the  quantities  of  sugar  eliminated 
in  severe  diabetes  on  a  carbohydrate  free  diet  cannot  be  explained  on  the 
basis  of  the  preformed  glycogen  and  glycosides,  or  the  preformed  car- 
bohydrate contained  in  protein.  The  sugar  must  be  derived  from  the 
protein  or  the  fat.  Under  fat  is  understood  fatty  acid;  though  glycerine 
can  be  converted  into  fat,  the  available  quantity  is  too  low  to  make  it  of 
moment.  Within  recent  years  the  views  with  reference  to  the  formation 
of  sugar  from  protein  have  undergone  a  change.  Formerly  it  was  assumed 
that  protein  Avas  separated  into  a  nitrogenous  and  non-nitrogenous  moiety; 
from  the  latter  the  glycogen  was  derived  directly.  Recent  studies  have 
shown  that  the  end-products  of  protein  catabolism  are  amido-acids,  and 
that  the  carbon  as  well  as  the  nitrogen  of  the  protein  is  to  be  found  in  these 
products.  Consequently,  the  formation  of  sugar  from  protein  means  the 
formation  of  sugar  from  amido-acids.  The  experimental  formation  of 
sugar  from  amido-acids  is  an  open  question.  It  must  be  pointed  out  that 
all  the  substances  theoretically  regarded  as  intermediary  stages  in  the 
formation  of  sugar  from  amido-acids  are  fatty  acids  that  could  be  easily 


INTOXICATIONS  IN  GENERAL  319 

derived  from  the  fats.  The  formation  pf  sugar  from  protein  in  the 
diabetic  body  has  been  recently  made  probable  by  the  study  of  the  utili- 
zation of  leucin  and  phenylalanine  in  the  depancreatized  dog. 

The  fallowing  facis  speak  for  the  formation  of  sugar  from  protein  :  The 
elimination  of  sugar  in  diabetes  is  often  parallel  to  the  protein  catabolisrn  • 
the  ratio  of  glucose  to  nitrogen  is  often  about  3  to  1  which  corresponds  to 
the  relations  in  the  molecule  of  protein.  The  ingestion  of  pure  protein  (as 
casein)  is  often  followed  by  a  proportional  rise  in  the  glycosuria;  reduction 
of  the  protein  in  the  diet  will  often  lead  to  a  diminution  in  the  glycosuria. 
The  glycosuria  goes  hand  in  hand  with  nitrogen  deficit,  if  the  j)rotein  in 
the  diet  be  insufficient.  When  starved  animals  freed  of  glycogen  by 
strychnine  are  infected  with  the  colon  bacillus,  their  bodies  [)resent  more 
glycogen  than  the  controls  and  this  is  held  to  have  been  derived  from  the 
products  of  excessive  protein  catabolism.  The  respiratory  quotient  in 
diabetes  is  low.  In  favor  of  the  origin  of  the  sugar  from  the  fats  are  the 
following  facts:  In  many  of  the  worst  instances  of  diabetes,  especially 
experimental,  the  ratio  of  glucose  to  nitrogen  is  far  higher  than  the  ratio 
in  protein,  as  high  as  8  or  10  to  1 ;  the  sugar  could  not  be  derived  from  the 
protein  except  upon  the  assumption  that  a  remarkable  nitrogen  retention 
has  occurred.  In  many  instances  of  ordinary  diabetes  the  regular  ratio 
speaks  against  a  derivation  of  the  sugar  from  the  protein  alone.  The 
greatest  glycosuria  is  often  associated  with  the  most  marked  excesses  of  fat 
combustion  as  revealed  by  the  acidosis.  The  digestion  of  fatty  acids 
with  liver  pulp  yields  sugar. 

Against  the  origin  from  protein  speaks  the  practical  impossibility  of 
showing  experimentally  that  a  healthy  animal  ever  derives  sugar  from 
protein,  but  it  is  going  too  far  to  apply  these  results  unreservedly  to  the 
diabetic.  Directly  opposed  is  the  fact  that  when  the  fatty  acids  held  to  be 
intermediary  between  leucin  and  alanine  (capronic  and  propionic  acids) 
are  administered  to  diabetics,  they  appear  in  the  urine  as  acetone  and  not 
as  sugar.  Opposed  to  the  origin  of  sugar  from  fat  is  the  fact  that  one 
cannot  increase  the  glycosuria  by  increasing  the  fat  in  the  diet.  The 
ingestion  of  lecithin  does  increase  the  glycosuria. 

Some  of  these  interpretations  rest  upon  misconceptions  of  general 
metabolic  relations.  That  the  ingestion  of  protein  may  increase  the  gly- 
cosuria, while  the  ingestion  of  fat  does  not,  cannot  speak  directly  in  favor 
of  the  origin  of  sugar  from  protein  instead  of  fat,  because  the  disinte- 
gration of  protein  within  the  body  is  proportional  to  the  input  while  the 
combustion  of  fat  is  not  proportional  to  or  dependent  upon  the  input. 
The  ratio  of  nitrogen  to  sugar  cannot  be  employed  in  favor  of  the  origin 
of  sugar  from  protein  when  the  ratio  is  low,  or  the  origin  from  fat  when  the 
ratio  is  high,  because  in  neither  case  are  we  able  to  fix  the  relations  of 
nitrogen  input,  retention,  and  output.  The  only  proper  standpoint  is  that 
the  source  of  the  excessive  sugar  in  diabetes,  whether  from  the  protein  or 
the  fat,  is  undetermined.  From  theoretical  relations,  the  origin  of  the 
sugar  from  fat  would  be  the  more  simple,  as  we  would  have  sugar 
derived  normally  from  fat  and  representing  the  intermediary  product  of 
fat  on  the  route  to  combustion ;  in  diabetes  the  loss  of  the  power  of  burning 
glucose  with  the  continuation  of  the  conversion  of  fat  to  sugar  would 
account  for  the  hyperglycsemia,  leaving  more  or  less  entirely  to  the  pro- 
tein catabolism  the  heating  of  the  body.    On  the  other  hand,  since  it  seemis 


320  DISEASES  CAUSED  BY  OBGAXIC  AGEXTS 

quite  certain  that  norinally  sugar  is  not  formed  from  protein,  we  need  in 
the  diabetic  the  postidation  that  accompanying  the  non-oxidation  of 
sugar  is  an  abnormal  formation  of  sugar  (that  cannot  be  burned)  from  the 
intermediary  products  of  protein  metaboHsm — just  the  converse  of  a  com- 
pensatory mechanism.  The  crucial  experiment  would  be  the  demon- 
stration that  the  diabetic  man  or  dog  during  the  course  of  the  disease 
elaborates  upon  a  protein  diet  more  sugar  than  could  be  accounted  for  l)y 
the  glycogen  and  other  carbohydrates  and  the  body  fats;  this  experiment 
has  been  several  times  attempted  in  dogs,  with  negative  results 

The  gas-exchange  is  normal  in  diabetes,  except  in  the  attacks  of  coma, 
where  it  is  probably  subnormal.  The  carbonous  metabolism  is  always 
unbalanced.  The  respiratory  quotient  is  very  low  and  is  not  raised  by  the 
ingestion  of  carbohydrate.  With  good  powers  of  digestion  it  is  usually 
possible  to  obtain  a  nitrogen  balance,  except  in  the  periods  of  deteriora- 
tion. It  recjuires  much  more  protein  than  normal  to  accomplish  this  and 
this  greater  amount  of  protein  is  directly  proportional  to  the  gravity  of  the 
case.  For  this  condition,  which  is  an  important  practical  one,  we  have 
first  the  explanation  that  fat  does  not  equal  sugar  in  its  power  of  sparing 
protein.  But  only  in  the  mild  cases  is  this  explanation  sufficient;  a 
diabetic  will  commonly  have  a  nitrogen  deficit  on  a  diet  of  fat  and  protein 
such  as  would  fully  suffice  for  a  normal  individual.  Those  who  consider 
that  in  diabetes  sugar  is  regularl}^  formed  from  protein,  explain  this  on  the 
ground  that  the  diabetic  does  not  utilize  the  n  on -nitrogenous  moiety  of  the 
protein  consumed.  Those  who  incline  to  the  view  that  the  diabetic  forms 
sugar  from  fat  explain  the  condition  by  the  assumption  that  the  body  has 
lost  in  part  the  power  of  burning  fats,  of  which  the  acetone  acidosis  is  an 
evidence,  and  this  leaves  a  deficit  that  must  be  made  good  by  the  utili- 
zation of  more  protein.  In  attacks  of  diabetic  coma  the  nitrogen  deficit  is 
most  marked,  so  marked  in  fact  that  an  additional  explanation  is  usually 
sought  in  a  toxic  exaggeration  of  the  protein  catabolism. 

To  what  the  toxic  symptoms  of  diabetes  are  due  is  known  only  in  part. 
In  all  probability  the  intoxications  come  rather  from  the  perverted  pro- 
tem  and  fat  metabolism  than  from  the  suboxidation  of  sugar.  The  coma 
is  an  acidosis,  due  to  the  perversion  of  the  fat  catabolism.  While  there 
is  no  direct  evidence  that  hyperglycsemia  per  se  exerts  a  toxic  action,  the 
fact  remains  that  the  general  condition  of  the  diabetic  is  made  worse  and 
his  power  of  burning  sugar  still  further  reduced  by  the  ingestion  of  car- 
bohydrate, while  the  maintenance  of  a  strict  diet  will  ameliorate  the 
symptoms  and  tend  to  a  recovery  of  the  power  of  burning  sugar.  Some 
of  the  toxic  symptoms,  as  the  disturbances  in  nutrition  of  tissues,  are  not 
related  to  the  acidosis,  the  toxicity  of  the  acetone  bodies  or  to  the  hyper- 
glycaemia,  but  seem  to  rest  upon  some  deeper  abnormality  in  the  protein 
metabolism. 

The  investigations  on  diabetes  teach  another  lesson.  We  hear  so  much 
of  suboxidation,  it  seems  as  though  it  were  supposed  that  the  body  would 
suffer  such  a  condition  without  any  attempt  at  a  regulation.  Now  all 
these  alterations  in  the  protein  and  fat  metabolism  in  diabetes  are  in  a 
general  sense  simply  the  regulatory  mechanism  that  prevents  a  sub- 
oxidation. There  is  a  great  leeway  in  the  direction  of  increase  in  the 
physical  dissipation  of  heat,  there  is  much  less  in  the  direction  of  reduction. 
W'hen  one  main  combustion  is  cut  out,  practically  the  full  normal  function 


INTOXICATIONS  IN  GENERAL  321 

of  heat  production  is  thrown  upon  some  other  metabolism.  There  is  no 
evidence  that  the  diabetic  attempts  tc;  minimize  the  results  of  the  kjss  of 
the  power  of  burning  sugar  by  restricting  the  dissipation  of  heat  as  the 
myxoedematous  seem  to  do.  Yet  this  would  be  directly  the  most  saving 
act  the  body  could  attempt. 


AUTO-INTOXICATION  ASSOCIATED  WITH  THE  FAT  METABO- 
LISM. 

The  digestion  of  fat  is  an  act  of  simple  hydrolysis,  the  fats  being  split 
into  the  fatty  acids  and  glycerine  Fat  is  carried  in  the  circulation  partly 
in  emulsion,  favored  by  the  colloidal  nature  of  the  blood  plasma,  but 
largely  in  solution.  The  fat  in  solution  in  the  blood  is  dialyzable  and 
apparently  enters  tho  cells  in  that  form,  there  to  be  in  part  reconverted  into 
insoluble  fat.  Since  it  is  easier  to  picture  chemical  reactions  in  a  homog- 
enous rather  than  in  a  heterogenous  system,  we  may  assume  that  the  fat 
is  utilized  in  the  metabolism  in  this  soluble  state  of  unknown  nature.  The 
process  of  formation  of  fat  from  sugar  is  not  known ;  it  seems  likely  that  it 
is  formed  indirectly  from  fatty  acids  derived  from  the  partial  oxidation  of 
sugar.  The  seat  of  the  conversion  is  also  unknown,  though  the  liver  is 
credited  with  the  function.  That  fat  is  normally  formed  from  protein  is 
very  unlikely.  Fat  is  the  most  potential  form  of  carbonous  food  and  is 
able  to  supply  the  entire  caloric  demands  of  the  body.  Nevertheless  fats 
do  not  equal  carbohydrates  in  the  power  of  saving  protein. 

The  reaction  of  the  combustion  of  fat  is  not  known.  A  direct  com- 
bustion could  occur,  successive  CH2  groups  being  split  off  and  burned.  It 
is,  however,  a  question  whether  a  different  procedure  be  not  the  true  one. 
A  trace  of  acetone  is  present  in  normal  urine,  derived  from  the  reduction 
of  diacetic  acid.  Whenever  the  fat  catabolism  is  exaggerated,  the  acetone 
is  increased  and  diacetic  and  /?-oxybutyric  acids  may  appear.  We  do  not 
know  whether  these  substances  are  normal  intermediary  products  in  the 
fat  combustion  or  products  of  an  abnormal  reaction  of  oxidation .  If  the 
acetone  group  represents  an  abnormal  qualitative  variation,  it  could  be 
compared  to  cystin  in  the  purin  metabolism;  if  an  intermediary  product, 
it  may  be  compared  to  leucin  and  tyrosin.  Acetone  itself  is  not  oxidized 
in  the  body  It  is  derived  from  aceto-acetic  acid  by  reduction,  carbon 
dioxide  being  split  off.  The  diacetic  acid  is  derived  from  /?-oxybutyric 
acid  by  oxidation.  If  these  acids  are  normal  products  in  the  oxidation  of 
fats,  the  reduction  of  diacetic  acid  to  acetone  is  an  abnormal  reaction. 
Nevertheless,  the  normal  trace  of  acetone  is  increased  in  every  condition 
accompanied  by  an  exaggeration  in  the  combustion  of  fat.  Normally 
/?-oxybutyric  and  diacetic  acids,  when  ingested,  are  oxidized,  no  apprecia- 
ble reduction  of  the  diacetic  acid  to  acetone  occurs.  It  is  known  that 
the  normal  body  could  not  oxidize  the  quantities  of  these  acids  that  are  to 
be  met  with  in  the  diabetic  If  the  combustion  of  fats  proceeded  directly 
these  oxy-acids  would  not  be  formed.  There  is  some  evidence  that  nor- 
mally the  body  does  not  oxidize  butyric  acid  to  oxy-butyric  acid,  but 
instead  splits  it  into  two  molecules  of  acetic  acid  and  bums  these  directly. 
Since  the  normal  urine  contains  a  trace  of  acetone,  it  is  apparent  that  w'e 

have  here  a  condition  common  enough  in  the  domain  of  organic  reactions, 
21 


322  DISEASES  CAUSED  BY  ORGAMC  AGEXTS 

where  a  major  reaction  is  accompanied  by  a  minor  side  reaction.  In 
the  state  of  the  acetone  complex,  something  converts  the  side  reaction 
into  the  main  reaction  in  the  (juantitative  sense. 

Suboxidation. — Of  a  suboxidation  of  fat  Ave  have  no  knowledge. 
There  is  no  call  for  any  oxidation  of  body-fat  so  long  as  the  sugar  and 
protein  of  the  diet  are  sufficient  to  the  caloric  needs  of  the  body.  When 
the  calories  of  the  diet  are  presented  partly  in  the  form  of  fat,  the  diet-fat 
and  not  the  body-fat  is  utilized. 

Superoxidation. — A  .superoxidation  of  fat  occurs  under  all  circum- 
stances associated  with  a  superoxidation  of  sugar  if  the  sugar  of  the  diet 
be  insufficient.  Except  in  Graves's  disease  and  rai)itlly  advancing  ma- 
lignant neoplasms,  it  is  usually  possible,  if  the  powers  of  digestion  are 
normal,  to  administer  such  an  amount  of  sugar  and  fat  as  to  leave  the 
body-fat  intact.  The  greatest  exaggeration  of  the  fat  catabolism  is  seen 
in  tliabetes.  Here  it  is  always  associated  with  an  excessive  utilization  of 
protein  from  the  diet  or  body.  It  is  often  impossible  in  a  diabetic  by 
the  administration  of  fat  to  hold  the  catabolism  to  the  level  of  the  normal. 
More  fat  is  furthermore  utilized  than  is  apparent  in  the  respiratory  ex- 
change. 

Superoxidation  of  fat  is  always  associated  with  the  appearance  of  the 
acetone  bodies  in  the  urine.  This  supports  the  theory  that  these  acids  are 
normal  intermediary  jiroducts  in  the  fat  catabolism.  Their  appearance 
indicates  either  some  limit  to  their  oxidation  or  an  abnormality  in  the  last 
stages  of  the  reactions.  The  interpretation  of  this  would  obviously  be 
totally  different,  depending  on  whether  one  considers  that  the  fats  are 
burned  as  such  or  converted  into  sugar.  The  formation  of  the  acetone 
substances  bears  no  known  constant  relation  to  the  total  combustion  of 
fat;  apparently  it  represents  but  a  small  fraction,  the  larger  part  proceeding 
to  the  natural  end-products.  In  grave  terminal  diabetic  coma,  however, 
but  little  of  the  fat  combustion  reaches  the  final  stage;  it  seems  largely 
diverted  in  the  acetone  direction  (1  mol.  fat- — 4  mol.  /5-oxybutyric  acid). 
This  of  course  does  not  furnish  much  heat,  and  is  one  reason  why  the 
protein  catabolism  is  so  exaggerated  in  these  comas,  since  it  is  then  the 
only  metabolism  that  can  furnish  heat  for  the  body. 

The  Acetone  Complex. — ^Under  this  term  we  group  the  associated 
elimination  of  acetone,  diacetic  acid,  and  ^-oxybutyric  acids  in  the  urine. 
The  term  acetone  complex  is  coined  to  differentiate  the  condition  from  the 
acidosis  due  to  other  acids.  Except  in  the  last  stages  of  diabetic  coma,  the 
acids  circulate  and  are  eliminated  as  salts.  The  acetone  bodies  are  derived 
from  the  fats  and  not  from  the  carbohydrates  or  protein.  Perfusion  of  the 
liver  with  phenyl-amido-acids  will  yield  acetone,  and  there  is  no  bar 
chemically  to  its  derivation  from  lactic  acid.  Clinically,  in  all  the  different 
groups  of  the  acetone  complex,  when  the  condition  is  severe  the  acids 
accompany  the  acetone,  and  this  speaks  directly  against  the  origin  of  the 
acetone  from  the  protein  catabolism  in  these  cases. 

The  current  conception  of  the  acetone  complex  connects  with  it  dis- 
turbances in  the  carbohydrate  metabolism  in  the  sense  that  a  cessation  of 
the  carbohydrate  metabolism  comprises  the  essential  condition  for  the 
elimination  of  acetone,  diacetic,  and  /J-oxybutyric  acids,  the  oxidation  of 
the  higher  fatty  acids  to  carbon  dioxide  and  water  being  only  then  com- 
pleted;  when  a  certain  amount  of  carbohydrate  is  simultaneously  burned. 


INTOXICATIONS  IN  GENERAL  323 

There  are  instances  of  aeetonuria  in  which  this  does  not  hold,  and  in 
which  there  are  many  things  tending  to  prove  the  contrary.  In  phloridzin 
diabetes  the  acetone  comj)Iex  does  not  appear  so  long  as  the  animals  are 
in  nitrogen  balance,  but  appears  with  the  installation  of  a  nitrogen  deficit. 
If  a  phloridzin  dog  be  starved,  the  acetonuria  disappears  with  the  gly- 
cosuria. There  are  instances  of  the  acetone  complex  in  which  there  are 
no  signs  to  indicate  any  disturbance  in  the  carbohydrate  metabolism,  or 
indeed  any  exaggeration  in  fat  combustion.  Cases  occur  in  which  we  have 
no  evidence  that  the  protein,  carbohydrate  or  fat  metabolism  exhibit  any 
quantitative  variations,  and  only  the  fat  metabolism  displays  this  qualita- 
tive variation.  Acidosis  from  any  cause  is  very  easily  developed  in  child- 
hood and  often  to  an  exaggerated  degree  under  even  trivial  illness.  The 
origin  of  the  acetone  complex  in  diabetes  would  be  simplified  if  we  believed 
in  the  normal  conversion  of  fats  into  sugar;  an  interruption  in  the  com- 
bustion of  the  sugar  would  necessarily  entrain  a  disturbance  in  the 
intermediary  fat  metabolism. 

Acetone  Complex  Associated  with  a  Low  Carbohydrate  Combustion. 
— Starvation. — A  few  days  after  the  withdrawal  of  food,  the  acetone 
group  appears  in  the  urine.  When  the  stored  glycogen  is  burned  up,  the 
heat  must  be  derived  from  protein  and  fat,  and  since  the  nitrogen  out- 
put is  restricted,  the  bulk  of  the  heating  falls  to  the  burning  of  the  fats. 
It  persists  so  long  as  the  starvation  continues.  A  pure  protein  diet  or  a 
protein-fat  diet  has  the  same  result. 

In  febrile  diseases  the  complex  is  common.  The  fever  makes  large 
demands  on  the  carbohydrate  metabolism,  the  hepatic  glycogen  dis- 
appears, and,  as  the  input  is  under  these  circumstances  usually  diminished, 
an  exaggerated  burden  falls  on  the  combustion  of  fats.  /?-oxy butyric  acid 
is  rare  in  the  febrile  acetonuria;  diacetic  acid  is  often  present.  In  diabetes 
the  body  seems  to  have  lost  in  large  part  the  normal  power  of  burning 
diacetic  and  /?-oxybutyric  acids.  In  diabetes,  as  in  the  two  previous  con- 
ditions, the  administration  of  sugar  will  lov/er  the  output  of  the  acetone 
substances.  In  severe  cases  the  administration  of  sugar  will  not  lower  the 
output  of  the  acetone  substances,  but  this  may  be  done  by  the  adminis- 
tration of  alcohol  or  glycuronic  acid. 

Instances  of  Acetone  Complex  in  which  there  is  no  Evidence  that 
the  Carbohydrate  Metabohsm  is  Deranged. — In  the  cachexia  of  carci- 
noma, in  severe  infections,  in  atrophy  of  the  gastric  mucosa,  in  severe  cases 
of  anaemia  accompanied  by  a  rapid  loss  of  flesh,  we  may  encounter  the 
acetone  complex,  it  is  rarely  marked,  /?-oxybutyric  acid  is  usually  absent 
while  diacetic  acid  is  not  always  present.  In  these  cases  the  individuals 
are  ingesting  carbohydrate,  there  is  no  mellituria,  there  are  no  signs 
that  the  carbohydrate  metabolism  is  exaggerated  or  depressed,  there  is 
nothing  to  indicate  that  there  is  in  the  body  either  a  diminution  of  the 
glycogen  or  a  loss  of  the  power  to  convert  it  into  sugar,  to  burn  sugar,  or 
convert  it  into  fat.  In  this  group  the  fat  catabolism  is  abnormally  in- 
creased, body  fat  is  being  burned. 

Instances  of  the  Acetone  Complex  without  Quantitative  Alterations 
in  Any  Metabolism,  with  Normal  Qualitative  Protein  and  Carbohy- 
drate Metabolism. — Here  are  to  be  classed  those  seizures  associated  with 
marked  gastro-intestinal  symptoms.  The  subjects  are  usually  m  good 
health,  the  onset  is  sudden,  the  symptoms  of  irritation  of  the  alimentary 


324  DISEASES  CAUSED  BY  ORGAXIC  AGENTS 

tract  are  marked.  There  is  pronounced  urinary  acidosis;  grave  nervous 
symptoms  may  supervene,  even  death.  IMost  of  them  yield  })romj)tly  on 
lavage  of  the  stomach  and  colon,  free  purgation,  and  symptomatic  treat- 
ment. INIany  resemble  exactly  toxic  gastro-enteritis  but  others  are  ob- 
viously something  more.  Fatal  cases  have  been  reported.  Here  also 
must  be  grouped  the  cases  of  recurrent  vomiting  in  children  associated 
\\itli  this  comi)lex.  There  are  in  these  no  symptoms  of  gastro-intestinal 
lesion;  the  vomiting  is  reflex  in  all  likelihood.  Probably  related  are  the 
cases  of  convulsive  pscudo-ejiileptic  seizures  associated  with  acetonuria. 
These  subjects  are  all  on  ordinary  mixed  diet,  have  no  glycosuria  or  albu- 
minuria, and  usually  recover  under  symptomatic  treatment.  The  admin- 
istration of  sugar  does  not  affect  the  acetonuria.  That  they  are  ever  of 
gastro-intestinal  origin,  in  the  sense  that  the  acetone  bodies  are  formed 
in  the  alimentary  tract  and  then  absorbed,  is  entirely  without  evidence; 
it  has  never  been  shown  that  these  substances  can  be  formed  by  any  ab- 
normality of  fat  digestion  or  bacterial  fermentation.  The  only  logical 
explanation,  if  one  inclines  to  a  gastro-intestinal  etiology,  is  to  assume 
that  a  hypothetical  gastro-intestinal  auto-intoxication  inaugurates  sec- 
ondarily a  perversion  of  the  intermediary  fat  metabolism. 

In  this  connection  the  writer  can  report  a  controlled  experimental  obser- 
vation. A  healthy  man  was  placed  on  an  ash-free  diet  composed  of 
washed  egg  albumin  (75  gm.),  olive  oil  (120  gm.)  and  cane-sugar  (250 
gm.).  A  nitrogen  balance  was  promptly  established;  the  urine  was  in 
every  way  normal.  On  the  seventh  day,  following  the  onset  of  prodromal 
nervous  symptoms,  a  marked  elimination  of  acetone  and  diacetic  acid 
set  in,  following  which  the  experiment  was  discontinued.  The  complex 
disappeared  within  a  few  hours  after  the  ingestion  of  salt.  No  weight 
was  lost.  Here,  therefore,  the  acetone  complex  was  the  result  of  with- 
drawal of  salts  and  cations,  of  an  acid  intoxication.  There  is  no  reason  to 
suppose  that  there  was  any  qualitative  or  quantitative  abnormality  in 
either  the  protein  or  carbohydrate  metabolism  or  any  exaggeration  in  the 
fat  combustion.  A  person  on  a  normal  diet  of  protein,  in  nitrogen 
balance,  on  250  gm.  of  sugar  and  free  from  glycosuria,  cannot  be  con- 
sidered to  have  any  abnormality  in  those  metabolisms  upon  which  to 
rest  an  association  with  the  acetone  complex. 

Instances  of  Acetone  Complex  Associated  with  Disturbances  in  the 
Protein  Metabolism. — There  are  now  quite  a  number  of  cases  reported 
in  which  following  anaesthesia  the  patients  suddenly  pass  into  a  state  of 
intoxication,  often  with  jaundice,  acetone  acidosis,  the  elimination  of 
leucin  and  ty rosin  in  the  urine,  coma  and  death,  with  the  finding  of 
extensive  degeneration  of  the  liver  at  autopsy.  In  many  cases  following 
operations,  particularly  in  children,  a  transient  acetonuria  occurs  without 
dangerous  symptoms  These  cases  present  no  signs  of  abnormality  in  the 
carbohydrate  metabolism.  Hemorrhage  into  the  large  body  cavities 
seems  to  be  followed  by  acetonuria. 

An  interestmg  group  of  conditions  in  which  the  acetone  complex  may 
occur  is  seen  in  diverse  exogenous  intoxications  with  phosphorus,  phlorid- 
zin,  etc.  It  is  not  possible  to  believe  in  advance  that  these  poisons  act  alike 
in  this  regard,  nor  can  it  be  urged  that  they  bring  about  a  cessation  or 
reduction  of  the  carbohydrate  metabolism.  Very  interesting  is  the 
acetonuria  commonly  seen  on  withdrawing  morphine  from  an  habitue; 


INTOXICATIONS  IN  GENERAL  325 

if  the  drug  be  resumed  the  complex  disappears.  The  logical  interpretation 
is  that  the  deviation  in  the  fat  combustion  resulting  in  the  acetone  complex 
may  be  brought  about  by  several  causes.  How  these  operate  to  disturb 
the  intermediary  fat  metabolism  is  unknown;  but  that  many  cases  exist 
in  which  the  phenomenon  cannot  be  explained  as  associated  with  any 
known  abnormality  in  the  carbohydrate  metabolism  must  be  obvious. 

Mode  of  Action  of  Intoxication  in  the  Acetone  Complex. — The  mode 
of  intoxication  may  be  referable  to  the  substances  themselves  or  to  their 
behavior  as  acids.  The  term  acidosis  expresses  the  view  that  in  their 
behavior  as  acids  lies  the  chief  harm.  Acetone  is  but  slightly  toxic.  The 
salts  of  diacetic  and  /?-oxybutyric  acid  have  some  toxicity,  which  is  prob- 
bably  greater  in  the  diabetic  because  of  the  inability  to  oxidize  them. 
When  one  considers  the  really  enormous  quantities  of  the  substances  that 
may  be  voided  in  a  day,  one  must  hesitate  to  say  that  there  can  be  no 
direct  intoxication  from  them.  The  general  interpretation  is  that  these 
acids  act  by  withdrawal  of  cations.  How  this  leads  to  a  secondary 
intoxication  is  not  known,  but  it  does  so  in  experimental  acid  intoxication. 
That  the  acids  circulate  as  such  cannot  be  true,  except  during  the  closing 
hours  of  life.  The  carbon  dioxide  of  the  blood  in  diabetic  coma  has  been 
found  reduced  to  less  than  one-half  the  normal.  This  cannot  be  neces- 
sarily attributed  to  any  alteration  in  the  reaction  of  the  blood  and  it  is 
probably  the  result  of  moribund  suboxidation.  The  sudden  onset  of 
symptoms  in  the  acute  cases  can  scarcely  be  explained  on  the  ground  of 
simple  acidosis,  yet  alkali  treatment  is  here  most  effective.  It  is  a  note- 
worthy fact  that  the  injection  of  sodium  bicarbonate  is  follov/ed  as  a  rule 
by  recovery  in  the  non-diabetic  cases,  as  an  exception  in  diabetes — 
although  this  does  not  in  itself  antagonize  the  contention  that  the  intoxi- 
cation is  simply  an  acidosis. 

It  is  possible  that  an  acidosis  may  be  brought  about  by  the  reversed 
process:  not  by  formation  of  organic  fatty  acids  with  secondary  with- 
drawal of  ammonia  from  the  urea  metabolism,  but  by  the  non-function- 
ation  of  the  urea  metabolism,  whereby  large  amounts  of  ammonia  are  not 
utilized  and  thus  bind  fatty  acids  that  would  otherwise  have  been  oxi- 
dized. In  some  severe  hepatic  diseases,  unassociated  with  disturbances 
in  the  carbonous  metabolism,  acidosis  appears  and  the  attempt  has  been 
made  to  refer  it  to  the  abolition  of  the  hepatic  functions. 


PART  V. 

DISEASES  DUE  TO  VEGETABLE  PAEASITES 
OTHEK  THAN  BACTERIA. 

By  JAMES  HOMER  WRIGHT,  A.  M.,  M.  D.,  Hon.  S.  D.  (Harv.) 

In  this  section  are  considered  certain  general  and  local  diseases  due 
to  infection  with  fungi  and  certain  branching  filamentous  microorganisms 
which  are  classed  by  some  writers  also  among  the  fungi,  but  which  may  be 
regarded  as  representing  intermediate  forms  between  the  bacteria  and 
the  fungi.  Various  local  fungus  diseases  of  the  skin,  such  as  favus, 
pityriasis  versicolor,  and  erythrasma,  known  collectively  as  the  derma- 
tomycoses,  are  not  included. 

Concerning  the  relationship  and  classification  of  the  parasitic  and 
pathogenic  fungi,  there  is  much  uncertainty  and  lack  of  agreement 
among  authorities.  The  subject  has  been  thoroughly  covered  by  Plaut,* 
Busse,^  and  Ricketts.^ 

The  theory  of  the  etiological  relationship  of  yeast-like  fungi,  or  so- 
called  blastomycetes,  to  malignant  tumors  now  requires  no  further  con- 
sideration than  the  statement  that  the  results  of  all  the  most  trustworthy 
work  of  the  past  few  years  have  brought  nothing  in  the  support  of  the 
theory  but  have  tended  thoroughly  to  discredit  it. 


CHAPTER  XV. 

ACTINOMYCOSIS. 

Actinomycosis  is  a  suppurative  process  combined  with  growth  of  con- 
nective tissue  and  characterized  by  the  presence  in  the  lesions  of  vegeta- 
tions or  colonies  of  a  specific  microorganism,  Actinomyces  bovis.  The 
disease  may  be  local  or  general,  subacute  or  chronic.  It  should  be  dis- 
tinguished from  so-called  pseudotuberculosis  or  Streptothrix  or  Clado- 
thrix  infections  or  atypical  actinomycosis.  Such  processes  are  considered 
in  Chapter  XVI,  under  the  name  of  Nocardiosis. 

Actinomycosis  affects  man  and  certain  mammals,  particularly  cattle, 
in  which  it  has  been  called  "lump  jaw,"  or  "big  jaw."    The  disease  has 

^Handb.  d.  Path.  Mikroorganismen.    KoUe  u.  Wassermann,  1903,  I,  526. 

^  Handb.  d.  Path.  Mikroorganismen.    Kolle  u.  Wassermann,  1903,  I,  661. 

^Journal  of  Medical  Research,  1901,  VI. 

•'  '  '  327 


328  DISEASES  DUE  TO  VEGETABLE  PARASITES 

a  wide  geographical  tlistribution  and  is  probably  much  more  common  in 
man  than  is  generally  recognized  According  to  Erving/  one  hundred 
cases  in  man  had  been  observed  in  America  up  to  December,  1901. 

In  cattle,  bovine  actinomycosis  had  long  been  known  chiefly  as  a  form 
of  sarcoma  of  the  jaw,  when  Bollinger,  in  1877,  first  clearly  showed  that 
the  disease  was  due  to  infection  with  a  vegetable  parasite,  to  which  Harz 
gave  the  name  of  Actinomyces  bovis  on  account  of  the  radiate  structure 
of  its  colonies  or  vegetations  in  the  tissues.  Shortly  after  this,  J.  Israel 
described  cases  in  man,  which  we  now  know  to  be  actinomycosis,  and 
also  described  the  characteristic  microorganism,  which  he  regarded  as 
the  infectious  agent,  but  he  did  not  recognize  its  identity  with  the  micro- 
organism described  by  Bollinger.  The  identity  of  the  human  and  bovine 
disease  was  first  pointed  out  by  Ponfik." 

Etiology. — The  specific  infectious  agent  exists  in  the  lesions  and  in  the 
pus  in  the  form  of  small  whitish,  or  yellowish,  irregular  shaped  granules 
varying  in  diameter  from  a  fraction  of  a  mm.  to  1  or  2  mm.  Larger 
granules  are  usually  made  up  of  aggregations  of  smaller  ones  so  that  they 
present  a  mulberry-shape.  The  granules  may  be  soft  and  easily  crushed 
or  hard,  resistant,  and  even  calcareous.  The  essential  element  of  the 
granules  is  a  branching  filamentous  microorganism  and  certain  trans- 
formation and  degeneration  products  thereof.  Typically  the  granules 
present  the  following  peculiarities  of  structure  under  the  microscope. 
Over  more  or  less  of  the  periphery  of  the  granule,  are  closely  set,  hyaline, 
refringent,  club-shaped  bodies  of  varying  size  and  thickness  arranged  in  a 
radiate  manner,  while  elsewhere  the  periphery  is  occupied  by  filaments  of 
the  microorganism  likewise  closely  set  together  and  disposed  in  a  radiate 
manner.  All  transitions  between  the  filaments  and  the  club-shaped  bodies 
may  be  present.  Beneath  this  peripheral  layer  of  radiating  club-shaped 
bodies  and  filaments  is  a  dense  network  of  branching  interlacing  fila- 
ments, while  the  central  part  of  the  granule  may  be  occupied  by  necrotic 
and  degenerate  filaments  and  pus  cells.  The  club-shaped  bodies  develop 
out  of  the  peripheral  filaments  by  the  latter  becoming  invested  with  a 
sheath  of  hyaline  refringent  material  which  is  usually  thickest  at  or  near 
the  distal  extremity  of  the  filaments,  and  thus  club-shaped  bodies  with 
filaments  in  the  centre  are  produced.  The  "clubs"  may  attain  a  thickness 
many  times  that  of  the  filaments,  which  may  degenerate  and  disappear 
from  within  them.  This  sheath  formation  may  extend  to  the  deeper 
lying  filaments  in  the  granule  and  these,  likewise,  may  degenerate  and 
become  invisible  so  that  the  granule  may  finally  be  transformed  into  a 
mass  of  hyaline  refringent  substance  and  necrotic  material,  invested  at 
the  periphery  with  closely  set  radiating  club-shaped  bodies  but  without  a 
trace  of  the  filamentous  microorganism  out  of  which  it  was  originally 
formed.  In  the  "clubs,"  degenerate  changes  may  occur  whereby  they 
acquire  a  lamellated  structure  or  assume  a  variety  of  shapes  and  appear- 
ances.   Eventually  the  granule  may  be  absorbed  or  become  calcified. 

The  "clubs,"  or  rays,  are  usually  better  developed  in  the  granules  in 
bovine  lesions  than  in  human  lesions.  In  the  latter  they  may  be  absent 
or  poorly  developed  and  the  granules  may  consist  entirely  or  chiefly  of 
filaments.    Certain  cases  in  which  the  granules  were  destitute  of  "clubs' 

*  Bulletin  of  the  Johns  Hopkins  Hospital,  1902,  XIII,  261. 
^  Berlin  Klin.,  Wochenschr.,  1879,  345. 


A  CTINOM  YCOSIS  329 

have  been  erroneously  regarded  as  not  cases  of  genuine  actinomycosis 
and  have  been  called  pseudo-actinomycosis.  This  name  has  also  been 
applied  to  certain  suppurative  conditions  in  which  masses  of  various 
bacteria  have  been  observed. 

Harz'  regarded  the  "clubs"  as  organs  of  fructification,  and  Bostroem^ 
and  others  regarded  them  as  degeneration  products  of  the  microorganism. 

In  general,  the  club  formation  is  most  marked  in  lesions  in  which 
there  is  considerable  development  of  connective  tissue  and  in  which  the 
progress  of  the  disease  is  slow,  with  manifest  resistance  on  the  part  of  the 
tissue  to  the  spread  of  the  process;  while  in  relatively  rapidly  progressive 
cases  or  those  in  which  there  is  little  evidence  of  resistance  on  the  part  of 
the  tissue  to  the  infection,  "clubs"  may  be  wanting  on  the  granules.  The 
writer^  has  shown  that  blood  serum  and  serous  pleuritic  fluids  are  capable 
of  provoking  club  formation  by  filaments  in  artificial  growths  of  the 
microorganism  that  had  been  immersed  in  these  fluids.  From  these 
facts  and  observations  it  seems  probable  that  the  club  formation  is  a 
protective  device,  adopted  by  the  microorganism  to  protect  for  a  time 
the  main  mass  of  the  microorganism  constituting  the  granule  from  the 
destructive  action  of  the  tissue  cells  and  juices. 

Concerning  the  biology  of  the  specific  microorganism  of  actinomycosis, 
much  confusion  has  existed  for  a  long  time  and  much  that  is  erroneous 
has  been  written.  Many  workers  have  made  culture  experiments  with 
the  microorganism  with  very  varying  and  often  contradictory  results. 
The  subject  has  been  further  confused  by  classing  with  actinomycosis 
certain  other  suppurative  processes  due  to  infection  with  branching 
microorganisms  which  are  widely  difl^erent  from  the  specific  micro- 
organism of  actinomycosis,  and  should  be  called  Nocardia. 

The  various  branching  microorganisms  claimed  to  have  been  isolated 
in  cultures  from  actinomycotic  lesions,  and  to  represent  the  microorgan- 
ism of  the  lesions,  may  be  roughly  divided  into  two  groups.  All  of  these 
at  some  stage  in  their  developmental  cycle  occur  in  filamentous  forms, 
without  sheaths  or  septa,  and  of  a  thickness  of  a  medium  sized  bacillus. 
They  are  distinguished  from  the  bacteria  by  their  peculiarity  of  truly 
branching,  and  may  be  regarded  as  occupying  a  position  in  the  botanical 
kingdom  between  the  bacteria,  on  the  one  hand,  and  the  hyphomycetes 
or  mould  fungi,  on  the  other.  One  group  is  represented  by  the  micro- 
organisms described  by  Bostroem,*  and  a  few  others;  the  other  group, 
by  the  microorganisms  of  Wolff  and  Israel,^  the  writer,^  and  many  others. 

The  first  mentioned  group  grow  readily  on  all  culture  media,  both  at 
the  room  temperature  and  in  the  incubator.  Their  chief  characteristic 
is  the  formation  in  cultures  of  spherical,  spore-like,  reproductive  elements 
out  of  the  substance  of  their  filaments.  None  of  this  group  are  known  to 
be  capable  of  producing  in  animals  inoculated  with  them,  lesions  like 
actinomycosis  and  containing  the  characteristic  granules. 

^Jahresber.  Thierarzneischule.  Milnchen,  1877-1878;  Deutsch  Zeitschr. 
Thiermed.,  1879,  V,  Suppl.  heft.,  125. 

^Beitr.  Path.  Anat.  u.  allgem.  Path.,  1891,  IX,  1. 

^"The  Biology  of  the  Microorganism  of  Actinomycosis,"  The  Samuel  D. 
Gross  Prize  Essay,  Journal  of  Medical  Research,  1905,  XIII,  349. 

*Beitzr.  z.  Path.  Anat.  u.  z.  Allgem.  Path.,  1891,  IX,  I. 

5  Virchow.  Arch.,  1891,  CXXVI,  II. 

"^Loc.  at. 


330  DISEASES  DUE  TO  VEGETABLE  PARASITES 

The  memoers  of  the  other  group  do  not  grow  on  all  the  usual  culture 
media  and  only  feebly  or  not  at  all  at  room  temperature.  They  do  not 
form  spore-like  reproductive  elements.  Some  of  them  have  been  shown  to 
produce  in  animals  inoculated  with  them,  lesions  essentially  identical  with 
those  of  typiciil  actinomycosis  although  not  of  a  jirogressive  character. 

The  subject  of  the  biology  of  the  microorganism  of  actinomycosis  has 
recently  been  discussed  by  the  writer,  who  concludes,  from  his  own 
culture  experiments  and  the  analysis  of  the  work  of  many  others,  that 
only  one  species  of  microorganism,  Actinomyces  bovis,  represents  the 
specific  infectious  agent  of  true  actinomycosis  in  man  and  animals.. 

This  microorganism  has  properties  essentially  like  those  of  the  second 
group  above  mentioned.  The  microorganisms  of  the  first  group,  des- 
cribed by  Bostroem  and  others,  should  not  be  considered  as  representing 
the  micro5rganisms  in  the  lesions,  but  are  to  be  regarded  as  secondary 
invaders  of  the  lesions  or  extraneous  microorganisms  accidentally  infecting 
the  cultures. 

Concerning  the  mode  of  entrance  of  actinomyces  into  the  tissues,  it  is 
generally  taught  and  believed  that  this  microorganism  is  widely  dis- 
tributed in  the  outer  world  on  grains  and  vegetable  material  and  that 
it  is  carried  into  the  tissues  by  penetrating  foreign  bodies  of  this  kind,  upon 
which  it  has  its  normal  habitat.  This  idea  is  based  on  the  following 
considerations: 

The  frequent  occurrence  of  such  foreign  bodies  in  actinomycotic  lesions; 
a  history,  in  many  cases,  of  the  patient  having  taken  uncooked  grains  or 
other  vegetable  material  into  the  mouth;  the  occurrence  of  pulmonary 
actinomycosis  in  those  who  have  breathed  the  dust  of  dried  grains;  the 
occurrence  in  the  outer  world,  upon  grains  and  grasses,  of  microorgan- 
isms with  biological  characters  similar  to,  or  identical  with,  those  of  the 
first  group  above  mentioned — which  Bostroem,  Gasperini  and  others 
claim  to  have  isolated  from  actinomycotic  lesions;  the  almost  exclusive 
origin  of  actinomycotic  lesions  in  the  tissues  and  structures  associated 
with  the  respiratory  or  alimentary  tracts. 

This  widely  accepted  idea  is  erroneous,  because  Actinomyces  bovis 
does  not  have  the  biological  characters  of  this  saprophytic  group  as- 
signed to  it  by  Bostroem  and  a  few  others  whose  culture  Avork  is  open  to 
doubt,  but  has  biological  characters  which  would  suggest  that  it  does  not 
have  its  normal  habitat  outside  the  body.  The  specific  microorganism 
of  actinomycosis  probably  exists  normally  among  the  abundant  flora  of 
the  secretions  of  the  alimentary  tract,  where  it  has  not  been  recognized 
because  it  exists  there  in  a  form  which  is  not  characteristic  and  very  un- 
like that  which  it  assumes  in  the  lesions;  it  may  gain  entrance  to  the 
tissues  through  wounds,  made  by  penetrating  foreign  bodies  or  otherwise, 
or  through  lesions  due  to  carious  teeth,  or  may  invade  the  lungs  as  do 
other  bacteria  of  the  mouth  and  pharynx;  in  the  tissues,  under  certain 
conditions  it  develops  into  the  characteristic  colonies  or  granules  and  by 
further  proliferation  gives  rise  to  the  disease.  The  disease  in  and  about 
the  jaw  is  frequently  associated  with  carious  teeth. 

Besides  the  specific  and  characteristic  microorganism,  various  bacteria 
are  also  present  in  the  lesions  in  many,  if  not  most,  cases  of  actinomycosis, 
and  it  seems  very  probable  that  these  play  an  important  part  in  the  pro- 
duction of  the  disease  in  these  cases. 


ACTINOMYCOSIS  331 

Contagiousness  has  not  been  shown  for  actinomycosis.  The  small 
amount  of  evidence  tending  to  show  that  it  is  contagious  will  not  stand 
critical  examination  and  there  is  much  direct  evidence  that  it  is  not. 

Many  experimenters  have  attempted  to  reproduce  the  disease  by 
inoculating  animals  with  material  from  actinomycotic  lesions,  but  the 
results  of  most  of  them  have  been  negative  or  ambiguous.  Only  a  few 
report  results  that  apparently  constitute  a  true  reproduction  of  the  disease. 
In  view  of  the  low  degree  of  virulence  thus  manifested  by  Actinomyces 
bovis  in  healthy  experimental  animals,  it  would  seem  that  the  occurrence 
of  the  natural  disease  must  be  due  in  large  measure  to  thie  existence  of  an 
individual  susceptibility  to  the  infection.  Thus  it  is  most  frequent  in 
individuals  living  under  unfavorable  hygienic  conditions.  Infection 
from  drinking  milk  and  eating  the  flesh  of  diseased  animals  has  never 
been  proved. 

It  is  claimed  that  more  cases  of  the  disease  are  found  among  persons 
living  in  cities  and  that  it  is  more  frequent  in  the  months  from  August  to 
January.  It  is  more  frequent  in  men  than  in  women  and  in  the  middle 
decades  of  life. 

Special  Pathology. — The  essential  effects  produced  in  the  tissues  by 
actinomyees  are  suppuration  and  tissue  destruction,  combined,  in  most 
cases,  with  new  formation  of  granulation  and  connective  tissue.  In  some 
cases  the  new  formation  of  connective  tissue  may  be  excessive  in  amount, 
and  thus  simulate  a  neoplasm.  The  granulation  tissue  usually  contains 
many  large  cells  filled  with  fat  globules.    Giant  cells  may  also  be  present. 

The  area  of  tissue  affected  by  a  given  vegetation  or  colony  of  Actino- 
myces bovis  is  usually  many  times  greater  than  the  colony,  the  poisonous 
and  irritative  action  of  the  parasite  affecting  a  wide  area  of  the  surround- 
ing tissue.  Almost  any  organ  or  part  of  the  body  may  be  the  seat  of  the 
lesions.  The  extension  of  the  actinomycotic  process  takes  place  both  by 
continuity  of  the  lesions  and  by  metastases,  the  latter  almost  always 
occurring  by  way  of  the  bloodvessels.  In  the  lung  the  process  may  also 
be  disseminated  by  way  of  the  bronchi.  The  extension  by  continuity 
probably  takes  place  by  means  of  the  separation  from  a  colony  of  fila- 
ments and  fragments  of  the  microorganism,  and  the  transportation  of 
these  in  some  unknown  manner  into  the  neighboring  tissue,  where  they 
form  new  colonies  and  produce  more  foci  of  suppuration,  tissue  destruc- 
tion and  inflammatory  reaction  on  the  part  of  the  surrounding  connective 
tissue.  In  this  way  large  portions  of  an  organ  or  region  may  become  re- 
placed by  granulation  and  connective  tissue,  enclosing  pus  cavities;  or 
large  abscesses  may  be  formed  having  the  characters  of  cold  abscesses. 
The  small  abscesses  enclosed  in  the  granulation  and  connective  tissue 
often  communicate  with  one  another  and  may  form  sinuses  discharging 
pus  and  inflammatory  products.  The  small  abscesses,  with  their  associated 
connective  tissue,  may  become  very  numerous  and  closely  set  together  so 
that  a  focal  lesion  may  arise,  having  the  gross  appearance  of  a  sponge-like 
mass  of  connective  tissue  saturated  with  pus.  This  is  typically  seen  in 
actinomycosis  of  the  liver.  A  wide  extension  by  continuity  over  extensive 
areas  and  to  distant  portions  of  the  body,  and  the  formation  of  suppura- 
tive tracts  and  of  sinuses,  opening  either  on  the  skin  or  in  mucous  mem- 
branes, is  a  marked  feature  of  the  disease.  Another  marked  feature  is 
that  the  older  lesions  may  heal  by  cicatrization  and  the  dying  out  and 


332  DISEASES  DUE  TO  VEGETABLE  PARASITES 

absorption  of  the  inicroorgaiiism,  so  that  it  may  happen  that  the  starting 
point  of  an  extensive  process  may  be  difHcult  or  impossible  to  find  Com- 
plete healing  nia}'  occur  spontaneously  through  the  death  and  destruction 
of  the  microorganism  in  the  lesions  and  by  its  extrusion  from  the  body 
by  the  way  of  sinuses  or  fistuhe. 

Extension  by  metastasis  takes  place  by  the  rupture  of  a  focal  lesion 
into  a  bloodvessel,  thus  discharging  the  parasite  into  the  circulating 
blood,  whereby  the  lesions  may  be  widely  disseminated  throughout  the 
body,  affecting  first  the  lungs,  if  a  vein  of  the  systemic  system  is  involved, 
or  the  liver,  if  a  vein  in  the  portal  system.  Among  many  other  possible 
localizations  of  metastatic  lesions,  the  brain,  the  heart  and  the  extremities 
may  be  mentioned.  In  the  heart  the  lesions  may  take  the  form  of  tumor- 
like  masses  projecting  into  its  cavities  from  the  walls.  In  these  embolic 
disseminated  cases,  the  process  may  have  the  character  of  multiple 
subacute  abscess  formation  and  thus  be  essentially  a  subacute  pysemia. 
Extension  by  the  lymphatics  and  involvement  of  lymphatic  glands  is  very 
exceptional,  if  it  occurs  at  all. 

In  extensive  chronic  cases  amyloid  infiltration  ma}'^  occur.  Carcinoma 
has  been  observed  to  develop  in  old  lesions  in  a  few  cases. 

According  to  the  point  of  origin  or  the  principal  location  of  the  lesions, 
four  forms  of  the  diseases  may  be  differentiated;  viz.,  head  and  neck, 
thoracic,  abdominal  and  cutaneous. 

Actinomycosis  of  the  Head  and  Neck. — More  than  half  of  all  the  cases 
in  man  are  of  this  form.  It  includes  those  in  which  are  involved  the  struc- 
tures in  relation  with  the  buccal  and  pharyngeal  cavities,  the  tongue,  the 
soft  parts  and  the  skin  of  the  face  and  neck,  the  bones  of  the  skull  and  jaws, 
the  larynx,  the  thyroid,  the  lachrymal  ducts  and  the  brain.  In  these  cases 
there  may  be  extension  to  the  meninges  and  brain  through  the  skull  or 
down  the  prevertebral  space  to  the  mediastinum  and  more  distant  parts. 
With  the  exception  of  the  localizations  in  the  lachrymal  duct  and  in  the 
brain  by  metastasis,  it  seems  probable  that  the  process  in  nearly  all,  if  not 
all,  cases  of  this  form  of  the  disease  originates  in  the  tissues  immediately 
about  the  buccal  and  pharyngeal  cavities.  Cases  in  which  this  mode  of 
origin  is  not  obvious  may  be  explained  by  the  healing  of  earlier  lesions. 
So-called  primary  cutaneous  actinomycosis  of  the  head  or  neck  is  open 
to  ciuestion  as  to  its  origin  in  the  skin  in  these  situations.  Lesions  in  the 
brain  are  usually  metastatic.  Only  one  case  of  apparently  primary  actino- 
mycosis of  the  brain  is  known. 

The  muscular,  bony  and  other  tissues  may  be  extensively  replaced  by 
granulation  and  connective  tissue  enclosing  suppurative  foci,  abscess 
cavities,  and  sinuses.  The  inflammatory  tissue  and  infiltration  may  be 
excessive  in  amount,  characteristically  forming  brawny  indurations  or 
sarcoma-like  infiltrations  and  swellings  in  the  parts  affected.  The  skin 
over  these  may  be  oedematous,  of  a  bluish  or  reddish  color,  and  may  pre- 
sent projecting  folds  or  elevations  with  furrows  between.  Here  and  there 
points  of  suppuration,  or  the  orifices  of  sinuses  surrounded  by  red  granu- 
lation tissue,  may  be  apparent.  In  less  extensive  cases  the  inflammatory 
process  may  be  insignificant  and  may  heal  spontaneously.  Primary 
involvement  of  the  jaw  bones  is  rare.  In  the  brain  the  lesions  may  be 
like  abscesses  or  cystic  cavities  filled  with  a  gelatinous  grayish-yellow 
substance. 


ACTINOMYCOSIS  333 

Thoracic  Actinomycosis.— About  15  per  cent,  of  all  cases  in  man  are 
of  this  form.  In  most  cases  the  lungs  are  the  seat  of  lesions  which  consist 
chiefly  of  abscess  and  cavity  formation,  usually  combined  with  the 
growth  of  granulation  and  connective  tissue  at  the  expense  of  the  pul- 
monary tissue,  so  that  larger  or  smaller  portions  of  the  lungs  may  be  trans- 
formed into  fibrous  tissue  permeated  with  cavities  and  sinuses.  The 
cavities,  as  a  rule,  are  small.  The  inferior  are  more  frecjuently  affected 
than  are  the  superior  lobes.  Lesions  of  the  bronchi  may  be  extensive. 
The  rupture  of  a  focal  lesion  into  a  bronchus  often  leads  to  dissemination  of 
the  process  by  way  of  the  bronchial  tree.  The  disease  may  originate  in 
the  bronchi,  from  the  oesophagus,  or  from  lesions  involving  the  neck  by 
extension  downward  into  the  mediastinum,  or  by  extension  upward  from 
lesions  in  the  abdomen,  or  by  metastasis.  From  these  situations  the 
process  may  extend  widely  and  involve  the  lungs  and  thoracic  wall,  pro- 
ducing retraction  and  deformity  of  the  chest. 

The  initial  and  intermediate  lesions  in  the  evolution  of  the  process  may 
be  healed  and  be  neither  obvious  nor  demonstrable.  Cases  of  so-called 
primary  cutaneous  actinomycosis  of  the  thorax  probably  represent  an 
extension  from  within  outward.  The  extension  of  the  process  through 
the  wall  of  the  thorax  and  the  production  on  the  exterior  of  the  body  of 
swollen  and  indurated  areas  in  which  are  the  orifices  of  sinuses,  are  char- 
acteristic features  of  this  form  of  actinomycosis.  These  sinuses  may  open 
in  the  epigastrium  as  well  as  on  the  thorax. 

In  the  pleural  cavities  an  accumulation  of  serous  fluids  may  occur,  and 
empyema  has  been  observed.  The  disease  may  extend  from  the  medias- 
tinum to  involve  the  pericardium  and  heart.  As  in  the  lung,  the  lesions 
consist  essentially  in  extensive  replacement  of  the  natural  structures  of  the 
parts  by  inflammatory  tissue  in  which  are  abscesses  and  sinuses._ 

Abdominal  Actinomycosis.— About  20  per  cent,  of  all  cases  in  man 
are  of  this  form.  Any  organ  or  region  of  the  abdominal  portion  of  the 
body  may  be  affected  and  the  lesions  are  very  varied  in  character.  The 
process  may  arise  by  extension  from  the  thorax,  by  metastases  or  by  in- 
fection from  the  gastro-intestinal  canal.  It  is  probable  that  primary  ac- 
tinomycosis of  the  abdomen  is  always  due  to  infection  from  the  stomach 
or  intestines  and  that  the  starting  point  in  these  situations,  when  not  de- 
monstrable, has  been  a  lesion  that  has  healed.  Primary  lesions  in  the 
intestine  appear  as  ulcerative  processes. 

The  most  frequent  localization  of  the  primary  disease  in  the  abdominal 
form  is  in  the  region  of  the  csecum  and  vermiform  appendix.  From  the 
intestine  the  disease  usually  extends— producing  fibrous  adhesions,  sup- 
purative foci  and  abscesses  between  intestinal  coils — to  the  abdominal 
wall,  most  frequently  in  the  right  anterior  half.  Here  the  muscular  and 
other  tissues  become  replaced  by  inflammatory  connective  tissue  in  which 
are  abscesses,  sinuses,  and  intestinal  fistulse.  The  portions  of  the  abdo- 
minal wall  involved  becomes  brawny,  and  the  amount  of  inflammatory 
connective  tissue  produced  may  give  the  appearance  of  a  fibrous  neo- 
plasm. The  skin  over  the  affected  region  may  be  red,  oedematous,  and 
contain  fluctuating  suppurative  foci  which  by  their  rupture  become  the 
orifices  of  sinuses  and  fistulae. 

Peritoneal  abscesses  may  rupture  into  the  intestine  or  bladder.  From 
the  abdominal  wall  the  process  may  travel  further  and  produce  extensive 


334  DISEASES  DUE  TO  VEGETABLE  PARASITES 

suppurating  necrotic  tracts  extending  througli  the  crural  ring  or  along 
the  psoas  muscle  to  the  hip-joint.  The  process  may  also  spread  from 
the  intestinal  canal  along  the  retroperitoneal  tissues,  producing  exten- 
sive destruction  of  the  nuiscles  and  bone  in  this  region,  and  eventually 
involve  the  thorax,  or  extend  down  into  the  ischio-rectal  fossa  and  per- 
forate the  skin  in  the  region  of  the  anus.  Any  of  the  abdominal  or  pelvic 
organs  may  become  involvetl  by  direct  extension  of  the  process. 

A  frequent  location  of  the  lesions  is  in  the  liver,  in  which  the  foci  may  be 
single  or  multiple  and  are  sometimes  of  large  size.  The  lesions  in  the  liver 
present  the  appearance  of  a  sponge-work  or  honeycomb  structure  of  con- 
nective tissue  saturated  with  pus.  They  frequently  arise  from  metastasis 
through  the  portal  system  as  well  as  by  direct  extension.  Cases  of  so-called 
primary  actinomycosis  of  the  liver  have  probably  arisen  by  metastases  from 
healed  or  unrecognized  lesions  involving  the  portal  system  of  veins.  Me- 
tastatic lesions  in  abdominal  actinomycosis  arising  from  foci  outside  of  the 
abdomen  most  frequently  occur  in  the  spleen,  kidneys,  and  abdominal  wall. 

Cutaneous  Actinomycosis. — This  form  includes  those  comparatively 
rare  cases  in  Avhich  the  lesions  are  regarded  as  primary  in  the  skin.  As 
already  suggested,  some  of  these  cases  represent  secondary  invasion  of  the 
skin  from  deeper  structures.  The  lesions  are  ulcerative  or  may  have  great 
resemblance  to  lupus  and  to  certain  forms  of  cutaneous  syphilis.  The  pro- 
cess is  essentially  a  local  one  and  is  outside  of  the  scope  of  this  article. 

Symptoms. — In  a  disease  with  such  a  great  variety  of  localizations  and 
of  such  varying  extent,  it  is  impossible  within  the  scope  of  this  article  to 
give  an  adequate  account  of  all  its  signs  and  symptoms.  These  in  general 
are  like  those  of  a  subacute  or  chronic  inflammatory  process,  or  of  a  ma- 
lignant neoplasm.  In  many  cases  the  disease  is  far  advanced  and  has 
extensively  invaded  important  internal  organs  and  regions  before  any 
symptoms  are  apparent. 

In  cases  involving  the  external  soft  parts,  prominent  signs  are  swellings 
and  indurations  of  the  infected  region  in  which  suppurative  foci,  often 
recurrent,  may  develop,  break  through  the  skin  and  become  the  orifices 
of  recurrent  sinuses  and  fistulse.  The  skin  over  the  affected  part  may  be 
cedematous,  discolored,  and  warm,  or  the  swelling  may  have  no  inflam- 
matory character  and  simulate  a  neoplasm.  Fever  and  pain  may  or  may 
not  be  present. 

In  the  frequent  cases  in  which  the  disease  affects  the  temporomaxillary 
region  the  prominent  symptoms  are  trismus,  pain,  swelling,  and  limitation 
of  motion  of  the  jaws.  Involvement  of  the  skin  of  the  neck  is  character- 
ized by  ridge-like  elevations,  or  folds  with  sulci  between,  associated  with 
the  orifices  of  sinuses.  The  lesions  in  the  tongue  are  usually  nodular  or 
tumor-like. 

Lesions  of  the  brain,  spinal  cord,  or  meninges  may  give  rise  to  all  the 
various  signs  and  symptoms  of  meningitis,  encephalitis,  myelitis,  cerebral 
thrombosis,  and  tumor. 

In  those  cases  originating  in  any  region  of  the  body  with  extensive 
suppuration  or  with  metastases,  the  symptoms  are  usually  those  of  pyae- 
mia, with  chills,  sweats,  fever,  pain,  vomiting,  and  diarrhoea.  In  such 
cases  the  primary  process  may  not  be  obvious  until  the  autopsy. 

In  the  thoracic  form  definite  symptoms  and  signs  are  usually  wanting 
until  the  disease  is  far  advanced.    If  the  lungs  are  extensively  involved 


ACTINOMYCOSIS  335 

there  is  cough  with  foetid,  sometimes  bloody,  sputum,  and  signs  of  bron- 
chitis, pulmonary  consolidation  and  cavity  formation.  These  usually 
are  in  the  inferior  portions  of  the  lungs.  There  is  also  cachexia,  anaemia, 
fever  of  a  variable  type,  and  the  habitus  of  pulmonary  phthisis.  The 
frequent  involvement  of  the  pleura  and  thoracic  vv^all  is  a  marked  feature 
of  this  form  of  the  disease  and  may  give  rise  to  the  first  symptoms.  A 
prominent  symptom  of  this  localization  is  pain  in  the  afi'ected  region. 
Retraction  of  the  thoracic  wall,  signs  of  pleuritis,  progressive  emaciation, 
weakness,  diarrhoea,  night  sweats,  and  fever  may  be  present.  The  pres- 
ence of  an  inflammatory  swelling  or  a  board-like  induration  in  the  wall  of 
the  thorax  or  epigastrium,  with  suppurative  foci  or  sinuses  in  it,  is  very 
characteristic. 

Lesions  of  the  oesophagus  have  been  attended  with  pain  on  swallowing 
or  pain  behind  the  sternum. 

In  primary  abdominal  actinomycosis  the  most  conspicuous  sign  in  the 
majority  of  cases  is  a  deeply  seated  tumor-like  mass  or  a  hard  infiltration, 
involving  the  abdominal  wall,  in  the  midst  of  which  may  be  fluctuating 
foci  or  orifices  or  sinuses  and  intestinal  fistulse.  The  skin  over  the  affected 
part  may  be  red  to  brown  in  color  and  may  be  the  seat  of  ulcers.  Usually 
the  affected  region  has  a  board-like  consistence  and  is  only  slightly  pain- 
ful on  pressure.  The  tumor-like  masses  are  only  slightly  movable.  The 
right  half  of  the  abdomen  is  most  frequently  involved,  commonly  in  the 
ileo-csecal  region.  The  left  half  is  less  frequently  involved,  while  localiza- 
tion of  the  lesions  about  the  umbilicus  or  in  the  lumbar  or  gluteal  regions 
is  rare.  These  local  signs  may  or  may  not  be  preceded  or  accompanied 
by  intestinal  colic,  vomiting,  fever,  diarrhoea,  constipation,  swelling  of  the 
abdomen,  and  pain  referred  to  the  ileo-csecal  region  or  elsewhere. 

The  clinical  course  of  the  disease  may  be  acute,  with  much  fever  and 
pain,  as  in  the  disseminated  embolic  forms,  or  it  may  be  subacute  or 
chronic  with  little  or  no  pain  and  fever.  Any  of  the  types  may  develop 
from  one  of  the  others.  Fever  may  occur  at  any  time.  Thespleenmay 
be  enlarged. 

In  the  chronic  cases  especially,  there  may  be  anaemia,  diarrhoea, 
emaciation,  weakness,  oedema,  and  cachexia.  Ascites  rarely  occurs. 
In  cases  in  which  the  liver  is  extensively  involved  the  organ  is  enlarged, 
but  there  may  be  little  fever  and  but  little  pain  referred  to  it.  Pain  in  the 
lower  ribs,  jaundice,  and  constipation  may  be  present.  An  abscess  may  be 
evident  in  the  right  hypochondrium,  and  there  is  the  fever  curve  of  sup- 
puration. Sometimes  there  is  a  painless  tumor  at  the  right  costal  border, 
with  only  moderate  fever.  Involvement  of  the  urinary  tract  may  pro- 
duce symptoms  of  cystitis  and  pyelonephritis. 

Diagnosis. — So  closely  does  actinomycosis  simulate  various  inflamma- 
tory conditions  and  tumor  formations  that  the  diagnosis  is  definitely 
established  only  by  the  demonstration  of  the  characteristic  microorgan- 
ism in  the  lesions,  or  in  the  pus  aspirated  or  discharged  from  them.  The 
characteristic  granules  are  rather  to  be  sought  for  in  the  pus  or  discharges 
from  the  lesions  than  in  pieces  of  excised  tissue,  because  the  granules  or 
vegetations  commonly  exist  in  little  cavities  or  sinuses  in  the  tissue,  from 
which  they  readily  escape  and  are  lost,  or  in  which  they  may  be  concealed 
and  elude  observation  owing  to  the  small  size  of  the  granule  as  com- 
pared with  the  mass  of  the  lesion. 


336  DISEASES  DUE  TO  VEGETABLE  PARASITES 

The  pus,  or  the  sputum,  in  cases  of  suspected  pulmonary  actinomycosis, 
should  be  spread  out  thinly  on  a  glass  surface  and  the  granules  sought  for 
against  a  dark  background.  A  careful  examination  may  be  necessary  to 
find  them.  Suspected  granules  should  be  transferred  to  a  slide,  with  a 
small  amount  of  water,  and  gently  flattened  under  a  coverglass.  Under 
the  microscope  with  a  low  power  objective  a  typical  granule  appears  as  a 
brownish  refringent,  more  or  less  lobulated  mass  or  masses  showing 
radiate  striated  appearances  at  the  periphery.  More  or  less  pus  adheres 
to  the  granule  so  that  the  masses  of  the  parasite  are  seen  to  be  surrounded 
by  pus  cells.  Under  an  objective  of  medium  magnifying  power  the 
peripheral  portions  of  the  granule  are  seen  to  be  composed  of  the  charac- 
teristic refringcnt  radiating  club-shaped  bodies  or  filaments  closely 
j)acked  together  and  the  central  portions  are  seen  to  be  granular  or 
hyaline.  In  some  instances  the  clubs  may  not  be  present  and  filaments 
only  may  be  apparent  at  the  margin. 

Granules  composed  of  conglomerates  of  various  bacteria,  such  as  may 
be  observed  in  pus  from  inflammatory  processes  about  the  mouth,  should 
not  be  mistaken  for  granules  or  colonies  of  actinomyces.  Cases  of  this 
kind  have  been  called  pseudo-actinomycosis.  The  same  name  has  been 
erroneously  applied  to  genuine  actinomycosis,  because  the  granules  failed 
to  show  the  "clubs."  If  the  granules  do  not  show  the  "clubs,"  the  demon- 
stration in  smear  preparations  made  from  them  of  truly  branched  fila- 
ments, like  those  of  actinomyces,  is  sufficient  to  justify  the  diagnosis  of 
actinomycosis.  This  is  best  done  by  breaking  up  one  or  more  of  the  gran- 
ules on  a  coverglass  so  as  to  form  a  smear  preparation,  staining  it 
by  Gram's  method  and  examining  it  with  an  oil-immersion  objective. 
In  addition  to  longer  and  shorter  irregularly  staining  filaments,  often 
branched  and  occurring  singly  or  in  groups  or  in  masses,  coccus-like  or 
bacillus-like  forms  may  be  seen.  These  are  either  products  of  disintegra- 
tion and  generation  of  the  filaments  of  actinomyces  or  are  true  micrococci 
and  bacilli  that  have  been  growing  in  symbiosis  with  them.  The  coccus- 
like forms  have  been  erroneously  regarded  by  some  writers  as  spore-like 
reproductive  elements  of  actinomyces. 

The  pus  of  closed  suppurative  foci  is  most  favorable  for  the  finding  of 
the  microorganism,  and  the  first  drops  of  pus  or  inflammatory  fluid  which 
issue  from  the  focus  are  best  to  examine,  for  the  granules  are  usually  most 
numerous  therein.  They  may  be  very  few  and  difficult  to  find  in  the  in- 
flammatory fluid  that  may  be  expressed  later  from  the  lesions.  The 
secretions  from  open  sinuses  may  be  very  poor  in  granules  and,  in  sus- 
pected cases  with  sinus  formation,  it  may  be  necessary  to  examine  the 
secretion  accumulated  during  some  time  before  the  granules  are  found. 
This  may  be  conveniently  done  by  plugging  the  sinuses  with  a  wick. 

The  existence  of  subacute  or  chronic  indurated  swellings,  associated 
with  recurrent  suppurative  foci  or  sinuses  or  fistuUie  in  any  situation,  is 
suggestive  of  actinomycosis. 

Actinomycosis  of  the  neck  and  head  may  be  confounded  with  any  of 
the  tumors  or  inflammatory  conditions  occurring  in  these  parts,  especially 
with  sarcoma  of  the  jaw.  In  every  inflammatory  process  about  the  mouth 
or  pharynx  actinomycosis  should  be  considered.  Actinomycosis  of  the 
tongue  may  be  confused  with  cancer  and  other  conditions.  Actinomycosis 
of  the  brain  may  be  suspected  only  when  cerebral  symptoms  occur  in  as- 


ACTINOMYCOSIS  337 

sociation  with  a  focus  of  known  actinomycosis  elsewhere.  Actinomycosis 
of  the  thorax  may  simulate  every  inflammatory  or  neoplastic  affection 
of  that  part  of  the  body. 

In  cases  involving  the  lung  without  obvious  lesions  of  the  thoracic  wall, 
the  disease  is  most  likely  to  be  confused  with  pulmonary  tuberculosis 
from  whichit  differs  clinically  practically  only  inthe  morefrequent  localiza- 
tions of  the  signs  in  the  inferior  lobes  and  in  the  less  frequent  occurrence 
of  haemoptysis.  In  these  cases  the  diagnosis  can  be  made  with  certainty 
only  by  finding  the  characteristic  granules  or  colonies  of  actinomyces 
in  the  sputum  or  in  the  pleural  exudate.  The  sputum  in  all  cases  of 
chronic  pulmonary  disease  in  which  tubercle  bacilli  cannot  be  found, 
should  be  examined  for  actinomyces.  The  granules  usually  sink  to  the 
bottom  of  the  sputum  receptacle.  Any  concretions  in  the  sputum  should 
be  carefully  examined. 

The  early  symptoms  of  the  disease  may  be  those  of  typhoid  fever  or 
influenza  accompanied  by  pleuritis,  and  the  persistent  pulmonary  symp- 
toms may  be  regarded  as  sequelae  of  these  affections.  In  cases  in  which 
the  thoracic  wall  or  vertebral  column  is  involved  the  disease  may  simu- 
late chiefly  tuberculosis  or  secondary  carcinoma  of  the  spine,  or  sarcoma 
or  cold  abscess  of  the  thoracic  wall. 

Involvement  of  the  oesophagus  may  simulate  cancer  of  that  organ. 

Abdominal  actinomycosis  may  simulate  a  great  variety  of  diseases  and 
conditions,  among  which  may  be  mentioned  tumors,  gumma,  and  phleg- 
mon of  the  abdominal  wall,  appendicitis,  typhoid  fever,  carcinoma  of  the 
intestines,  tuberculosis  of  the  ileo-csecal  lymph  nodes,  abscess  of  the 
liver,  psoas  abscess,  perinephric  abscess,  and  sarcoma  of  the  iliac  bone. 
If  neither  superficial  suppurative  foci,  nor  sinuses,  nor  fistulse  exist,  it  is 
possible  that  the  actinomyces  granules  might  be  found  in  the  faeces  or  in 
the  urine,  if  the  bladder  be  involved  in  the  process. 

Prognosis. — The  prognosis  in  actinomycosis  depends  chiefly  upon  the 
extent  and  localization  of  the  lesions.  In  nearly  all  cases  the  disease  is 
chronic,  lasting  for  months  and  years.  Some  cases  recover  spontane- 
ously but  for  the  great  majority  treatment  is  necessary  to  make  recovery 
possible. 

In  cases  affecting  the  head  and  neck  the  general  prognosis  is  much 
better  than  in  the  other  forms.  Poncet  and  Berard^  state  that  three- 
fourths  of  these  cases  get  well.  Of  the  49  cases  analyzed  by  Leiblein,^ 
3  died  and  36  recovered.  Of  52  cases  treated  by  v.  Baracz,^  45  recovered 
and  the  fate  of  7  was  unknown.  Heinzelmann^  has  recently  reported 
that  of  39  cases  treated  surgically,  35  apparently  were  cured  and  1,  or 
possibly  2  had  died  of  the  disease.  Of  the  53  American  cases  analyzed 
by  Erving^  36  had  recovered  and  5  had  died.  When  the  disease  involves 
the  superior  maxilla  and  the  pharynx  the  prognosis  is  not  as  good  as  in 
the  generality  of  the  cases  involving  the  head  and  neck. 

^  Traite  Clinique  de  I' Actinomycose  humaine,  Pseudo-Actinomycose  et  Botry- 
omycose,  Paris,  Masson  et  Cie,  1898. 

^Beitr.  z.  klin.  Chir.,  XXVIII,  198. 

^Arch.  f.  klin.  Chir.,  1902,  LXVIII,  1050 

^"Ucber  Endresultate  bei  der  Behandlung  der  Aktinomykose,  "/nott^.  Diss., 
Tubingen,  1903. 

^Bulletin  of  the  Johns  Hopkins  Hospital,  1902,  XIII,  261, 
22 


338  DISEASES  DUE  TO  VEGETABLE  PARASITES 

Recurrences  are  not  infrequent  after  operation  or  apparent  cure,  and  a 
case  should  not  be  regardetl  as  cured  until  f\vo  years  have  elapsed  without 
recurrence.  Thus  Heinzehnann  reports  that  0  out  of  31  cases  had  suf- 
fered recurrence  before  a  cure  was  effected. 

The  prognosis  in  the  thoracic  form  is  bad.  As  in  nearly  all  of  the  cases 
of  the  thoracic  foitn  the  lung  is  involved,  statistics  bearing  upon  progno- 
sis in  this  form  deal  chiefly  with  pulmonary  actinomycosis.  Of  34  cases 
collected  by  Ilodenj^vl/  all  died  exce])t  2.  Among  58  cases  collected  by 
Illich,-  no  recoveries  are  recorded.  Of  the  20  American  cases  collected  by 
Erving,  15  died  and  but  2  recovered.  Apparently  only  about  half  a  dozen 
cases  of  pulmonary  actinomycosis  arc  recorded  in  the  literature  in  which 
a  recovery  is  claimed.  In  most  of  these  the  permanency  of  the  recovery 
is  doubtful. 

In  abdominal  actinomycosis  the  prognosis  is  not  good  but  it  is  better 
than  in  the  thoracic  form.  It  is  especially  bad  if  the  retro-peritoneal 
tissues  are  involved.  It  is  better  if  the  process  is  localized  in  the  anterior 
abdominal  wall,  is  accessible  to  surgical  treatment,  and  the  visceral  in- 
volvement is  lacking  or  not  extensive.  Of  64  cases  analyzed  by  Harz,^  22 
died  and  22  recovered.  Of  107  cases  reported  by  Grill, ^  of  which  77 
were  treated  surgically,  22  recovered  and  45  died.  Lowe^  selected  67 
cases  in  which  the  disease  was  localized  about  the  ileo-ctrcal  region  and 
found  that  12  recovered  and  36  died.  Of  the  23  American  cases  analyzed 
by  Erving,  10  died  and  5  recovered.  At  least  1  case  of  spontaneous 
recovery  is  known. 

Treatment. — The  weight  of  experier.ce  in  the  treatment  of  actinomy- 
cosis is  in  favor  of  surgical  means  combined  with  the  internal  administra- 
tion of  large  doses  of  iodide  of  potassium  continued  over  long  periods  of 
time.  The  favorable  effect  of  this  drug  in  many  cases  seems  to  be  gener- 
ally admitted.  It  is  said  to  cause  more  or  less  absorption  of  suppurative 
foci  and  to  facilitate  the  discharge  of  the  specific  infectious  agent  from  the 
tissues.  It  seems  also  to  inhibit  the  development  of  new  suppurative  foci. 
Cures  are  claimed  to  have  been  effected  by  the  use  of  this  drug  alone.  It  is 
said  to  act  less  favorably  in  pulmonary  actinomycosis  than  in  other  forms. 
It  must  be  given  in  the  largest  doses  that  can  be  borne.  Favorable  effects 
may  not  be  apparent  in  the  lesions  until  its  administration  has  been  con- 
tinued for  a  considerable  length  of  time.  Treatment  with  the  .r-rays 
combined  with  the  internal  administration  of  large  doses  of  potassium 
iodide  has  been  highly  recommended. 

Opinion  is  divided  as  to  the  character  of  the  surgical  treatment.  Some 
advocate  the  radical  excision  of  the  diseased  tissue  when  the  character  of 
the  case  admits  of  it.  Others  believe  that  wide  opening  and  drainage  of 
abscesses,  sinuses,  and  fistulse,  with  or  without  thorough  curetting,  is 
sufficient.  With  the  latter  mode  of  treatment  tamponades  of  iodide  of 
potassium  and  of  various  antiseptics  have  been  advocated,  such  as  tinc- 
ture of  iod  ine,  corrosive  sublimate,  sulphate  of  copper  and  nitrate  of  silver. 

^New  York  Medical  Record,  1890,  XXXVIII,  653. 
^ Beitr.  zur  Klinik  der  Aktinomycose,  1892,  Wien. 
^Centralbl.  f.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  1900,  III,  561. 
^Beitr.  z.  klin.  Chir.,  1895,  XIII,  551. 

®  "Statistischesund  Klinisches  zur  Kentniss  der  Actinomycose  des  Wurmfort- 
satzes  und  des  Coecums,"  Inaug.  Diss.,Greifswald,  1904. 


ACTINOMYCOSIS  339 

In  localizations  about  the  jaw,  any  carious  teeth  that  seem  to  be  in  relation 
with  the  lesions  should  be  extracted.  For  rectal  actinomycosis,  Poncet  has 
recommended  the  thermocautery. 

Recurrence  is  frequent  in  cases  treated  by  simple  incision  and  drainage 
and  it  may  occur  even  after  the  most  radical  procedure,  so  that  repeated 
operation  may  be  necessary  before  a  cure  is  effected.  As  a  pro]) hyl actio 
against  recurrence  a  course  of  treatment  with  iodide  of  potassium  has  Ijcen 
advocated.  This  has  also  been  advised  as  a  preliminary  to  surgical  treat- 
ment in  cases  with  extensive  lesions,  as  in  abdominal  actinomycosis,  be- 
cause its  effects  on  the  lesions  tend  to  make  the  suppurative  foci  more 
evident,  and  thus  more  easily  found  and  evacuated  by  operation.  The 
internal  administration  of  arsenic  and  of  sulphate  of  copper  has  also  been 
advised  in  place  of  iodide  of  potassium. 

V.  Baracz  recommends  in  circumscribed  lesions,  especially  those  about 
the  face  and  neck,  where  it  is  desirable  to  avoid  cicatrices  for  cosmetic 
reasons,  the  parenchymatous  injection  of  tincture  of  iodine,  or  of  a  20  per 
cent,  solution  of  nitrate  of  silver  without  extensive  surgical  interference, 
one  cc.  or  sixteen  minims  of  either  of  these  to  be  injected  into  the  lesions 
repeatedly  every  few  days.  One  case  of  pulmonary  actinomycosis  is 
claimed  to  have  recovered  under  treatment  with  oil  of  eucalyptus.  Ac- 
cording to  V.  Baracz  the  surgical  treatment  of  pulmonary  actinomycosis 
has  not  given  hopeful  results. 


CHAPTER  XVL 

NOCARDIOSIS,  iNIYCETOMA,  OIDIOiAIYCOSIS,  BLASTOMY- 
COSIS,   PULMONARY   ASPERGILLOSIS,    MYCOSIS 
MUCORINA. 

By  J  MIES  HOMER  WRIGHT,  A.  M.,  M.D.,  Hon.  S.  D.  (Harv.) 
NOCARDIOSIS. 

Definition. — A  considerable  number  of  cases  of  inflammatory  charac- 
ter, due  to  infection  with  branched  filamentous  microorganisms  more 
or  less  similar  to  Actinomycosis  bovis,  are  recorded  in  the  literature 
and  have  been  the  source  of  much  confusion.  A  few  of  these  cases  are 
infections  with  branched  tubercle  bacilli  or  are  cases  of  pulmonary  gan- 
grene associated  with  so-called  branched  bacilli,  the  pathogenic  signifi- 
cance of  which  is  doubtful;  these  need  not  be  further  considered  here. 

Excluding  a  few  cases,  which  are  more  or  less  probably  genuine 
actinomycosis,  in  which  the  infecting  microorganism  had  not  developed 
the  characteristic  "clubs,"  and  some  cases  that  are  very  meagerly  re- 
ported, there  remains  a  considerable  group  of  cases  which  either  have  been 
shown,  or  may  at  present  be  assumed,  to  be  cases  of  infection  with  different 
species  of  a  single  genus  of  microorganisms  the  chief  characters  of  which 
are  described  below.  To  the  cases  in  this  group  the  terms  pseudotuber- 
culosis, or  streptothrix,  or  cladothrix  infection,  or  atypical  actinomycosis 
have  been  applied.  None  of  these  names  are  satisfactory.  Pseudotuber- 
culosis is  too  indefinite  a  term  and  carries  no  etiological  suggestion  with  it. 
Streptothrix  and  cladothrix  are  generic  terms  that  are  untenable  for  the 
group  of  infecting  microorganisms  in  question,  for  they  are  well  recognized 
generic  names  for  microorganisms  quite  different  from  these.  Atypical 
actinomycosis  is  objectionable,  because  it  leads  to  the  confusion  of  these 
cases  with  actinomycosis  and  because  it  implies  that  the  infection  micro- 
organism is  so  closely  related  to  Actinomyces  bovis  as  to  be  classed  in  the 
same  genus  with  it. 

This  idea  of  the  close  relationship  of  the  infecting  microorganism  in 
these  cases  to  Actinomyces  bovis  is  widely  accepted,  but  the  writer^  has 
shown  that  it  is  erroneous  and  that  Actinomyces  bovis  differs  so  markedly 
from  the  microorganisms  of  this  group  that  it  should  not  be  placed  in  the 
same  genus  with  them. 

It  has  been  pointed  out  that  if  the  name  Actinomyces  be  not  used  for 
these  microorganisms  then  the  only  permissable  generic  term  to  apply  to 
them,  in  accordance  with  the  principles  of  botanical  nomenclature,  is 
Nocardia,^  and  disease  processes   produced  by  them  should  be  called 

^Journal  of  Medical  Research,  1905,  XIII,  349. 

'^De  Toni  et  Trevisan.    Saccardo.    Sylloge  Fungorum,  VIII,  927. 

340 


NOCARDIOSIS,  MYCETOMA,  ETC.  341 

nocardiosis.  In  accordance  with  this  view  these  cases  are  grouped  to- 
gether under  the  name  nocardiosis  and  the  infecting  microorganisms  will 
Be  called  Nocardia  in  this  article. 

The  first  description,  although  an  imperfect  one,  of  a  nocardia  is  that 
of  Cohn,^  who  found  it  in  a  concretion  in  the  lachrymal  duct  and  gave  it 
the  untenable  generic  name  of  Streptothrix.  Tho  first  extensive  study  of 
a  case  of  nocardiosis  was  that  of  Eppinger,^  in  1891. 

Etiology. — The  nocardia,  the  infecting  microorganisms  in  nocard- 
iosis, have  resemblances,  on  the  one  hand,  to  certain  bacteria  in  the 
structure,  thickness,  and  staining  of  their  filaments,  and,  on  the  other 
hand,  to  the  hyphomycetes  or  moulds  in  their  branching,  thread-like  form 
and  in  the  production  of  fine  conidia  or  spore-like  reproductive  elements 
out  of  the  substance  of  the  filaments.  They  differ  from  the  hyphomycetes 
in  that  their  filaments  are  more  slender  and  are  not  tubular  structures  with 
double  contoured  walls,  protoplasmic  contents,  and  transverse  septa.  They 
may  be  regarded  as  representing  a  further  transition  from  the  bacteria 
toward  the  lower  fungi  or  hyphomycetes  than  does  Actinomyces  bovis, 
because  they  have  this  property  of  producing  spore-like  reproductive 
elements  or  conidia,  a  property  not  possessed  by  that  microorganism. 

Most  of  the  known  species  grow  readily  on  the  ordinary  culture  media, 
are  aerobic  and  do  not  require  the  temperature  of  the  body  for  their 
multiplication.  They  grow  in  dense  masses  on  culture  media,  on  which 
the  younger  colonies  may  appear  as  aggregations  of  filaments  radiately 
arranged.  They  are  widely  distributed  in  the  outer  world,  especially  in  the 
air  and  on  grains  and  grasses  as  shown  by  the  work  of  Doria,^  Berestneff,^ 
and  others.  The  various  species  difl^er  chiefly  in  the  color  and  other 
appearances  of  their  growths  on  artificial  culture  media. 

It  is  very  probable  that  the  nocardia,  claimed  to  have  been  isolated 
from  certain  cases  of  inflammatory  lesions  as  well  as  from  certain  cases  of 
typical  actinomycosis,  gained  entrance  to  the  culture  tubes  by  accident  or 
were  secondary  invaders  of  the  lesions.  Among  such  nocardia  are  those 
microorganisms  described  by  Rosenbach,^  Naunyn,^  Almquist,^  Bost- 
roem,^  Vincent,^  and  others.  No.cardia  have  been  observed  in  the  sputum 
of  apparently  healthy  individuals. 

Infection  seems  to  take  place  most  frequently  through  the  respiratory 
tract.  In  three  cases  it  has  occurred  from  wounds.  Malnutrition  and 
chronic  disease  seem  to  predispose  the  individual  to  this  infection  as  to 
others.  Including  four  animal  cases,  there  are  some  twenty  well  authenti- 
cated cases^''  of  infection  with  nocardia  from  which  the  microorganism 

^Beitr.  z.  Biolog.  d.  Pflanzen,  1875,  I,  141. 

^Beitr.  z.  path.  Anat.,  1891,  IX,  276. 

^Ann.  deir  Inst.  d'Igiene  speriment. ,  della  R.  Univ.  di  Roma,  1892,  II,  1G7. 

*Zeitschr.  f.  Hyg.  u.  Infectionskrankh.,  XXIV,  94. 

^Archiv.  f.  Klin.  Chir.,  1887,  XXXVI,  346. 

^Mitth.  a.  d.  Med.  Klinik,  I   Konigsberg,  Leipzig,  1888,  296. 

''  Zeitschr.  f  Hyg.  u.  Infektionskrankh.,  1890,  VIII. 

^  Beitr.  z.  Path.  Anat.  u.  z.  allgem.  Path.,  1890,  IX. 

^Ann.  de  I'lnst.,  Pasteur,  1894,  VIII. 

^° Epp'mgev,  Ref.  Zeigler  Beitr.  z.  path.  Anat.,  1890,  IX.  Dessy,  La  Settimana 
medica  dello  " Sperimentale,"  Firenze,  March  28,  1896,  156.  Aoyma  and  Miya- 
moto, Mii^/i.  a.  d.med.  Facultat  d.  kaiserl.,  japanisch  Univ.  z.  Tokio,  1902,  IV, 
231.  MacCallum,  Centralhl.  f.  Bakteriol.,  I  Abt.,  1902,  XXXI,  529.  Birt  and 
Leishman,  Jour.  Hyg.,  1902.     TroUdeiner,  Zeitschr.  /.  Thiermed.,  1903,  XVII, 


342  DISEASES  DUE  TO  VEGETABLE  PARASITES 

has  been  isolated  and  studied  in  pure  culture.  In  a  smaller  number  of 
cases*  regarded  as  nocardiosis,  culture  experiments  have  not  been 
successful  or  -were  not  attempted. 

The  nocardia  isolated  in  the  cultures  have  shown  sufficient  differences 
among  themselves  to  be  regarded  as  belonging  to  various  species. 

Analysis  of  the  better  studied  cases  shows  that  the  microorganisms  from 
at  least  eleven  of  the  human  cases  and  from  one  case  in  a  dog  were  suffi- 
ciently alike  to  be  considered  as  probably  belonging  to  the  species  first 
described  by  Eppinger,  who  gave  it  the  specific  name  of  "asteroides"  and 
the  untenable  generic  name  of  Cladothrix.  This  species  is  characterized 
by  the  reddisii  color  of  its  growths  on  culture  metUa,  by  not  liquefying 
the  gelatin  and  by  producing  so-called  pseudotuberculosis  in  animals 
inoculated  with  it.  The  lesions  in  these  animals  consist  of  foci  of  sup- 
puration surrounded  in  typical  instances  by  more  or  less  well  developed 
granulation  tissue.  They  may  be  very  extensive  and  widely  disseminated 
throughout  the  body.  A  marked  peculiarity  of  most  of  the  microor- 
ganisms concerned  in  nocardiosis  is  their  resistance  to  decolorization  by 
weak  acids  after  being  stained  by  fuchsin. 

The  wide  distribution  of  the  nocardia  in  the  outer  world  has  already 
been  referred  to  and  it  seems  very  probable,  in  view  of  the  biological 
characters  of  those  that  have  been  isolated  from  pathogenic  processes,  that 
they  likewise  have  a  natural  habitat  outside  of  the  body. 

Special  Pathology. — The  lesions  ascribed  to  the  action  of  nocardia 
are  of  varied  character.  There  is  no  doubt  that  these  microorganisms 
produce  necrosis,  suppuration,  abscesses  and  granulation  tissue  formation 
as  well  as  miliary  focal  lesions  that  are  essentially  suppurative  foci  sur- 
rounded by  more  or  less  granulation  tissue,  but  it  is  not  proven  that 
fibrous  or  calcareous  nodules,  areas  of  caseation  and  tubercles  identical 
in  structure  with  those  of  tuberculosis,  can  be  produced  by  them.  The 
best  evidence  in  favor  of  the  idea  that  lesions,  histologically  identical  with 
those  of  tuberculosis,  may  be  produced  by  them  is  offered  by  Flexner; 
but  the  microorganism  in  his  case  was  not  studied  in  cultures,  and  it  is 
therefore  not  certain  that  it  was  a  nocardia.  The  filaments  of  the  in- 
fecting microorganism  in  nocardiosis  are  scattered  among  the  cells  of  the 
lesions  or  are  loosely  grouped  together,  and  are  not  aggregated  so  as  to 

81.  Horst,  Zeischr.  f  Heilkunde,  Abth.  f.  path.  Anat.,  1903,  XXIV,  157. 
Tuttle,  Med.  &  Surg.,  Rep.  Presbyterian  Hospital,  N.  Y.,  1904,  VI,  147.  Mc- 
Donald. Scot.  Med.  &  Surg.  Jour.,  1904,  XIV,  305-321.  Schabad,  Zeitschr.  f. 
Hyg.,  1904,  XL VII,  41.  Stokes,  Am.  Jour.  Med.  Sci.,  1904,  CXXVIII,  No.  5, 
861.  Memmo,  Quoted  by  RuUman,  Munch,  med.  Wochenschr.,  1898,  No.  29, 
920.  Berestneff,  "Die  Aktinomykose und  ihre  Erreger,"  (Russian),  Inaug.  Diss., 
Moskau,  1897.  Scheele  and  Petruschky,  Deutsch.  med.  Wochenschr.  Vereins 
beilage,  1897,  No.  17, 124.  Sabrazes  et  Riviere,  La  Sem.  Med.,  1895,  383.  Ferre 
and  Farquet,  La  Sem.  Med.,  1895,  3.59.  Nocard,  Ann.  de  I'Inst.  Pasteur,  1888,  II. 
Kruse  and  Pasquale,  Zeistche.  f.  Hyg.,  XVI.  Terni,  Ref.  Centralbl.  f.  Bakteriol, 
1896,  XIX,  160.  Ophtils,  Jour.  Med.  Research,  1904,  VI,  439.  Mayer,  Miinch. 
rmd.  Wochenschr.,  1901,  No.  44.    Saint  Servin,  La  Sem.  Med.,  1895. 

^Flexner,  Jour.  Uxper.  Med.,  1898,  III.  Warthin  and  Olney,  Am.  Jour.  Med. 
Sci.,  1903,  Oct.,  637.  Buchholz,  Zeitschr.  f.  Hyg.,  1897,  XXIV.  Ohlmacher, 
Clevelav''  Med.  Jour.,  1902,  29.  RuUman,  Miinch.  med.  Wochenschr.,  1898, 
No.  23,  920.  Ucke,  St.  Petersburg  med.  Wochenschr.,  1901,  XVIII,  87.  Rabe, 
Berlin  Thier.  Wochenschr.,  1888,  65.  Butterfiekl,  Jour.  Infect.  Diseases,  1905, 
II.  421„   Musser  and  Gwyn,  Trans.  Assoc.  American  Physicians,  1901^  XVI,  208. 


NOCARDIOSIS,  MYCETOMA,  ETC.  343 

form  thecompact  masses  orradiate  structures  or  granules  that  are  charac- 
teristic of  actinomycosis. 

The  process  in  most  of  the  cases  has  been  situated  in  the  lung  or  has 
originated  there.  In  the  lungs  jjneumonia,  abscesses,  gangrene,  in- 
durative processes,  fibrous  nodules,  cavities,  caseous  pneumonia,  miliary 
tubercles,  and  other  lesions  like  those  of  tuberculosis,  have  been  described. 
As  has  been  already  pointed  out,  it  is  uncertain  whether  these  lesions,  like 
those  of  tuberculosis,  are  due  to  nocardia  rather  than  to  the  tubercle 
bacillus.  In  two  cases  the  reporters  considered  tuberculosis  to  be  coin- 
cident. 

Metastatic  lesions  have  been  observed  in  nine  cases,  among  which  the 
brain,  myocardium,  lung,  kidney,  peritoneum,  lymphatic  glands  and 
subcutaneous  tissue  have  been  involved.  The  primary  process  was  in  the 
lung  in  five  of  these  cases;  in  a  bronchial  gland  in  one  or  two;  in  the 
region  of  the  knee-joint  in  one;  and  was  unknown  in  one.  In  six  cases 
there  were  one  or  more  abscesses  in  the  brain.  In  two  cases  there  was 
empyema  and  pericarditis.  One  case  was  of  the  nature  of  a  subacute 
purulent  peritonitis.  Conjunctivitis  and  subcutaneous  abscess  have  also 
been  ascribed  to  infection  with  nocardia.  In  the  animal  cases  there  was 
suppuration  in  various  regions. 

Symptoms. — The  symptoms,  as  far  as  has  been  ascertained  from  the 
reports,  have  been  m  general  those  of  suppuration  or  inflammation  and 
have  varied  with  the  location  and  extent  of  the  process.  The  clinical 
course  was  either  acute  or  chronic. 

In  most  of  the  pulmonary  cases  the  signs  and  symptoms  have  been  those 
of  pulmonary  tuberculosis  or  of  pneumonia  and  abscess.  Cough,  fever, 
pain,  and  emaciation  have  been  observed.  In  two  cases  there  was 
haemoptysis.  Signs  of  empyema  were  present  in  two  cases,  in  one  of  which 
there  was  an  inflammatory  fluctuating  tumor  on  the  external  aspect  of  the 
chest  wall.  In  one  of  these  cases  also,  signs  of  pericarditis  were  made  out. 
In  two  cases  there  were  multiple  metastatic  abscesses  in  the  subcutaneous 
tissue  with  symptoms  of  pyaemia.  In  one  of  these  infection  with  the 
bacillus  of  glanders  was  suspected. 

In  a  few  cases  the  process  has  been  essentially  •  of  the  character  of  a 
terminal  infection.  In  three  of  the  cases  in  which  there  was  abscess  for- 
mation in  the  brain,  there  were  symptoms  of  tumor  and  abscess  in  two, 
while  m  one  the  diagnosis  of  tuberculous  meningitis  was  made.  In  the 
case  of  subacute  peritonitis  which  followed  gastrotomy,  the  prominent 
symptom  was  diarrhoea. 

Diagnosis. — Nocardiosis  may  be  confused  with  a  variety  of  diseases, 
but  especially  with  pulmonary  tuberculosis  and  actinomycosis.  In  cases 
with  multiple  abscess  formation  in  the  subcutaneous  tissue,  the  disease 
may  simulate  infection  with  the  bacillus  of  glanders.  The  diagnosis 
depends  upon  finding  the  special  microorganism  in  the  sputum  or  in  the 
lesions.  It  occurs  typically  in  the  form  of  branched  filaments  of  the 
character  above  described,  which  resist  decolorization  by  dilute  acids  after 
having  been  stained  with  fuchsin.  Fragments  of  the  nocardia  may  be 
mistaken  for  tubercle  bacilli,  especially  for  the  rare  branched  forms  of 
that  microorganism. 

The  nocardia  may  be  distinguished  from  the  tubercle  bacillus  by  their 
longer  filaments  and  more  marked  branching  and  also  by  their  occurrence 


344  DISEASES  DUE  TO  VEGETABLE  PARASITES 

in  loose  aggregations.  A  further  distinction  lies  in  the  fact  tliat  most  of  tht 
nocardia  after  staining  with  fuchsin  do  not  resist  decolorization  with  acids 
as  strongly  as  does  the  tubercle  bacillus,  and  are  decolorized  by  alcohol, 
whereas  the  tubercle  bacillus  is  not.  Probably  the  best  way  of  finding 
nocardia  in  sinituin  or  pus  is  by  the  microscopic  examination  of  smear 
pre])arations  stained  by  Gabbet's  method,  for  this  does  not  employ  alcohol 
ancl  is  not  a  very  vigorous  discolorizer. 

The  nocardia  are  distinguished  from  the  microorganism  of  actinomy- 
cosis in  that  they  do  not  occur  in  the  inflammatory  fluids  or  lesions  in  man 
in  the  compact  masses  nor  form  the  radiate  club-bearing  structures  or 
granules  so  characteristic  of  actinomycosis.  Moreover,  the  microor- 
ganism of  actinomycosis  does  not  resist  decolorization  by  dilute  acids  after 
having  been  stained  with  fuchsin.  Localization  of  the  lesions  about  the 
mouth  and  jaws,  so  common  in  actinomycotis,  is  unknown  in  nocardiosis. 

Prognosis. — All  of  the  cases  in  which  the  lung  or  brain  was  involved 
died  except  two,  which  got  very  much  better  or  recovered.  These  two 
cases  were  among  the  less  well  authenticated  ones. 

Treatment. — No  specific  is  known  and  the  treatment  will  vary  Avith  the 
character  of  the  process  and  the  situation  of  the  lesions.  In  cases  re- 
sembling pulmonary  tuberculosis  the  treatment  should  be  essentially  the 
same  as  for  that  disease.  Empyema  and  abscesses  should  be  treated 
according  to  the  usual  surgical  principles. 


MYCETOMA  (MADURA  FOOT). 

Definition. — Mycetoma  is  a  chronic  infectious  process,  most  commonly 
affecting  the  foot,  the  prominent  features  of  which  are  multiple  sinuses 
and  enlargement  and  distortion  of  the  parts.  Carter^  first  assigned  to  the 
disease  a  separate  identity  and  a  special  parasitic  causation.  He  gave  it 
the  name  Mycetoma. 

Etiology. — The  affection  is  characterized  by  the  presence,  in  the  dis- 
eased tissue  and  in  the  discharges  from  sinuses,  of  peculiar  granules  usually 
not  more  than  1  mm.  in  diameter  but  sometimes  larger.  In  certain 
cases  these  granules  are  of  a  black  color,  of  irregular  shape,  hard,  rather 
brittle,  and,  in  general,  resemble  grains  of  gunpowder  In  other  cases 
the  granules  are  whitish,  grayish  or  yellowish  in  color,  of  a  soft  or  cheesy 
consistence,  and  have  been  compared  to  fish  roe  in  appearance.  A  few 
cases  are  also  recorded  in  which  the  granules  were  of  a  red  color. 

According  to  the  observations  of  Carter  and  others,  the  granules  are 
composed  of  aggregations  of  vegetable  parasites  and  their  products.  On 
account  of  their  relation  to  the  lesions  the  granules  are  ]:»resumed  to  be 
the  infectious  cause  of  the  disease  and  not  merely  secondary  invaders  of 
the  lesions.  They  have  not  been  shown  by  experimental  inoculation  to 
be  capable  of  producing  the  disease.  On  account  of  the  fact  that  at  least 
tw^o  very  different  kinds  of  granules  are  foimd  associated  with  the  lesions, 
two  varieties  or  forms  of  the  disease  are  recognized:  the  "melanoid"  or 
black  variety,  in  which  the  granules  are  black,  and  the  "ochroid"  or 
pale  veriety,  in  which  the  granules  are  white  to  yellow  in  color. 

^A.  V.  Carter:  On  Mycetoma  or  the  Fungus  Disease  of  India,  London,  1874. 


NOCARDIOSIS,  MYCETOMA,  ETC.  345 

The  ochroid  granules,  as  shown  by  the  studies  of  Kanthack^  and 
Bishop,^  are  apparently  identieal  with  the  granules  of  actinomyees; 
and  at  the  present  time  the  ochroid  or  pale  form  of  mycetoma  must  be 
regarded  as  actinomycosis  of  the  part.  Boyce^  and  Vincent^  claim  to 
have  obtained  cultures  of  the  specific  microorganism  from  two  cases  of 
this  form  of  the  disease,  but  their  microorganisms  are  widely  difl'erent 
from  each  other  and  neither  of  them  was  proved  to  be  identical  with  the 
microorganisms  in  the  lesions  and  not  a  secondary  invader  or  a  con- 
tamination of  the  cultures. 

The  black  or  malanoid  granules,  on  the  other  hand,  as  shown  by  the 
studies  of  Bristowe,^  Carter,  Wright,**  and  others,  are  of  entirely  different 
character.  They  consist  of  a  mass  of  hyaline  refringent,  brown-colored, 
brittle  substance,  forming  a  matrix  in  which  are  imbedded  a  tangle  of 
fungus  tubules  or  hyphte  with  doubly  contoured  walls  and  transverse 
septa.  This  fungus  of  the  melanoid  form  of  the  disease  has  been  isolated 
in  cultures  by  the  writer  from  a  single  case.  This  is  very  probably  the  only 
instance  in  which  its  cultivation  has  been  accomplished,  for  Carter's 
claims  that  he  had  grown  the  fungus  in  cultures  do  not  bear  critical  ex- 
amination. The  writer  obtained  a  growth  of  the  fungus  from  about 
twenty-five  out  of  approximately  sixty-five  of  the  black  granules  experi- 
mented with  in  this  case. 

The  mode  of  entrance  of  the  parasite  into  the  tissues  is  not  known. 
The  disease  is  endemic  in  certain  districts  in  India,  especially  in  Madura, 
and  has  been  observed  in  Africa,  Italy,  and  other  tropical  or  subtropical 
countries.  It  seeins  to  be  acquired  in  the  country  districts  and  not  in 
towns.  In  America  it  is  of  very  rare  occurrence,  only  four  undoubted 
cases  having  been  reported,  and  three  of  these  were  of  the  pale  variety  of 
the  disease,  which,  as  has  been  pointed  out  above,  is  to  be  regarded  as 
actinomycosis. 

Special  Pathology. — The  process  consists  essentially  in  abscess  and 
sinus  formation,  associated  with  extensive  development  of  granulation 
and  connective  tissue.  The  granules  are  found  in  the  abscesses  or  sinuses 
and  sometimes  they  may  be  found  surrounded  by  epithelioid  cells  and 
giant  cells.  Giant  cells  may  be  frequent  in  the  granulation  tissue.  The 
inflammatory  tissue  may  very  extensively  replace  the  muscles  and  bones 
of  the  affected  part,  the  tendons  and  fascia  most  resisting  replacement. 
In  advanced  cases  the  granules  may  exist  in  sinus  cavities  in  masses.  The 
foot  is  most  commonly  affected,  but  occasionally  the  hand  and,  rarely, 
other  parts.     The  internal  organs  are  never  involved. 

Symptoms. — The  process  usually  begins  as  a  firm  nodular  swelling 
in  the  sole  of  the  foot,  which  is  followed  by  others  in  the  neighborhood  or 
elsewhere.  These  break  down  and  become  the  seat  of  the  openings  of 
sinuses  which  rarely  heal.  By  extension  of  the  process  the  foot  increases 
in  breadth  and  thickness  and  may  attain  a  considerable  bulk  and  weight, 
eventually  becoming  very  burdensome  to  the  patient.    The  toes  become 

^Journal  of  Pathology  and  Bacteriology ,  1893,  I,  140. 

^Hyde,  Senn  and  Bishop:  Journal  of  Cutaneous  and  Genito-urinary  Diseases, 
XIV,  1.  1896, 

^Hyg.  Rundschau,  1894,  IV,  529. 
*Ann.  de  VInst.  Pasteur,  1894,  VIII,  129. 
^Transactions  of  the  Pathological  Society,  London,  1871. 
^Journal  of  Experimental  Medicine,  1898,  III,  421. 


846  DISEASES  DUE  TO  VEGETABLE  PARASITES 

more  or  less  displaced  and  deformed.  The  orifices  of  sinuses  may 
be  obscured  by  masses  of  granulation  tissue.  The  discharges  from  the 
sinuses  are  oily,  mucopurulent  and  may  have  a  very  bad  odor.  They  con- 
tain the  characteristic  granules  above  described.  Severe  pain  is  rare.  In 
advanced  cases  the  great  weight  of  the  foot  prevents  its  use  in  walking, 
and  atrophy  of  the  leg  muscles  occurs. 

Diagnosis. — The  disease  may  be  mistaken  for  syphilis  or  for  sarcoma. 
The  diagnosis  depends  upon  finding  the  granules  and  upon  recognizing 
their  characteristic  structure.  To  cases  of  the  pale  or  ochroid  variety, 
what  has  been  written  upon  the  subject  of  the  diagnosis  of  actinomycosis 
applies.  The  fungus  elements  in  the  black  granules  are  best  demonstrated 
by  softening  and  bleaching  the  granules  with  liquor  sodre  chlorati  and 
examining  teased  preparations  of  them  under  the  microscope.  In  such 
preparations  the  fungus  elements  should  be  clearly  visible  as  septate, 
tubular,  cylindrical  or  spherical  structures  with  doubly  contoured  walls. 

Prognosis. — The  process  is  very  chronic  and  may  last  for  years.  Spon- 
taneous recovery  never  occurs.  Death  may  follow  from  secondary  in- 
fection with  pyogenic  microorganisms  or  may  be  due  to  exhaustion 
incident  to  the  burden  of  carrying  about  the  greatly  enlarged  and  heavy, 
diseased  foot. 

Treatment. — The  internal  administration  of  iodide  of  potassium  is  said 
to  have  no  favorable  effect  upon  the  process.  The  only  effective  treat- 
ment is  excision  of  the  lesions  or  amputation. 


OIDIOMYCOSIS. 

Definition. — A  granulomatous  and  suppurative  process  affecting  the 
skin  and  internal  organs.  It  is  called  dermatitis  coccidioides,  protozoic 
dermatitis,  blastomycetic  dermatitis,  psorospermiasis,  coccidioidal  granu- 
loma, blastomycosis,  and  saccharomycosis.  Apparently  about  forty-five 
cases  have  been  reported.  It  is  probable  that  some  cases  of  this  disease 
now  go  unrecognized  and  are  classed  under  tuberculosis.  The  first 
cases  were  described  by  Wernicke,^  Busse,^  and  Gilchrist  and  Stokes.^ 
A  good  description  of  the  cutaneous  forms  of  the  disease  is  given  by 
F.  H.  Montgomery.* 

Etiology. — The  disease  is  due  to  infection  with  certain  fungi  wdiich 
although  showing  various  differences  in  biological  characters  among 
themselves  may,  according  to  Ricketts,^  be  classed  asspecies  of  thegenus 
Oidium.  In  the  lesions  the  microorganisms  appear  chiefly  as  spherical 
bodies,  each  consisting  of  a  protoplasmic  mass  enclosed  in  a  doubly  con- 
toured hyaline  capsule,  which  may  be  provided  wdth  prickles  or  spines  in 
some  instances.  The  diameter  of  the  bodies  varies  up  to  thirty  microns 
or  more.  In  the  protoplasm,  vacuoles,  granules  and  various  markings 
may  be  seen,  but  no  nucleus  is  apparent.  The  mode  of  proliferation  in 
the  lesions  in  the  majority  of  cases  is  by  gemmation  or  budding.    The 

^Centralbl.  f.  Bakteriol,  1892,  XII,  859. 

^Centralbl.  f.  Bakteriol,  1894,  XVI,  175. 

^Bulletin  of  the  Johns  Hopkins  Hospital,  1896,  VII,  129. 

^Journal  of  the  Arfierican  Medical  Association,  June  7,  1902. 

"Journal  of  Medical  Research,  1901,  VI. 


NOCARDIOSIS,  MYCETOMA,  ETC.  347 

microorganisms  in  some  cases  have  great  rcscmljlance  to  yeast  fungi  or 
saccharomyces.  Busse  regarded  the  microorganism  in  his  case  as  a 
yeast  and  called  the  })rocess  sacchromycosis.  In  a  minority  of  the  known 
cases,  proliferation  of  the  microorganisms  in  the  lesions  is  not  by  bud- 
ding but  by  a  process  which  is  regarded  as  one  of  sporulation,  the  pro- 
toplasm of  the  larger  forms  segmenting  into  many  small  spherical  bodies 
Each  of  these  small  spherical  bodies  acquires  a  capsule  and,  being  set 
free  by  the  rupture  of  the  capsule  of  the  mother  cell,  develops  into  the 
adult  parasite. 

Wernicke,  and  Rixford  and  Gilchrist/  first  described  cases  with  these 
sporulating  forms  in  the  lesions  and  they  regarded  tho  microorganisms  as 
protozoa;  but,  later,  Ophiils  and  Moffitt^  showed  that  they  are  stages 
in  the  life-cycle  of  a  mould  fungus.  The  microorganisms  may  be  few  or 
very  numerous  in  the  lesions.  In  cultures  the  microorganisms  show  con- 
siderable variation  in  biological  character. 

According  to  Ricketts,  the  microorganisms  obtained  from  various 
cases  may  be  divided  into  three  groups  according  to  their  biological  char- 
acters as  shown  in  the  cultures  as  follows: 

1.  Those  growing  chiefly  as  spherical  or  oval  budding  cells  and  re- 
sembling yeasts,  but  capable  of  producing  mycelium. 

2.  Those  forming  submerged  mycelium,  which  breaks  up  into  chains  of 
spores,  while  proliferation  by  budding  is  not  a  prominent  feature. 

3.  Those  producing  mycelium  with  fruit-bearing  aerial  hyphse  and  also 
capable  of  multiplying  by  gemmation  or  budding. 

The  microorganisms  of  the  first  and  second  groups  are  capable  of 
producing  fermentation,  while  those  of  the  third  group  are  not.  In 
animals  inoculated  with  cultures  of  some,  but  not  all,  of  these  micro- 
organisms, abscesses,  granulomatous  tumors  and  tubercle-like  nodules 
widely  disseminated  have  been  produced.  In  these  lesions  in  the  animals 
the  microorganisms  exist  in  the  same  form  as  in  the  human  lesions. 

Wolbach,^  working  with  a  microorganism  of  the  type  which  prolifer- 
ates in  the  tissues  by  sporulation,  has  studied  carefully,  in  animals  inocu- 
lated with  pure  cultures,  the  transformation  of  the  hyphee  of  the  cultures 
into  the  characteristic  spherical  bodies  of  the  lesions.  He  finds  that  the 
spherical  bodies  arise  by  the  segments  of  the  hyphae  enlarging  and  assum- 
ing a  spherical  shape,  the  wall  of  the  segment  thus  becoming  the  capsule 
of  the  spherical  body.  In  his  experimental  lesions,  Wolbach  has  also  ob- 
served pointed  and  club-shaped  hyaline  bodies  radiately  arranged  con- 
tinuous with  the  capsules  of  the  microorganisms. 

The  conditions  underlying  infection  in  oidiomycosis  are  not  yet  known. 
There  is  no  definite  relation  between  the  disease  and  the  sex,  age,  occupa- 
tion, nativity,  or  habits  of  the  patients.  Most  of  the  cases  with  so-called 
sporulating  forms  in  the  lesions  have  occurred  in  California.  All  of  the 
cases  except  two  have  been  observed  in  the  United  States.  A  few  cases 
followed  traumatism. 

Special  Pathology. — The  process  usually  consists  in  abscess  forma- 
tion, combined  with  proliferation  of  the  fixed  cells  of  the  infected  region ; 
but  it  may  be  characterized  by  the  formation  of  caseating  aggregations  of 

^  Johns  Hopkins  Hospital  Reports,  1896,  I,  209. 
^Philadelphia  Medical  Journal,  June  30,  1900. 
^Journal  of  Medical  Research,  1904.,  XIII,  53. 


348  DISEASES  DUE  TO  VEGETABLE  PARASITES 

epithelioid  colls  accompanied  by  giant  cells,  thus  simulatino-  the  lesions  of 
tuberculosis.  The  reaction  on  the  part  of  the  tissue  in  some  cases  may  be 
comparatively  slight  and  the  lesions  may  consist  chiefly  of  masses  of  the 
microcirganisms.  jNIultinucleated  giant  cells  containing  the  parasites 
are  jjrominent  features  of  the  lesions.  In  the  skin  there  is,  in  most  cases, 
extensive  hyperplasia  of  the  rete  mucosum,  abscesses  botli  in  the  corium 
and  in  the  rete,  aiid  tubercle-like  aggregations  of  e])ithelial  cells  A\ith 
giant  cells.  The  microscopical  a})])earances  may  simulate  scjuamous- 
cell  carcinoma  or  verrucous  tuberculosis  and  the  microorganism  may  be 
present  in  comparativly  small  numbers.  The  lesions  may  be  limited  to 
the  skin  or  may  involve  also  the  lungs  and  internal  organs.  The  disease 
may  take  origin  in  the  lungs.  The  face  is  most  frequently  the  seat  of 
cutaneous  lesions,  but  the  skin  of  almost  any  region  of  the  body  may  be 
involved. 

The  skin  involvement  may  be  very  extensive.  There  is  but  little  tend- 
ency to  involve  mucous  membranes.  In  the  skin  the  process  begins  usually 
as  a  papule  or  pustule  and  slowly  enlarges  during  the  course  of  months, 
producing  an  elevated  area,  which  may  be  of  large  size,  with  rough,  scabby 
surface  and  enclosing  numbers  of  minute  abscesses.  Later,  ulceration 
occurs,  and  ultimately  there  may  be  cicatrization  and  healing.  In  many 
cases  the  cutaneous  lesions  are  multiple  and  they  may  be  situated  in  wddely 
separated  parts  of  the  body.  Involvement  of  the  lungs,  and  of  other 
organs  and  structures  not  cutaneous,  has  been  observed  in  sixteen  or  more 
cases, ^  in  six  of  which  cutaneous  lesions  were  absent.  Among  these  cases 
in  addition  to  the  lungs  and  skin,  the  pleura,  liver,  kidneys,  spleen,  bones, 
suprarenals,  testicles,  peritoneum,  meninges,  and  various  lymphatic  glands 
have  been  the  seat  of  lesions.  In  the  lungs  the  lesions  have  consisted  of 
abscesses,  miliary  nodules,  bronchopneumonia,  and  areas  of  consolidation. 
The  meninges  w^ere  affected  in  two  cases  and  the  lesions  were  very  similar 
to  those  of  tuberculous  meningitis,  both  grossly  and  microscopically.  In 
the  liver,  spleen,  kidneys,  adrenals,  testicles  and  lymphatic  glands,  the 
lesions  have  consisted  of  small  nodules,  abscesses,  cheesy  or  necrotic  areas 
or  grayish-white  infiltrations.  When  the  process  has  involved  the  bones 
it  has  been  suppurative  and  necrotic  in  character,  sometimes  simulating 
tuberculosis.    Amyloid  infiltration  has  been  observed  in  two  cases. 

Symptoms. — In  most  of  the  cases  the  disease  is  very  chronic,  lasting  for 
years.  The  cutaneous  lesions  in  most  cases  have  periods  of  rapid  pro- 
gression interrupted  by  periods  of  relative  quiescence.  There  may  be 
severe  pain.  In  cases  involving  the  lungs  and  other  internal  organs,  the 
symptoms  and  signs  are  very  similar  to  those  of  pulmonary  tuberculosis. 
Prominent  symptoms  are  cough,  pain,  profuse  expectoration,  and  fever, 
highest  at  night.  Sweating  has  been  observed  in  these  cases.  Eventually 
there  is  emaciation  and  asthenia. 

Diagnosis.- — The  cutaneous  lesions  are  most  likely  to  be  confounded 
with  verrucose  tuberculosis  but  they  may  also  resemble  carcinoma, 
mycosis  fungoides,  as  well  as  certain  forms  of  syphilis  of  the  skin.  The 
diagnosis  can  only  be  made  with  certainty  by  finding  the  microorganism 

'Otis  and  Evans,  Journal  American  Medical  Association,  October  31,  1903, 
1075;  Cleary,  Transactions  of  the  Chicago  Pathological  Society,  1904,  VI,  105. 
Ophiils  Journal  American  Medical  Association,  October  28,  1905,  p.  1291. 
References  to  other  cases  may  be  found  in  the  papers  already  quoted. 


NOCARDIOSIS,  MYCETOMA,  ETC.  349 

in  the  lesions.  This  is  best  done  by  examining  the  cont(;nts  of  tlie  small 
abscesses  or  a  fragment  of  the  tissue  with  the  microscope  and  finding  the 
fungus  cells.  A  drop  of  the  pus  mixed  with  water  or  a  30  per  cent,  sodium 
hydrate  solution  may  be  placed  under  a  coverglass  and  examined  directly 
with  the  microscope  without  staining.  The  cases  in  which  the  lungs  are 
involved  may  be  regarded  as  pulmonary  tuberculosis.  The  diagnosis  in 
such  cases  will  depend  upon  the  recognition  of  the  nature  of  any  co- 
existent cutaneous  lesions,  or  it  might  be  made  by  finding  the  fungus  in  the 
sputum.  Diagnosis  by  means  of  the  examination  of  the  sputum  has  never 
been  made. 

Prognosis. — When  the  disease  is  primary  in  the  skin  it  is  generally 
very  chronic  and  may  persist  for  ten  years  or  longer  Death  from  in- 
volvement of  the  lungs  and  other  internal  organs,  in  cases  in  which  the  skin 
has  been  primarily  the  seat  of  the  lesions,  has  been  observed  in  4  cases. 
As  far  as  is  known  the  cases  in  which  the  lungs  have  been  involved  have 
terminated  fatally. 

As  regards  prognosis  there  is  a  great  difference  between  those  cases  in 
which  the  microorganism  exists  in  the  lesions  in  budding  forms  and  those 
in  which  sporulating  forms  occur.  Thus,  of  the  13  or  14  cases  due  to 
infection  with  the  sporulating  form,  all  came  to  autopsy  except  4;  while 
of  the  30  odd  cases  due  to  infection  with  the  budding  forms,  apparently  but 
4  died  of  oidiomycosis. 

When  confined  to  the  skin  the  disease  yields  to  proper  treatment,  with 
a  varying  amount  of  cicatricial  deformity.  Spontaneous  healing  may 
occur,  at  least  in  some  of  the  lesions.  After  the  lungs  and  other  viscera 
have  become  extensively  involved  the  disease  may  terminate  fatally  within 
a  few  months. 

Treatment. — The  internal  administration  of  iodide  of  potassium  has 
been  employed  with  considerable  success  in  the  treatment  of  oidiomy- 
cosis. It  should  be  given  in  large  doses;  50  to  150  grains  (3.75  to  10  gm.) 
have  been  given  three  times  daily.  This  may  be  combined  with  treatment 
by  the  ic-ray,  especially  in  the  superficial  cases.  Simple  local  antiseptic 
treatment  of  the  cutaneous  lesions  has  not  given  good  results.  It  is,  how- 
ever, of  value  in  relieving  soreness  and  preventing  secondary  infections, 
as  well  as  in  cleansing  the  lesions.  Total  excision  when  the  lesions  are 
limited  gives  the  best  results.  Thorough  curetting  followed  by  cauteri- 
zation has  been  advised.  There  is  some  evidence,  however,  that  curetting 
may  lead  to  the  general  dissemination  of  the  process.  Walker  and  Mont- 
gomery^ recommend  the  actual  cautery  or  free  excision,  with  deep  dis- 
section and  repairs  by  skin-grafts  or  plastic  operations,  in  those  cases  in 
which  the  iodide  of  potassium  fails  to  cure.  They  do  not  recommend 
curetting  Sulphate  of  copper  administered  internally  in  doses  of  from 
one-fourth  to  one  grain  three  times  daily  and  applied  externally  as  a  wash 
in  1  per  cent   solution  has  been  employed  by  Bevan.^ 

Addendum.— Closely  allied  to  the  microorganisms  of  oidiomycosis  is 
the  microorganism  of  parasitic  stomatitis,  or  thrush, — the  Oidium  albi- 
cans. In  a  very  few  cases  this  oidium  has  invaded  internal  organs  and 
has  been  found  in  abscesses  in  the  brain,  spleen,  kidney,  and  lung. 

^  Journal  of  the  American  Medical  Association  April  5,  1902,  867. 
'''Journal  American  Medical  Association,  November  11,  1905,  1492. 


350  DISEASES  DUE  TO  VEGETABLE  PARASITES 

BLASTOMYCOSIS. 

The  ycast-likc  budding  fungi,  associated  with  some  of  the  cases  classed 
above  under  oidiomycosis,  are  called  by  some  writers  blastomycetes;  and, 
therefore,  such  cases  may  be  called  blastomycosis. 

In  addition  to  these  cases,  however,  a  considerable  number  of  obser- 
vations of  the  occurrence  of  yeast-like  fungi  in  a  variety  of  pathological 
conditions  both  in  man  and  animals  arc  on  record.  Of  these,  there  are 
only  two  isolated  cases  in  man  that  seem  worthy  of  mention.  They  are  of 
a  very  different  character  from  the  cases  grouped  under  oidiomycosis  and, 
therefore,  may  be  considered  under  blastomycosis.  One  of  these  cases* 
presented  myxomatous  tumors  beneath  the  skin  in  several  places.  Histo- 
logically, the  tumors  resembled  myxo-sarcoma  and  contained  the  fungi  in 
large  numbers.  In  the  other  case^  sarcoma-like  tumors  involved  the 
omentum  and  mesentery,  and  there  was  chylous  ascites.  In  the  ascitic 
fluid  a  yeast  or  blastomyces  was  found  but  in  the  tumors  it  was  not  satis- 
factorily demonstrated. 

In  animals,  several  infectious  processes  are  ascribed  to  blastomycetes. 
The  most  important  of  these  is  a  suppiu'ative  disease  in  horses,  resembling 
farcy,  characterized  by  chronic  inflammation  of  lymphatics  and  lymphatic 
glands  in  Avhich  there  is  proliferation  and  nodular  thickening  followed  by 
purulent  softening.  The  upper  air  passages  are  also  involved  in  the 
process. 

PULMONARY  ASPERGILLOSIS. 

Definition. — A  destructive  inflammatory  process  affecting  the  lungs, 
due  to  infection  with  one  or  more  species  of  fungus  of  the  genus  Asper- 
gillus. The  first  observation  of  the  occurrence  of  a  fungus  that  was 
probably  an  aspergillus,  in  a  human  lung,  was  made  by  Bennett,  in  1842; 
but  the  first  scientific  description  of  cases  with  an  exact  determination  of 
the  identity  of  the  fungus  Avas  by  Virchow,  in  1856. 

Etiology. — The  disease  is  due  to  infection  with  the  spores  of  the  mic- 
roorganism, and  the  species  fumigatus  is  probably  the  only  one  concerned. 
The  spores  gain  entrance  to  the  lung  through  the  respiratory  tract.  The 
Aspergillus  fumigatus  is  a  true  fungus  belonging  to  the  family  Peris- 
poreacea.  In  cultures  it  grows  in  the  foi'm  of  a  mould  consisting  of  a  thick 
felt-work  of  septate  tubular  hyph?e,  a  few  micra  in  diameter,  some  of  which 
grow  upward  into  the  air  and  produce  masses  of  spores  at  their  free  ex- 
tremities. The  spores  are  spherical,  2.5  or  3  5  micra  in  diameter  and  are 
easily  transported  through  the  air.  The  various  species  of  aspergillus 
are  common  in  the  outer  world  and  the  spores  are  widely  distributed  on 
vegetable  material  of  all  kinds. 

The  Aspergillus  fumigatus  has  been  found  as  a  harmless  parasite  in 
the  auditory  canal,  tympanum,  nose,  mouth,  maxillary  sinuses,  throat, 
respiratory  passages,  eyes,  and  genitalia.  Sometimes  it  is  found  in  an 
inflammatory  condition  of  the  external  auditory  canal,  but  the  inflam- 
matory process  in  these  cases  is  probably  due,  in  part  at  least,  to  the  action 

1  Curtis,  Ann.  d.  I'lnst.  Pasteur,  1896,  X,    449. 

2  Corselli  and  Frisco,  Centralbl.  /.  Bakteriol.,  1895,  XVIII,  368. 


NOCARDIOSIS,  MYCETOMA,  ETC.  351 

of  pyogenic  bacteria.  It  is  said  to  be  capable  of  causing  keratosis,  derma- 
titis, a  peculiar  affection  of  the  nails,  rhinitis,  and  pliaryngitis. 

In  various  birds,  and  in  cattle,  horses,  and  dogs,  it  may  be  the  cause  of 
an  inflammatory  process  more  or  less  resembling  tuberculosis  in  which 
the  lesions  are  situated  chiefly  in  the  lungs.  In  birds,  the  liver,  the  kid- 
neys, and  the  air  sacs  may  also  be  infected  and  it  may  produce  a  pseudo- 
diphtheritic  condition  of  the  mouth  and  air  passages.  The  intravenous 
inoculation  of  birds  and  various  animals  with  spores  may  produce  death 
within  a  few  days.  The  lesions  produced  resemble  grossly  those  of  tuber- 
culosis. Histologically,  they  consist  of  foci  of  necrosis,  enclosing  the 
microorganisms,  together  with  more  or  less  infiltration  with  inflammatory 
cells.  Infection  may  be  produced  experimentally  by  way  of  the  respiratory 
tract  in  birds,  and  rabbits  may  be  infected  by  feeding. 

Most  of  the  cases  of  pulmonary  aspergillosis  in  man  may  be  regarded 
as  instances  of  secondary  infection  in  lungs  already  diseased  by  tuber- 
culosis or  other  processes,  and  some  have  been  mere  terminal  infections. 
But  little  clinical  importance  was  attached  to  pulmonary  aspergillosis 
until  the  observations  of  Dieulafoy,  Chantemesse,  and  Widal,^  published 
in  1890,  and  of  Renon,^  published  in  1897,  gave  good  grounds  for  believ- 
ing that  it  could  exist  as  a  primary  disease.  These  writers  claimed  that 
primary  pulmonary  aspergillosis  was  frequent  among  the  so-called  pigeon 
feeders  and  hair  sorters  of  Paris.  The  pigeon  feeders  are  accustomed  to 
feed  the  pigeons  from  their  own  mouths  with  a  mixture  of  millet  and  vetch 
seeds  in  water.  They  are  supposed  to  acquire  the  disease  either  from 
these  seeds  or  from  aspergillosis  in  the  birds.  The  hair  sorters  work  in  an 
atmosphere  charged  with  the  dust  of  rye  flour,  which  they  use  in  consider- 
able quantities  to  free  the  hair  from  grease.  Birds  kept  in  this  atmosphere 
died  in  two  or  three  days,  from  aspergillosis.  The  spores  of  the  asper- 
gillus  are  in  the  rye  flour  used  and  they  gain  entrance  to  the  lungs  directly 
from  the  air. 

Important  contributions  to  the  subject  have  been  made  by  Saxer.^ 
Good  general  articles  upon  the  disease  have  been  written  by  Rolleston* 
and  Sticker.^ 

Special  Pathology. — The  essential  effects  produced  upon  the  lung 
tissue  by  the  Aspergillus  fumigatus  are  necrosis  and  exudation  of  leuko- 
cytes. The  typical  appearances  are  areas  of  pneumonic  consolidation, 
or  necrosis  with  a  colony  of  the  fungus  in  the  centre.  Where  the  colony 
is  in  close  relation  with  a  bronchus  and  has  had  a  good  supply  of  oxygen, 
spores  are  produced  which  may  be  disseminated  through  the  lung  by 
way  of  the  bronchi  and  give  rise  to  further  extension  of  the  process. 
Eventually  the  necrotic  tissue  may  be  sequestrated  and  expectorated, 
thus  giving  rise  to  cavities  with  gangrenous  walls.  Usually  bacteria  do 
not  take  part  in  the  necrotic  process,  and  purulent  liquefaction  of  the 
necrotic  tissue  does  not  occur.  In  typical  cases  there  is  little  foetor  as- 
sociated with  the  process.  It  would  seem  that  the  fungus  inhibits  the 
invasion  of  the  putrefactive  bacteria  into  the  lesionso 

^  Tenth  International  Medical  Congress,  Berlin,  1890. 

"^Etude  sur  I' Aspergillose  chez  les  Animaux  et  chez  I'Homme,  Paris,   1897. 

^ Pneumonomykosis  Aspergillina,  Jena,  Germany,  1900. 

*Allbutt's  System  of  Medicine,  VI,  257. 

^Nothuagel;  Specielle  Pathologic  und  Therapie,  XIV,  2;  I.  Abth.  156. 


352  DISEASES  DUE  TO  VEGETABLE  PARASITES 

The  niicroorganisni  may  exist  in  the  lesions  in  eolonies,  ^vith  a  form 
suggestive  of  actinomyees;  or  the  hypha^  may  penetrate  the  diseased 
tissue  more  or  less  diffusely.  The  process  in  the  lungs  may  become 
arrested  and  the  fungus  may  disappear.  In  this  case,  extensive  fibroid 
changes  may  result,  or  the  lungs  may  become  the  seat  of  tuberculosis. 
INIetastatic  lesions  are  not  known  to  occur  in  aspergillosis. 

Symptoms. — The  clinical  course  of  the  disease  in  the  primary  cases 
is  either  that  of  chronic  pulmonary  tuberculosis  or  of  chronic  bronchio- 
litis, cm})hysema,  and  chronic  interstitial  pneumonitis.  In  secondary 
cases  symptoms  referable  to  the  infection  with  aspergillus  may  be  ab- 
sent or  of  little  importance. 

Diagnosis. — The  diagnosis  can  only  be  made  by  finding  fragments  of 
the  aspergillus  or  its  spores  in  the  sputum.  Culturc^s  may  be  necessary 
to  establish  the  identity  of  the  microorganism.  The  fragments  of  the 
microorganism  uuiy  be  found  imbedded  in  blood  clots  or  in  masses  of 
necrotic  tissue.  The  sputum  may  resemble  that  of  pulmonary  gangrene 
but  the  characteristic  foetor  of  that  process  is  absent.  Tubercle  bacilli 
may  be  found  coincidently  in  the  sputum. 

It  is  important  that  the  sputum  be  fresh,  for  it  may  be  secondarily  in- 
vaded by  spores  of  the  aspergillus  from  the  air.  Microscopical  exami- 
nation of  the  sputum  for  the  fungus  is  facilitated  by  mixing  a  small 
amount  of  it  with  a  20  ])er  cent,  solution  of  sodium  hydrate  in  order  to 
dissolve  the  cells  and  tissue  fragments  and  render  the  fungus  elements 
more  clearly  visible. 

Prognosis. — When  aspergillosis  is  engrafted  upon  a  chronic  disease  of 
the  lungs,  it  usually  does  not  seem  to  contribute  much  to  the  death  of  the 
individual.  In  primary  cases  the  prognosis  is  not  so  bad  as  in  pulmonary 
tuberculosis,  but  it  is  to  be  borne  in  mind  that  even  if  the  aspergillosis  is 
arrested  and  disappears,  the  permanent  injury  to  the  lungs  may  lead  to 
eventual  death  or  may  be  followed  by  pulmonary  tuberculosis.  Cases 
with  a  clinical  course  resembling  emphysema  and  chronic  bronchiolitis 
seem  to  have  a  worse  prognosis  than  those  resembling  pulmonary  tuber- 
culosis. 

Treatment. — In  the  primary  cases  it  is  of  the  utmost  importance  that 
the  patient  avoid  breathing  in  a  dust  laden  atmosphere,  or  contact  with 
dry  grains  and  vegetable  material.  The  main  reliance  should  be  placed 
upon  fresh  air,  good  food,  and  tonics.  The  internal  administration  of 
iodide  of  potassium  or  of  arsenic  has  been  advised.  In  the  secondary 
form  the  treatment  should  be  that  of  the  underlying  disease. 


MYCOSIS  MUCORINA. 

There  is  only  one  case  on  record  of  general  infection  with  fungi  of  the 
genus  mucor.  This  was  the  case  reported  by  Paltauf  in  which  there  was 
found  at  autopsy  ulcerative  enteritis,  pneumonia,  phlegmon  of  the  phar- 
ynx, and  multiple  abscesses  in  the  brain.  In  the  lesions  a  mucor  was  found. 

The  mucors  are  moulds,  a  typical  example  of  which  is  the  common 
bread  mould.  Their  spores,  when  injected  into  the  circulation  of  certain 
animals,  produce  effects  similar  to  ihose  produced  by  the  spores  of  asper- 
gillus. 


PART  VI. 
DISEASES  CAUSED  BY  PROTOZOA. 


CHAPTER    XVII. 

THE  PROTOZOA. 

By  GARY  N.  CALKINS,  Ph.  D. 

The  progress  made  during  the  last  few  years  in  the  study  of  pathogenic 
protozoa  justifies  us  in  expecting  that  discoveries  and  advances  v\^ill  ulti- 
mately place  the  subject  of  protozoan  pathology  upon  a  sound  scientific 
basis.  So  few  malignant  forms  have  as  yet  been  worked  out,  however, 
that  we  are  still  constrained  to  seek  analogies  in  rather  distantly  related 
non-parasitic  types.  Fortunately  we  have  here  a  wide  realm  of  facts 
which  have  been  accumulated  during  more  than  two  hundred  years  of 
study  upon  these  unicellular  forms;  facts  which  have  been  collected  and 
grouped  into  biological  laws  which  we  believe  are  applicable  to  all  forms, 
parasitic  and  pathogenic,  as  well  as  harmless  types. 

The  protozoa  are  unicellular  animal  organisms,  which  reproduce  by 
division  or  spore-formation.  They  invariably  have  nuclear  material, 
usually  in  the  form  of  a  definite  nucleus,  but  occasionally  scattered 
throughout  the  cell.  They  may  live  alone  or  associated  with  sister-cells 
in  colonies  of  varied  form,  size,  and  complexity.  They  have  two  well- 
defined  phases,  one  of  vegetative  activity,  the  other  of  quiescence;  during 
the  latter  the  organisms  are  protected  by  resistant  secretions,  termed 
cysts. 

Protozoa  are  organisms  of  a  different  type  from  the  bacteria  with  which 
they  are  often  compared.  The  difference  is  not  entirely  covered  by  the 
usual  statement  that  bacteria  are  plants  while  protozoa  are  animals,  for 
it  is  universally  agreed  that  there  is  no  hard  and  fast  line  between  the  two, 
but  a  distinction  is  rather  to  be  sought  in  the  life-cycle  involving  the  alter- 
nation of  sexual  and  asexual  phases.  The  protozoa  must  be  recognized 
as  organisms  of  a  higher  grade  than  the  bacteria,  with  more  varied  con- 
ditions of  life,  greater  complexity  of  functions,  and  probably  with  a  more 
variable  vitality.  Strictly  speaking  there  is  no  one  type  of  protozoa,  the 
thousands  of  species  which  have  been  named  and  described  being  grouped 
by  zoologists  into  four  great  divisions,  sarcodina,  mastigophora,  infusoria 

and  sporozoa. 

23  353 


354  DISEASES  CAUSED  BY  PROTOZOA 

The  sarcodina,  including  about  5,500  known  and  described  species,  are 
characterized  by  changeable  protoplasmic  j)rocesses,  called  ])seudopo- 
dia.  The  great  majority  are  marine  or  salt  -water  forms  antl  have  played 
an  important  part  in  the  formation  of  the  earth's  crust  through  the  deposi- 
tion of  their  calcareous  or  silicious  shells  and  skeletons. 

The  masiujo'phora,  including  those  forms  which  move  by  one  or  a  few 
undulating  processes  called  flagella,  are  the  closest  protozoan  allies  to  the 
bacteria,  and  also,  through  their  colonial  forms,  to  the  metazoa.  Numeri- 
cally they  are  much  less  important  than  the  preceding  class,  having  less 
than  500  species,  but  economically  they  are  rapidly  assuming  a  first  im- 
portance, and  diseases  like  trypanosomiasis  in  man  and  domestic  animals, 
and  syphilis,  are  due  to  flagellates. 

The  injusoria  arc  characterized  by  numerous  fine  cilia,  distinguished 
from  flagella  by  their  greater  number,  shorter  length  and  sweej)ing  stroke. 
The  class  comprises  the  most  highly  dift'erentiated  types  of  protozoa  and 
includes  about  600  or  700  species,  among  which  are  several  families  of 
highly  modified  infusoria  in  which  the  cilia  are  replaced  in  the  adult  by 
suctorial  tentacles  (suctoria).  So  far  as  known,  these  higher  types  are 
never  pathogenic. 

The  sporozoa,  finally,  have  no  motile  organs  and  are  invariably  para- 
sitic. Their  name  comes  from  the  characteristic  method  of  reproduction, 
by  sporulation.  This  group,  more  than  any  of  the  others,  has  a  practical 
interest  inasmuch  as  a  number  of  diseases  in  man,  as  well  as  in  the  lower 
animals,  can  be  traced  to  them.  It  is  not  particularly  rich  in  species, 
about  250  to  300  being  known. 

Were  we  to  select  a  single  cause  for  the  origin  of  the  many  variations  of 
structure  in  protozoa,  it  might  well  be  the  adaptations  brought  about  by 
the  various  methods  of  food-getting  due  to  the  varied  conditions  of  life. 
Many,  like  amoeba  and  its  allies,  take  only  living  food  which  is  captured 
by  the  pseudopodia  and  digested  in  internal  cavities  termed  gastric 
vacuoles;  others,  like  some  mastigophora  and  infusoria,  capture  their 
prey  by  whirlpool  currents  caused  by  flagella  or  cilia;  some,  like  certain 
ciliates,  capture  it  by  specialized  harpooning  organs,  the  trichocysts; 
others,  like  certain  flagellates  and  sporozoa,  have  no  food-procuring 
organs,  but  (like  bacteria)  living  in  a  nutrient  medium,  absorb  it  directly 
without  gastric  digestion;  still  others,  like  suctoria,  procure  it  through 
special  sucking  tentacles,  and  others,  finally,  like  the  phytoflagellates, 
manufacture  their  food  through  the  agency  of  chlorophyl. 

Although  many  protozoa  are  parasitic — one  group,  the  sporozoa,  in- 
variably so— they  form  a  small  minority  in  the  total  number  of  protozoa. 
Some  of  these  parasites  are  comparatively  harmless  (gregarines) ;  others, 
like  the  pebrine  organisms  of  silk  worms,  or  epithelial-cell  parasites  of 
various  animals,  are  extremely  harmful.  The  majority  are  restricted  to 
a  particular  organ  or  tissue;  i.  c,  are  limited  to  a  particular  kind  of  food; 
thus  the  organisms  of  smallpox  and  of  scarlet  fever  thrive  in  skin  cells,  the 
organisms  of  malaria  and  of  trypanosomiasis,  of  Texas  fever  and  east 
coast  fever,  etc.,  in  the  blood;  coccidia,  in  epithelial  cells,  eimeria  sala- 
mandree  and  cyclospora  karyolytica,  in  cell  nuclei,  and  myxosporidia  and 
sarcosporidia  in  muscle  cells.  It  is  not  improbable  that  this  apparent 
selection  is  due  to  chemical  or  physical  actions  which  the  organisms  have 
no  power  to  control,  any  more  than  some  free-living  forms  have  power  to 


THE  PROTOZOA  355 

control  the  selection  of  a  certain  kind  of  food  from  abundance  of  different 
kinds.  For  example,  actinobolus  radians,  found  in  pond  water,  gives  no 
reaction  to  the  impact  of  hundreds  of  minute  creatures  bumping  against 
it,  until  a  particular  form,  halteria  grandinella,  approaches,  when  tri- 
chocyst-bearing  tentacles  are  shot  out,  paralyzing  the  halteria,  which  is 
then  swallowed.  This  may  be  explained  as  a  chemical  or  physical  action 
which  neither  organism  apparently,  has  the  power  to  regulate. 

The  protozoa  have  the  usual  physiological  animal  activities;  proteids 
are  digested  through  the  agency  of  a  mineral  acid,  and  undigested  food  is 
voided,  in  many  cases  through  definite  and  permanent  anal  openings. 
The  waste  products  of  protoplasmic  combustion  are  thrown  oif  in  many 
cases  by  definite  organs,  the  contractile  vacuoles,  although  more  often 
by  osmosis.  They  respond  in  varying  degrees  to  stimuli — some  manifest- 
ing complex  motor  reactions,  as  definite  in  purpose  apparently  as  any  reflex 
action,  others  responding  sluggishly.  Finally,  in  self-reproduction,  the 
protozoa  are  exceeded  in  rapidity  only  by  bacteria,  and  every  conceiva- 
ble mode  of  reproduction  is  met  with  from  slow,  equal,  binary  fission,  to 
prolific  multiple  fragmentation  The  processes  of  reproduction  are 
governed  directly  by  the  food  supply,  and  indirectly  by  the  condition  of 
that  complex  of  functional  activities  which  will  be  spoken  of  subsequently 
as  vitality,  this  varying  with  the  different  phases  of  the  life-cycle.  The 
ordinary  methods  of  reproduction  are  simple  or  binary  division,  budding 
or  gemmule-formation,  and  spore-formation. 

Methods  of  Reproduction. — Under  proper  physical  and  vital  con- 
ditions, multiplication  of  the  protozoa  is  very  rapid.  If  certain  salts  are 
present,  protozoa  in  a  short  time  may  develop  in  the  purest  drinking 
waters  to  such  an  extent  that,  owing  to  odor  and  taste,  it  is  unfit  for  use. 
If  prey  is  abundant,  the  same  rapid  multiplication  will  take  place  in  all 
kinds  of  predatory  forms,  while  parasitic  forms  are  kept  down  only  by  the 
natural  immunity  of  their  hosts,  by  remedial  measures,  or  by  loss  of  their 
own  vitality. 

The  primary  method  of  increase  is  that  of  all  cells — simple  division — 
but  here,  as  in  all  other  living  things,  the  number  of  progeny  varies  with 
the  difficulties  in  perpetuating  the  species.  Thus  in  parasitic  forms  like 
sporozoa,  simple  division  has  been  replaced  by  the  far  more  prolific 
method  of  spore-formation,  while  the  same  end  is  attained  in  some  types 
by  budding  or  gemmation. 

1.  Binary  Fission. — ^The  process  of  division  in  a  protozoon  is  not  very 
different  from  that  in  a  tissue  cell.  The  nucleus  is  the  first  to  divide,  and 
then  the  cell  body.  Very  often  there  is  a  complicated  nuclear  figure  con- 
sisting of  centrosomes,  spindle-fibers  and  chromosomes,  but  more  often 
the  material  of  spindle  fibers  and  centrosome  is  compressed  into  a  single 
intranuclear  body  called  the  division-centre,  about  which  the  chromatin 
is  massed.  Nuclei  of  this  type  are  called  "centronuclei"  or  "amphi- 
nuclei"  and  these  are  probably  the  most  typical  of  all  protozoan  nuclei. 
There  are  many  modifications,  especially  in  the  primitive  forms,  the  most 
important  being  the  absence  of  nuclear  membranes  and  the  diffusion  of  the 
chromatin  granules  (chromidium)  throughout  the  cell  {e.g.,  tetramitus. 
Fig.  5).  In  such  cases  the  granules  are  collected  about  the  diAdsion  cen- 
tre prior  to  division,  and  at  this  period  the  nuclear  eleme-nts  appear  like 
a  typical  centronucleus.    This  "distributed"  condition  of  the  chromatin 


356 


DISEASES  CAUSED  BY  PROTOZOA 


is  also  characteristic  of  the  bacteria  and  possibly  re])resents  a  phylogenetic 
stage  which  is  jiresent  at  some  period  in  the  life-histoiy  of  every  known 
protozoon.  The  division-centre  frequently  plays  other  roles  in  the  cell — 
thus,  in  heliozoa  it  may  be  the  centre  of  the  radiating  axial  filaments  which 


Fig.  5. 


^  £  C  ^ 

Division  of  Tetramitus  Chilomonas  Calkins. — The  ordinary  vegetative  form  (A)  has  nuclear 
material  (c)  scattered  throughout  the  cell  (distributed  nucleus).  When  preparing  for  division 
these  granules  are  grouped  in  the  vicinity  of  the  division  centre  {B  s)  which  divides  first  (C) 
after  which  the  chromatin  granules  are  separated  into  two  similar  groups  about  the  two  parts 
of  the  division  centre  (D). 

support  the  pseudopodia,  while  in  trypanosoma  it  becomes  die  "blepharo- 
plast"  or  main  part  of  the  "micronucleus/'  and  furnishes  the  substance 
of  the  vibratile  flagellum. 

2.  Budding  and  Gemmation. — In  many  forms  of  protozoa,  division  is 
frequently  asymmetrical,  resulting  in  dissimilar  products.  Such  division 
may  be  multiple,  forming  three  or  more  smaller  organisms,  and  is  dis- 
tinguished from  simple,  binary  fission  by  the  terms  budding  or  gem- 
mation. The  budding  area,  as  in  the  free-living  heliozoon,  acanthocystis, 
or  in  the  fish  parasite,  myxidium,  may  be  the  entire  periphery,  or  as  in 
acineta  it  may  be  confined  to  a  limited  part  of  the  surface.  A  further  com- 
plication may  be  brought  about  by  the  insinking  of  the  budding  area  into 
the  body  substance  so  that  the  buds  are  contained  in  a  kind  of  brood  sac. 
These  are  distinguished  as  ectogenous  and  endogenous  budding;  the  latter 
is  characteristic  of  the  group  myxosporidia  to  which  some  of  the  most 
malignant  types  of  animal  parasites  belong.  Here  the  localized  budding 
areas  are  called  "pansporoblasts"  and,  as  in  typical  brood  pouches,^  the 
spores  are  formed  while  the  animal  continues  the  ordinary  vegetative  life.* 

3.  Spore  Formation.— In  some  free-living  forms,  reproduction  by 
division  takes  place  w'hile  the  animal  is  protected  by  a  cyst.  Thus  in 
colpidium,  an  infusorian  abounding  in  stagnant  waters,  the  cell  secretes 
a  cyst,  within  which  it  divides  twice  consecutively,  forming  four  daughter 

^In  some  types  the  entire  organism  forms  the  pansporoblast,  and  these  have 
been  interpreted  by  Stempel  and  Minchin  as  representing  the  pansporoblast 
areas  of  adult  organisms  which,  in  the  course  of  phylogenetic  development,  have 
become  free  and  now  develop  directly  into  pansporoblasts.  This  is  the  type, 
for  example,  in  the  genera  Thelohania,  Pleistophora,  and  Gurleya. 


THE  PROTOZOA 


357 


individuals.  Except  in  point  of  numbers  this  process  of  reproduction 
differs  in  no  wise  from  that  known  as  spore  formation,  whereby  tlie  single 
cell  divides  either  serially  or  at  one  time  into  hundreds  of  daughter 
individuals. 

Much  confusion  has  arisen  because  of  a  mixed  terminology,  especially 
in  the  case  of  parasitic  protozoa.  Consistent  terms  seem  to  be  sifting  out, 
however,  from  the  heterogeneous  collection,  and  these,  based  apparently 
upon  natural  lines,  will  probably  supplant  all  others.  Schaudinn,  whose 
genius  has  dominated  all  lines  of  protozoan  investigation,  suggested  in 


Different  stages  of  the  Flagellate  Tetramitus  Rostratus  Perty.  (  Stein.) — Ordinary  vege- 
tative individuals  {A.  B.  from  side  and  front)  reproduce  asexually  by  longitudinal  division. 
They  ultimately  become  plastic  (C)  and  miscible,  and  two  individuals  upon  meeting  {D)  fuse. 
The  copula  secretes  a  membrane,  and  its  protoplasm  fragments  into  hundreds  of  spores,  (£) 
which  qtiickly  grow  into  the  parent  type.     (F.  G.  H.) 

1899  that  a  consistent  terminology  of  spore-forms  is  offered  by  the  words 
"sporoblast,"  "sporozoite,"  and  "merozoite,"  and  by  the  words  "spo- 
ront"  and  "schizont"  which  designate  the  adult  forms  producing  spo- 
rozoites  and  merozoites  respectively. 

Merozoites  and  sporozoites  indicate  biological  conditions  which  are 
traceable  to  the  general  vitality  of  the  parent  forms,  conditions  which 


358  DISEASES  CAUSED  BY  PROTOZOA 

appear  not  only  in  parasitic  forms  but  apparently  in  all  protozoa.  After  a 
certain  niiinljer  of  reproductions  by  asexual  nierozoitc  formation,  vitality 
is  exhausted  and  conjugation,  or  the  union  of  gametes,  takes  ])lace,  renew- 
ing vitality  and  resulting  in  spores  and  sporozoites,  produced  when  the  vital- 
ity is  at  its  maximum.  The  s})orozoites  in  turn  develop  into  schizonts, 
completing  the  cycle.  A  simple  illustration  is  afi'orded  by  the  reproductive 
phases  of  certain  mastigo])hora  such  as  tetramitus  or  cercomonas  (Fig. 
6).  Here  in  both  cases  the  usual  mode  of  reproduction  is  by  simple 
longitudinal  division,  the  daughter  cells  being  equivalent  to  merozoites. 
After  division  has  been  repeated  for  many  generations,  the  organisms  lose 
their  definite  contour,  become  plastic,  and  two  of  them  ujion  meeting,  fuse 
to  form  a  fertilized  cell,  the  copula.  Within  the  copula  wall,  the  pro- 
toplasm breaks  up  into  hundreds  of  reproductive  bodies  equivalent  to 
sporozoites,  but  to  which  the  name  "spore"  has  been  applied  for  many 
years. 

Turning  from  these  simple  cases  to  the  complicated  but  analogous  re- 
production of  sporozoa,  we  find  that  the  same  principle  holds  good,  and 
"spore"  products  are  formed  after  sexual  union.  Confusion  has  arisen 
because  the  asexual  reproduction,  Avhich  in  tetramitus  takes  place  by  binary 
fission,  is  replaced  in  sporozoa  by  the  more  prolific  multiple  division  or 
spore-formation  in  the  old  sense.  The  reproductive  elements,  which  are 
formed  in  this  way,  are  termed  merozoites  to  distinguish  them  from  the 
reproductive  bodies  formed  after  conjugation,  while  the  process  by  which 
they  are  formed  is  termed  schizogony,  and  the  producing  adult,  the 
schizont.  After  this  asexual  method  has  been  repeated  for  a  more  or  less 
definite  period,  merozoites  are  formed  which  develop  into  conjugating 
individuals  termed  gametes,  which  like  tetramitus,  may  be  similar  to  one 
another,  or,  unlike  tetramitus,  may  be  sexually  differentiated.  If  the 
latter,  the  larger,  yolk-stored  cjviiescent  forms  are  the  macrogametes,  the 
minute,  actively  motile,  spermatozoa-like  forms,  are  the  microgametes. 
After  union  of  the  sexual  elements,  the  encysted  copula  becomes  either  a 
single  sporoblast,  or  it  divides  into  from  two  to  many  parts,  each  one  being 
a  sporoblast.  Each  sporoblast  may  be  separated  from  the  others  by  a 
special  sporocyst  (as  in  coccidia),  or  the  sporoblasts  may  be  merely  repro- 
ducing centres  W"ithout  special  sporocysts  (as  in  plasmodium  and  laver- 
ania),  but  in  all  cases  the  sporoblasts  give  rise  to  the  ultimate  reproductive 
bodies  or  sporozoites  w^hich,  usually  protected  by  spore-capsules,  are 
shielded  from  the  exigencies  of  a  more  or  less  prolonged  ectogenous  cycle. 

Spores  in  the  myxosporidia  differ  from  those  in  other  protozoa  in  having 
one  or  more  specialized  thread-holding  capsules.  These  so-called  "polar 
capsules"  are  sufficiently  characteristic  to  distinguish  the  spores  of 
myxosporidia  from  all  other  sporozoan  reproductive  bodies.  The 
function  of  the  thread  is  to  assist  the  sporozoite  in  securing  attachment  to 
epithelial  cells  when  taken  into  the  digestive  tract  of  a  new  host. 

The  variations  which  occur  in  the  different  types  of  sporulation  in 
sporozoa  are  legion;  among  these  monocystis  ascidife  is  noteworthy  in 
having  two  adult  organisms  (sporonts)  unite  to  form  a  common  cyst 
(Fig.  7).  Each  divides  into  a  number  of  amoeboid  elements,  the 
gametes,  which  fuse  two  by  two  (in  the  allied  genus  stylorhynchus  the  con- 
jugating gametes  come  from  different  cells  and  this  is  presumably  true  of 
monocystis).     Each  of  the  many  copulas  forms  a  single  sporoblast  and 


THE  PROTOZOA 


350 


gives  rise  to  eight  sporozoites.  Another  variation  is  seen  among  the 
coccidia  where  in  some  cases,  (adelea,  cyclospora,  etc.),  the  ultimate 
sexually  differentiated  gametes  are  represented  by  a  long  series  of  genera- 
tions of  sexually  differentiated  merozoites. 


Fig.  7. 


Life  Cycle  of  Monocystis  Ascidise.  (Siedlecki.) — The  young  sprozoites  enter  epithelial  cells 
(A,  B,  C),  and  grow  into  adult  gregarines  which  leave  the  cells  (£)),  and  live  as  "sporonts" 
in  the  cavity  of  tlie  intestine.  Two  sporonts  unite  {E),  their  nuclei  divide  repeatedly  (F), 
until  many  daughter-nuclei  are  formed  ((?).  These  become  nuclei  of  amcsboid  gametes  (H), 
which  move  about  inside  of  the  cyst,  and  soon  conjugate  two  by  two  (/),  the  nuclei  fusing 
to  form  cleavage  nuclei  of  the  sporoblasts  (J).  The  cleavage  nuclei  then  divide  thrice  to 
form  eight  daughter-nuclei  {K,L,M,N),  which  ultimately  become  nuclei  of  the  sporozoites 
(0).  The  sporoblasts,  meanwhile,  secrete  firm  cysts  within  which  the  sporozoites  are 
protected. 

The  merozoites  do  not  leave  the  host,  but  migrate  to  new  localities 
where  they  repeat  the  process  of  development  and  sporulation,  until  they 
ultimately  change  into  the  sexually  differentiated  reproductive  bodies; 
these,  after  fertilization,  produce  the  cyst-protected  sporozoites,  which 
remain  quiescent  until  carried  into  new  hosts.  Merozoites  thus  give  rise 
to  auto-infection  of  the  host,  and  sporozoites  to  fresh  infection  of  new 
hosts,  most  frequently  by  way  of  the  digestive  tract  where  they  are  carried 
with  the  food.  The  cysts  are  then  dissolved  off  by  the  gastric  fluids,  and 
the  liberated  sporozoites  make  their  way  into  the  epithelial  cells.  In 
appearance  they  closely  resemble  the  merozoites  but  can  be  usually  dis- 
tinguished by  minor  differences  such  as  general  contour,  presence  of  pig- 
ment, nuclear  characteristics,  or  other  features. 

In  non-parasitic  protozoa  we  meet  with  closely  similar  life-cycles  haA^ng 
the  same  alternation  of  sexually  and  asexually  produced  spores.     In 


360 


DISEASES  CAUSED  BY  PROTOZOA 


marine  foraminifera,  for  example  (poljstomella,  Fig.  S),  the  alter- 
nation is  shown  by  struetural  differences  in  the  atiult  shells  and  in  the 
reproductive  elements.  Shells  that  are  formed  by  recently  fertilized 
gametes    (equivalent   to   developing   sporozoites)    have  a  small  central 


Fig    8. 


D     ■■     i\\M\  \ 
'   '  j  I'.i.i 

Life  cycle  of  Polystomella  Crispa  <S.  (Lang  and  Schaudinn.) — A  young  form  derived  from 
tlie  union  of  two  flagellated  gametes  (A )  develops  into  an  organism  with  microsphseric  type 
of  shell.  The  nucleus  increases  by  mitosis  until  many  nuclei  are  present  when  they  break 
up  into  granules  of  chromatin  (B).  The  protoplasm  fragments  into  reproductive  bodies, 
equivalent  to  merozoites  (C),  each  having  several  granules  of  the  distributed  chromatin 
("Chromidien").  Each  reproductive  body  (D)  develops  into  an  adult  with  a  macrosphseric 
type  of  shell,  and  with  nuclei  in  the  form  of  small  chromatin  granules  {E)  When  mature 
these  forms  fragment  into  hundreds  of  flagellate  gametes  (F)  which  conjugate,  and  so  com- 
plete the  cycle. 

chamber  (microsphferic).  The  adult  reproduces  by  amoeboid  spores 
(pseudopodiospores),  equivalent  to  merozoites,  which  grow  directly  into 
shelled  organisms  with  comparatively  large  central  chambers  (macros- 
pha?ric).  These  ultimately  produce  flagellated  swarm  spores  (flagelli- 
spores  or  gametes)  which  conjugate  and  so  complete  the  cycle. 

The  universality  of  these  alternating  generations  indicates  that  we  have 
to  do  with  a  fundamental  biological  phenomenon  of  the  utmost  importance. 


niE  PROTOZOA  861 

Recent  research  has  given  a  hint  that  the  secret  may  lie  in  the  varying 
conditions  of  vitaHty  at  different  phases  of  the  cell-cycle.  A  protozoon 
begins  life  after  conjugation,  with  a  certain  potential  of  vitality  which  is 
gradually  used  up  in  the  continued  vegetative  activities  and  by  asexual 
multiplication.  With  advancing  age  and  decreasing  vitality  protoplasmic 
changes  occur  which  indicate  the  approach  of  renewed  sexual  activity. 
This  sequence  of  changes  is  known  as  the  life-cycle. 

The  Life-cycle. — Modern  research  on  protozoa  emphasizes  the  fact 
that  study  of  a  single  individual  or  of  a  group  of  individuals  in  the  same 
stage  of  their  life-cycle,  fails  to  give  an  adequate  conception  of  the  species 
to  which  they  belong  The  significance  of  this  is  evident  when  it  is  re- 
called that  recently  it  has  been  claimed  that  certain  species  of  the 
genus  halteridium  and  certain  species  of  trypanosoma  are  phases  of 
the  same  organism,  or  that  certain  species  of  pelomyxa  are  but  stages  in 
the  life-history  of  amoeba.  Earlier  evidence  of  the  same  confusion  was 
shown  by  the  polymitus  form  which  was  later  identified  as  the  sexual 
stage  of  malarial  organisms.  It  is  certainly  reasonable  to  expect  that 
further  research  on  life-cycles  will  prove  that  of  the  7,000  species  of 
protozoa  now  on  record,  many  are  but  form-changes  of  the  same  organ- 
isms. 

The  facts  which  have  been  obtained  from  the  study  of  a  few  life-his- 
tories indicate  that  these  form-changes  are  expressions  of  a  varying  vital- 
ity, and  even  more  important  than  this,  they  indicate  that  the  -general 
biological  laws  which  we  recognize  in  the  development  of  higher  animals 
and  plants  are  equally  applicable  to  protozoa.  We  now  know,  for  example, 
that  the  changes  are  characteristic  of  periods  in  the  life-history  which 
compare  with  the  metazoan  periods  of  youth,  adolescence,  and  old  age. 
We  know  that  natural  death  from  protoplasmic  old  age  is  as  inevitable 
in  protozoa  as  in  metazoa  provided  conjugation  is  prevented,  and  we  have 
strong  evidence,  though  as  yet  no  actual  proof,  that  conjugation,  the 
analogue  of  fertilization,  is  not  a  specific  process  of  reproduction,  but  a 
process  of  rejuvenescence,  through  which  a  weakened  vitality  is  restored 
to  full  activity. 

These  points  may  be  illustrated  by  the  comparatively  simple  life- 
history  of  a  free-living  form  like  paramoecium,  the  "slipper-animalcule." 
A  single  individual  was  isolated  and  placed  in  water  that  had  been  boiled 
with  hay;  on  the  following  day  the  paramoecium  had  divided  twice  and 
the  four  individuals  were  each  isolated  in  hay  infusion  as  before.  The 
four  lines  thus  started  were  kept  separate  and  daily  isolations  were  made 
for  a  period  of  twenty-three  months,  and  until  the  original  protoplasm 
had  divided  742  times.  The  accompanying  diagram  shows  the  variations 
in  vitality  during  the  entire  period,  the  number  of  generations  for  all  four 
lines  being  averaged  in  ten-day  periods.  After  about  200  generations  the 
vitality  of  the  race  sank  to  such  a  low  point  that  the  majority  died  and  the 
rest  were  saved  only  by  substituting,  for  a  few  days,  a  meat  extract  in 
place  of  the  hay  infusion.  The  result  was  a  vigorous  renewal  of  vitality 
lasting  for  approximately  200  generations  more,  when  a  second  period 
of  depression  set  in  (see  first  and  second  cycles  of  diagram) .  Again  some 
were  saved  by  a  change  of  diet,  and  others  by  adding  salts  to  the  hay  infu- 
sions (potassium  phosphate).  This  resulted  in  a  third  cycle  of  genera- 
tions which  again  ran  out,  this  time  at  the  end  of  193  generations  (see 


362 


DISEASES  CAUSED  BY  PROTOZOA 


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THE  PROTOZOA  3G3 

third  cycle  of  diagram).  This  time  there  was  more  difficulty  in  saving 
the  race  but  they  were  finally  rejuvenated  by  using  extracts  of  pancreas 
and  of  brain.  The  resulting  cycle  was  v/eak  however,  and  after  126  gen- 
erations the  entire  race  died  from  unmistakable  old  age. 

There  is  no  doubt  that  the  race  would  have  died  from  what  might  be 
called  old  age  in  any  one  of  the  three  periods  of  depression,  had  not  stimu- 
lants in  the  form  of  dissolved  salts  been  used.  The  effect  produced  by 
these  salts  was  exactly  the  same  as  that  produced  in  artificial  parthenogene- 
sis in  egg  cells,  and  apparently,  the  same  as  that  produced  in  conjuga- 
tion. With  the  exception  of  the  last,  each  cycle  (approximately  of  200 
generations)  represents  a  complete  life-cycle  in  which  can  be  distinguished 
periods  of  vigor,  sexual  activity  and  senescence  (Fig.  9).  It  is  in  the 
period  of  sexual  activity  which  begins  near  the  culminating  point  of 
the  life-cycle  curve,  that  changes  in  the  protoplasmic  composition  become 
apparent.  The  cell  body  becomes  plastic,  and  miscible — a  physical  state 
well  adapted  for  conjugation — and  two  or  more  organisms,  coming  in 
contact  at  this  period,  will  unite.  In  the  later  period  of  senescence  the 
various  organs  of  the  body  become  degenerated,  cell  division  is  imperfect, 
and  monsters  are  frequently  formed, — all  evidences  of  exhaustion. 

The  hfe-cycle  of  paramoecium  shows  evidence,  therefore,  of  variations  of 
vitality  which  correspond  with  periods  of  youth,  adolescence,  and  old  age 
in  metazoa.  During  these  several  periods  the  protoplasm  undergoes 
distinct  structural  changes,  evidenced  in  the  second  phase  by  a  miscible 
condition  during  which  conjugation  is  possible.  If  conjugation  is  pre- 
vented the  ordinary  metabolic  processes  come  to  an  end  and  the  organ- 
isms die.  Their  protoplasmic  structure  at  this  time  indicates  that  the 
metabolic  processes  have  reached  a  state  of  stable  equilibrium  from 
which  they  may  be  stimulated  to  renewed  activity  by  artificial  means. 
Ultimately,  however,  such  artificial  measures  as  change  of  diet,  salts,  etc., 
are  ineffectual,  and,  although  the  experiments  indicated  that  the  digestive 
processes  were  renewed,  the  results  showed  that  something — a  something 
which  may  be  called  the  dividing  energy — had  become  exhausted  and  the 
last  of  the  race  of  paramoecium  died.  There  is  reason  to  believe  that  con- 
jugation results  in  a  new  chemical  organization  of  the  nuclei,  and  with 
this,  a  renewal  of  the  processes  of  division,  of  digestion,  and  of  other 
functions,  so  that  immediately  after  conjugation,  if  this  supposition  is 
correct,  we  should  expect  the  most  vigorous  activity. 

Turning  now  to  other  protozoon-cycles,  we  find  similar  phenomena, 
intelligible  in  the  light  of  these  experiments ;  thus  in  the  flagellates,  Tetram- 
itus  and  Cercomonas,  after  a  period  of  increase  by  division,  the  regular 
contour  of  the  body  is  lost,  the  individuals  become  plastic  and,  while 
in  this  condition,  conjugate  and  form  their  spores  (Fig.  6).  The 
change  in  protoplasmic  structure  is  an  indication  of  a  period  in  the  life- 
cycle  equivalent  to  that  of  paramoecium,  in  which  the  miscible  state  is 
predominant.  In  some  forms  this  period  of  the  life-cycle  results  in  the 
formation  of  different  sizes  of  individuals  of  which  the  large  ones  remain 
fixed  and  quiescent  (female),  while  the  small  ones  are  migratory  (male) 
and  fuse  with  the  larger  ones.  This  size-difference  may  become  exagger- 
ated to  such  an  extent  in  coccidia  and  hsemosporidia,  that  the  equiva- 
lent of  metazoon  eggs  and  spermatozoa  result.  This  physiological 
condition  of  the  organism,  therefore,  is  apparently  the  signal  for  the 


364  DISEASES  CAUSED  BY  PROTOZOA 

development  of  sexually  differentiated  individuals,  a  view  which  Minot 
expressed  in  1879  in  the  statement:  "The  exhaustion  of  the  rejuven- 
ating power  becomes  the  stimulus  for  the  formation  of  the  sexual  pro- 
ducts." 

Not  only  is  the  cell-body  altered  in  composition  but,  in  many  forms,  the 
structure  of  the  nucleus  is  likewise  changed.  In  rhizopods  like  amoeba, 
arcella,  centropyxis,  etc.,  and  in  foraminifera  and  sporozoa,  a  quantity  of 
chromatin  is  given  oft"  from  the  nucleus  in  the  form  of  granules  which  lie 
distributed  throughout  the  cj'toplasm,  unconfined  by  a  nuclear  mem- 
brane, a  condition  exactly  comparable  with  the  distributed  nucleus  of 
tetramitus  or  of  bacteria.  These  granules  were  called  the  "Chromidien" 
by  Hertwig,  while  Schaudinn,  with  others,  has  shown  that  they  form  the 
minute  nuclei  of  the  sexually  ditt'erentiated  individuals.  These  nuclear 
processes  are  well  illustrated  in  the  life-cycle  of  the  foraminiferon,  poly- 
stomella,  which,  as  stated  above,  has  a  many-chambered  calcareous 
shell  occurring  in  two  forms,  one  with  a  large  central  chamber,  the  other 
with  the  corresponding  chamber  much  smaller.  The  explanation  of 
this  size-difterence  was  the  key  to  the  life-history  of  these  foraminifera. 
The  nuclei  of  the  small-chambered  individuals  break  up  into  countless 
fragments,  the  "Chromidien,"  (or  chromidium)  which  are  ultimately  dis- 
tributed to  small  amoeboid  fragments  of  the  parent  organism  formed  by  a 
process  analogous  to  merozoite  formation  in  coccidia.  These  amoeboid 
spores  develop  into  adult  organisms  with  the  large-chambered  shell  in 
which  the  distributed  chromatin  granules  become  the  minute  nuclei  of 
small  flagellated  gametes  which  swarm  out  from  the  parent  shell.  Two 
of  these  gametes  from  different  parents  upon  coming  together  conjugate, 
and  the  copula  develops  into  an  organism  with  a  minute  central  chamber. 
In  this  organism  when  grown,  the  distributed  nucleus  is  again  ultimately 
formed  in  preparation  for  future  conjugations  (Fig.  8). 

Another  life-history  w^orked  out  by  Siedlecki,  and  offering  some  varia- 
tions upon  the  above,  is  that  of  a  parasitic  gregarine  living  in  the  cavities 
of  a  salt  water  ascidian  (Fig,  7).  Here  the  distributed  chromatin  is 
formed  by  repeated  divisions  of  the  nucleus.  The  young  parasite  in  the 
sporozoite  stage  enters  an  epithelial  cell  of  the  gut  and  develops  into  the 
adult  gregarine.  It  becomes  free  in  the  lumen  of  the  intestine  and  is  soon 
joined  by  a  second.  They  secrete  a  common  cyst  in  which  the  nucleus  of 
each  individual  divides  many  times,  forming  two  multinucleate  cells. 
Each  cell  then  divides  into  as  many  minute  parts  as  there  are  nuclei.  A 
large  number  of  amoeboid  gametes  are  formed,  those  from  one  of  the 

...  .  . 

conjoint  animals  fusing  with  those  from  the  other.  After  this  union  of 
the  gametes  each  copula  becomes  a  sporoblast  and  secretes  a  capsule  in 
which  the  spore  contents  divides  into  eight  parts,  the  sporozoites.  The 
latter  are  retained  and  protected  within  the  spore-cysts  until  eaten  by 
some  new  host  when  the  cyst  walls  are  dissolved  by  the  digestive  fluids, 
and  the  sporozoites  are  liberated. 

A  still  more  complicated  process  is  shown  by  the  epithelial  cell-para- 
site, coccidium  schubergi,  described  by  Schaudinn  (Fig.  10).  Here  the 
sporozoite  enters  an  epithelial  cell,  grows  to  adult  size,  leaves  the  cell  and 
forms  merozoites  by  repeated  divisions  of  the  nucleus  and  of  the  cell- 
body.  The  merozoites  repeat  the  cycle  and  new  merozoites  are  formed 
again   and   again.     Ultimately   the   merozoites   develop   into   sexually- 


THE  PROTOZOA 


365 


differentiated  forms  which  produce  macro-  and  microgametes,  the  nuclei 
of  the  microgametes  being  formed  from  the  granules  of  the  "Chromidien." 
These  gametes  unite  and  each  copula  secretes  a  protecting  covering  and 
forms  four  sporoblasts.     In  each  sporoblast,  two  sporozoites  are  pro- 


FiG.  10. 


Life  cycle  of  Coccidium  Schubergi.  (After  Schaudinn.) — Sporozoites  penetrate  epitheb'al 
cells,  and  grow  into  adult  intracellular  parasites  (o).  When  mature,  the  nucleus  divides  re- 
peatedly (6)  ;  and  each  of  its  sub-divisions  becomes  the  nucleus  of  amerozoite  (c).  These  enter 
new  epithelial  cells,  and  the  cycle  is  repeated  many  times.  After  five  or  six  days  of  incuba- 
tion, the  merozoites  develop  into  sexually  differentiated  gametes  ;  some  are  large  and  well 
stored  with  yolk  material  {d,  e,  f)  ;  others  have  nuclei  which  fragment  into  many  small  par- 
ticles ("Chromidien")  each  granule  becoming  the  nucleus  of  a  microgamete  or  male  cell  {d, 
h,i,i);  The  macrogamete  is  fertilized  by  one  microgamete  (g),  and  the  copula  immediately 
secretes  a  fertilization  membrane  which  hardens  into  a  cyst.  The  cleavage  nucleus  divides 
twice,  and  each  of  the  four  daughter-nuclei  forms  a  sporoblast  (k)  in  which  two  sporozoites  are 
produced  (1). 

duced  which  are  protected  by  spore-cases  and  by  the  parent  sporocyst, 
until  the  walls  are  dissolved  and  the  sporozoites  are  liberated  to  repeat 
the  cycle. 

Other,  and  even  more  complicated  life-cycles  in  cyclospora,  arcella, 
centropyxis,  etc.,  might  be  cited,  but  they  all  agree  in  essential  features 
with  the  examples  given. 

Turning  now  to  the  malignant  protozoa  which  are  supposed  to  be  the 
causes  of  certain  human  diseases,  we  find,  for  the  most  part,  only  discon- 
nected portions  of  life-cycles.    With  the  exception  of  the  malaria  organ- 


366  DISEASES  CAUSED  BY  PROTOZOA 

isms,  the  complete  life-history  of  not  one  disease-causing  form  is  known. 
We  are  completely  in  the  dark  concerning  the  causes  of  many  of  the 
exanthematous  diseases,  yellow  fever  and  cancer,  and  of  some  of  these  we 
cannot  say,  even,  that  the  causes  are  parasites  and  still  less  can  we  affirm 
that  the  parasites  are  protozoa.  Even  in  diseases  that  are  known  to  be 
due  to  protozoa  much  remains  to  be  done  before  the  life-histories  are 
complete.  Trypanosoma,  being  a  saprophytic  type  and  therefore  capa- 
ble of  cultivation,  oii'ers  esi)ecial  advantages  for  study,  but  even  with 
these,  little  more  than  the  schizogony  is  known.  The  recent  preliminary 
account  which  Schaudinn  published,  according  to  which  the  life-cycle  of 
trypanosoma  involves  a  change  of  hosts,  and  an  alternation  of  intracel- 
lular and  extracellular  habitats,  cannot  be  acce})tcd  without  further 
evidence.  The  same  uncertainty  exists  in  regard  to  the  cycle  of  cytor- 
hyctes  variohi^,  where,  according  to  the  tentative  life-history  a  cytoplasmic 
phase  and  a  nuclear  phase  characterize  the  asexual  and  sexual  processes, 
respectively.  No  certainty  can  attach  to  such  a  life-history  until  the 
organism  can  be  followed  from  its  first  invasion  of  the  human  host  to  its 
last  spore-stage.  Cyclasterella  (Cyclaster)  scarlatinalis,  the  organism  found 
by  Mallory  in  skin  cells  of  scarlet  fever  patients,  has  been  seen  only  in  its 
vegetative  and  merozoite  stages.  Piroplasma  (Babesia)  hominis,  de- 
scribed by  Wilson  and  Chowning  as  the  cause  of  tick  fever,  is  known 
in  only  one  phase,  while  even  the  allied  and  better  known  piroplasma 
bigeminum  (Babesia  bovis)  of  cattle,  must  still  be  studied  for  its  sexual 
phases  and  sporogony.  Entamoeba  histolytica,  which,  according  to  Schau- 
dmn  is  the  malignant  amoeba  of  tropical  dysentery,  has  been  followed 
through  its  schizogony  and  as  far  as  the  development  of  the  "  Chromidien," 
while  entamoeba  coli  (amoeba  coli  syn.),  a  harmless  commensal  in  the 
human  intestine  has  been  followed  only  through  schizogony.  Spiro- 
chseta  of  syphilis  is  known  in  only  one  phase,  and  analogy  alone  suggests 
that  this  organism,  too,  has  a  complex  life-cycle. 

On  the  whole,  we  are  compelled  to  state  in  regard  to  pathogenic  proto- 
zoa in  man  that,  up  to  the  present  time,  little  more  has  been  done  than  to 
break  ground  in  an  extremely  difficult  field  of  research,  and  that,  de- 
prived for  the  most  part  of  the  possibility  of  experimentation,  and  rely- 
ing merely  upon  morphology,  future  progress  must  necessarily  be  slow. 
We  are  in  a  position,  however,  to  draw  some  positive  conclusions  from 
pure  morphology,  Enough  is  known  to  show  that  more  or  less  definite 
structural  characteristics  accompany  the  three  general  periods  of  a  pro- 
tozoan life  cycle.  The  youthful  organism  is  characterized  by  marked 
conformity  to  type;  the  older  organism  in  the  period  of  adolescence,  by 
well  marked  nuclear  changes,  by  chromidium  formation  and  by  physical 
changes  in  the  cytoplasm;  while  old  age  is  signalized  by  vacuolar  degen- 
eration and  decreased  size.  The  value  of  these  morphological  charac- 
teristics is  shown  by  A.W.Williams'  discovery  of  a  definite  chromidium 
in  the  Negri  bodies.  This  chromidium  being  of  the  same  type,  and 
ha\ing  a  history  similar  to  that  in  Orcella  or  Centropyscis  enables  us  to 
classify  these  organisms  of  rabies  as  rhizopods. 

The  importance  of  the  sexual  phase  in  the  life-history  of  protozoa  is 
unmistakable,  but  its  significance  has  been  variously  interpreted.  Some 
observers  include  phenomena  of  conjugation  with  those  of  egg  fertiliza- 


THE  PROTOZOA  367 

tion  and  agree  with  Darwin,  Spencer,  O.  Hcrtwig,  Hatschek  anrl  others, 
that  the  process  has  as  its  primary  object  the  prevention  of  indefinite 
variation,  and  tends  to  keep  the  species  true  to  its  type  Others,  hke 
Brooks  and  Weismann,  have  maintained  an  opposite  view,  that  sexual 
union  has  been  developed  as  a  method  of  originating  variations;  still 
others  agree  with  Biitschli,  Minot,  Jensen  and  Maupas,  that  conjugation, 
like  fertilization  of  the  egg,  involves  a  process  of  rejuvenation,  whereby 
the  cell  is  stimulated  to  renewed  activity.  The  experimental  evidence 
supports  the  latter  hypothesis.  While  Weismann,  on  an  a  priori  basis, 
maintained  that  protozoa  are  too  simply  organized  to  die  a  natural  death 
from  old  age,  Maupas'  experiments,  confirmed  by  later  researches, 
demonstrated  the  opposite.  "Senescence,"  Maupas  says,  "appears  to  be  a 
very  general  phenomenon,  at  least  in  the  animal  kingdom.  *  *  It  is 
inherent  in  the  organism  and  comes  from  internal  causes  which  act  inde- 
pendently of  the  surrounding  conditions.  *  '  Its  deleterious  action  is 
offset  and  annulled  by  sexual  rejuvenescence  or  conjugation  " 

In  the  experiments  with  paramoecium,  referred  to  above,  it  was  dem- 
onstrated that,  like  sea-urchin  eggs  artificially  fertilized,  senescent  pro- 
tozoa can  be  re-invigorated  by  stimuli, — in  paramcecium  by  potaasium 
phosphate  and  the  salts  of  meat  extract;  but  it  was  also  demonstrated 
that  these  stimuli  have  no  permanent  effect,  and  that  the  organisms  ulti- 
mately die  of  old  age.  In  some  forms  of  protozoa,  although  not  in  para- 
mcecium, similar  physiological  exhaustion  apparently  does  not  result  in 
death  of  the  organisms,  but  leads  to  the  formation  of  protecting  cysts, 
within  which  the  living  cells  remain  quiescent  for  varying  periods,  until 
environmental  conditions  are  favorable  to  liberation  and  renewed  activity. 

Experiments  upon  free-living  forms,  especially  upon  flagellated  types, 
have  shown  that  changes  in  density  of  the  surrounding  medium  produce 
these  physiological  conditions  necessary  to  gamete-formation,  and  sexual, 
conjugating  elements  are  formed. 

Applying  these  general  principles  to  pathogenic  protozoa,  we  note  that 
the  experiments  involving  changes  of  density  of  the  surrounding  medium 
are  reproduced  in  nature  in  the  life-history  of  the  blood-dwelling  malaria 
organisms,  when  sexual  elements  are  developed  upon  exposure  to  lowered 
temperature  of  the  air,  or  to  the  cold  environment  of  a  mosquito's  gut. 
Again,  from  these  general  principles,  it  is  reasonable  to  expect  that,  if 
prevented  from  conjugating,  the  virulence  of  a  specific  form  should  grad- 
ually decrease  until  the  disease  runs  itself  out.  We  should  expect  in  a 
malaria  infection,  for  example,  that  the  organisms  would  be  less  suscep- 
tible to  drugs  at  the  outset  than  later  when  their  vitality  is  reduced,  and 
that,  ultimately,  they  would  die  out  from  functional  degeneration,  sub- 
ject to  the  possibility,  however,  of  encystment  and  artificial  stimulation 
through  some  minute  change  in  chemical  composition  of  the  host's  blood. 
This  principle  is  illustrated  in  the  life-history  of  the  trypanosoma  of  the 
owl,  where,  according  to  Schaudinn's  descriptions,  one  of  the  types,  called 
by  him  the  "indifferent  form,"  is  capable  of  parthenogenetic  development 
within  the  host,  and  of  reproducing  the  disease.  It  is  illustrated  again 
in  the  history  of  the  Texas  fever  organism,  piroplasma  bigeminum,  where 
the  hsematozoa  apparently  lose  their  dividing  energy,  and  remain  latent 
in  the  blood  for  indefinite  periods,  and  still  again  in  human  malaria 
where  the  plasmodium  may  remain  latent,  sometimes  for  many  years 


368  DISEASES  CAUSED  BY  PROTOZOA 

CLASSIFICATION. 

SUB-KINGDOM.  Protozoa. — Unicellular    animal     organisms  which  repro- 

duce by  division  or  spore-fonnation;  solitary  or  united 
in  colonies;   free-living  or  parasitic. 

PHYLUM   I.     Sarcodina. — Protozoa  with  changeable  protoplasmic  processes  or 
pseudopodia. 
CLASS  I.     Rhizopoda. — Sarcodina   with   iDseudopodia  in  the  form  of  lobose  or 
reticulose  processes;   with  or  without  shells. 
SUB-CLASS.  Amoebida. — Pseudopodia  lobose. 

ORDEU  1.     Gymnamcehida. — Naked   ama:'boid  forms  with  lobose  pseudo- 
jjodia.    Here  are  placed  a  few  parasitic  forms  belonging 
to  the  genera  Amoeba,  Entama>ba,  and  Leydenia. 
ORDEU    2.     Thccamocbida. — Shell-bearing    amoeboid    forms    with    lobose 
pseudopodia;  no  parasitic  form. 
SUB-CLASS.   Foraminifera. — Divided  into  10  orders;     the  various  genera  are 
salt  water  forms  for  the  most  part,  and  are  never  para- 
sitic. 
(Sub-class  Mycetozoa  would  be  placed  here  were  we  to  consider  these  forms  as 
protozoa  instead  of  fungi.     Here  are  placed  parasitic 
forms  such  as  Plasmodiophora,  Tetramyxa,  Labyrin- 
thula  and  other  parasites  of  plants.) 
CL.\ss  II.     Heliozoa. — The  genera  are  confined  mainly  to  fresh  water  and  are 
never  parasitic.    They  are  sub-cl:vided  into  four  orders 
according  to  the  nature  of  the  skeleton. 
CLASS  III.   Radiolaria. — Salt-water  forms  of  protozoa,  never  parasitic. 

PHYLUM   II.     Mastigophora. — Protozoa  with  flagella. 

CLASS  I.     Flagellata. — Small  forms  with  from  one  to  several  flagella;    with  a 
strong  tendency  to  form  colonies. 

ORDER  1.  Monadida. — Minute  forms  with  from  one  to  three  flagella. 
There  is  no  definite  mouth-opening  and  nutrition  is 
holozoic,  saprophytic,  or  parasitic.  The  parasites  and 
commensals  which  belong  to  this  order  are  species  be- 
longing to  the  genera  Cercomonas,  Herpetomonas  and 
Trypanosoma. 

ORDER  2.  Choanoflagellida. — With  collar-like  processes  surrounding  the 
base  of  the  flagellum;  not  parasitic. 

ORDER  3.  Heteromastigida. — With  two  or  more  flagella  of  dissimilar 
length;  the  genus  Bodo  is  parasitic. 

ORDER  4.  Polymastigida. — The  flagella  are  numerous  and  of  similar  or 
dissimilar  size.  Here  are  several  ecto-  and  endo-para- 
sitic  forms  belonging  to  the  genera:  Costia,  Tetramitus, 
Trichomonas,  Monocercomonas,  Hexamitus,  Lamblia, 
Polymastix,  Lophomonas,  Trichonympha,  Pyrsonym- 
pha  and  Joenia. 

ORDER   5.     Euglenida. — No  parasites. 

ORDER  6.  Phytoflagellida. — Flagellates  with  coloring  matter  in  the  form 
of  green,  yellow,  or  brown  chromatophores.  Frequent- 
ly colonial.  Here  belong  the  most  frequent  sources  of 
odors  in  drinking  waters,  the  following  genera  being 
especially  noteworthy:  Dinobryon,  Synura,  and  Uro- 
glena,  all  colonial  forms,  with  yellow  chromatophores. 

ORDER    7.     Silicoflagellida. — A   single  genus  of  salt  water  mastigophora 
with  latticed  skeleton.    Distephanus,  parasitic  on  rad- 
iolaria. 
CLASS   II.     Dino flagellata. — Never  parasitic. 

CLASS  III.  Cysto flagellata. — Two  genera  of  characteristic  form.  One,  Nocti- 
luca,  is  remarkable  for  the  vivid  phosphorescence  which 
it  causes. 
PHYLUM  III.  Infusoria. — Protozoa  with  cilia.  In  the  sub-phylum  ciliata 
these  are  present  at  all  times;  in  the  sub-phylum 
suctoria  they  are  present  only  during  the  young  or 
embryonic  phases. 


THE  PROTOZOA  369 

ORDER  1.  liololrichida. — The  cilia  arc  di.stributed  over  the  surface,  und 
there  is  no  specialized  oral  apparatus  known  as  the 
"adoral  zone"  consisting  of  cilia  fused  into  "nicmbran- 
elles."  Here  are  found  some  parasites  belonfrjng  to  the 
genera  Ichthioplithirius,  Butschlia,  Anophrys,  Isotricha, 
Dasytricha,  Opalina. 

ORDER  2.  Heterotrichida. — With  cilia  distributed  over  the  general  sur- 
face and,  in  addition,  a  specialized  adoral  zone  in  the 
mouth  region.  Here  are  several  well-l^nown  parasitic 
forms  belonging  to  the  genera  Nyctotherus,  lialantid- 
ium,  Entodinium,  Diplodinium,  Ophryoscolex  and  (Jyc- 
loposthium. 

ORDER  3.  Hypotrichida. — The  cilia  are  limited  to  the  ventral  surface,  and 
are  frequently  fused  into  specialized  organs  of  motion 
and  touch,  the  cirri.  There  are  no  strictly  parasitic 
forms. 

ORDER  4.  Peritrichida. — The  cilia  are  greatly  reduced,  in  some  cases  to 
the  adoral  zone,  but  additional  rings  may  be  present. 
Several  ectoparasites  belong  here,  especially  the  genera, 
Spirochona,  Kentrochona,  Lichnophora,  Cyclochseta 
and  Trichodina. 
SUB-CLASS.  Suctoria. — Infusoria  with  suctorial  tentacles  in  the  place  of  cilia. 
They  are  frequently  ectoparasites  and  the  young  of  some 
genera.,  e.g.,  Spheerophrya  are  internal  parasites  in 
other  infusoria. 

PHYLUM   IV.     Sporozoa. — Protozoa  without  motile  organs;    reproduction  by 
sporulation;   always  parasites. 
CLASS  I.     Telosporidia. — Sporozoa  in  which  the  act  of  reproduction  ends  the 
individual's  life,  the  entire  protoplasm  being  used  in 
forming  spores. 
ORDER    1.     Gregarinida. — The  young  stages  alone  are  cell  parasites,  the 
adult  organisms  living  in  fluids  within  the  cavities  of 
animal  hosts.     There  are  no  human  parasites. 
ORDER   2.     Coccidia. — Intra-cellular  parasites,  mainly   in  the  epithelial 
cells  of  vertebrate  and  invertebrate  hosts.  Human  para- 
sites have  been  traced  mainly  to  the  genus  Coccidium. 
Here  also  we  should  place   Cyclasterella  scarlatinalis 
Mallory. 
ORDER   3.     Hoemosporidia. — Sporozoa  of  small  size  living  in  the  blood  cor- 
puscles of  vertebrates.     Human  parasites  belong  to  the 
genera  Laverania,  Plasmodium,  and  Piroplasma. 
CLASS  II.     Neosporidia. — Sporozoa  in  which  the  entire  cell  is  not  used  at  one 
time  in  forming  spores,  the  latter  developing  while  or- 
dinary vegetative  processes  are  carried  on. 
ORDER   4.     Myxosporidia. — Neosporidia  with  spores  containing  polar  cap- 
sules and  anchoring  threads.    Here  belong  several  gen- 
era of  note,  in  that  serious  epidemics  of  lower  animals 
are  caused  by  them,  e.  g.,  nosema — causing  pebrine  dis- 
ease in  silkworms,  Myxobolus,  Myxidium,  etc. 
ORDER    5.     Sarcosporidia. — Neosporida    in   which  the  initial  stages   are 
passed  in  muscle-cells  of  vertebrates.    Cysts  are  formed 
with  double   membranes   in  which  kidney-shaped  re- 
productive   elements   are   produced.      The  one  genus 
occasionally  parasitic  in  man  is  Sarcocystis. 
This  phylum  is  particularly  rich  in  forms  whose  affinities  are  too  obscure  to 
permit  of  taxonomic  position,  and  further  work  must  be  done  before  they  can  be 
accurately  placed.    There  is  strong   evidence  that  future  research  will  demon- 
strate the  necessity  of  another  class  to  hold  these  organisms,  or  perhaps,  several 
classes.     At  the  present  time  such  forms  can  only  be  admitted  as  Sporozoa  In- 
certceSedis,  and  as  such  we  would  include  the  genera  Ophryocystis,  Serum- 
sporidium,    Lymphosporidium,    Blanchardina,    Cytoryctes   and   Neurorycetes. 
(It  is  probable  from  Williams'  observations  that  Neurorytes,   the  cause  of  ra- 
bies, is  a  rhizopod  and  not  a  sporozoa;    if  so,  Cytoryctes,  which  is  closely  related, 
must  be  placed  there  too.) 

24  *• 


CHAPTER  XVIII. 

MOSQUITOES. 
By  L.  O.  HOWARD,  Ph.D. 

Every  person  interested  in  liiunan  health  should  have  some  knowledge 
of  mosquitoes.  The  carriage  of  malaria  by  the  different  species  of  the 
genus  Anopheles  and  the  transference  of  yellow  fever  by  Stegomyia  calo- 
pws  render  it  necessary  that  not  only  medical  practitioners  but  also  the 
laity  should  be  thoroughly  familiar  with  the  characters  which  distinguish 
these  mosquitoes  in  order  that  they  may  at  once  be  recognized  not  only 
in  the  adult  form  but  in  all  the  stages  of  their  existence.  The  important 
discoveries  which  have  been  made  regarding  the  carriage  of  disease  by 
mosquitoes  render  further  discoveries  of  a  similar  nature  not  only  possible 
but  rather  probable,  and  therefore  information  among  the  medical  pro- 
fession regarding  them  should  be  widespread;  or  at  least  there  should  be 
convenient  sources  of  information  for  the  use  of  those  who  wish  to  go 
rather  deeply  into  the  subject,  and  which  may  be  available  in  case  of 
needed  emergency  investigation.  It  is  for  these  reasons  that  considerable 
space  is  devoted  here  to  the  consideration  of  mosquitoes,  their  habits,  life 
history,  classification,  and  methods  of  control. 

So  far  as  is  known  definitely,  the  larvse  of  all  mosquitoes  inhabit  water, 
although  they  are  true  air-breathers — that  is  to  say,  they  come  to  the  sur- 
face of  the  water  at  longer  or  shorter  intervals  to  breathe. '^ 

Mosquitoes  are  rapid  breeders,  and  pass  the  pupal  condition  also  in  the 
water,  but  floating  normally  at  the  surface.  Most  species  pass  through 
several  generations  in  the  course  of  a  summer,  and  many  of  them  hibernate 
as  adults  hidden  away  under  the  bark  of  trees,  in  protected  places  like 
outbuildings,  the  under  side  of  bridge  culverts,  in  old  boxes,  and  in  the 
cellars  and  attics  of  houses.  In  the  extreme  southern  states  many  species 
are  active  throughout  the  winter,  and  even  as  far  north  as  Washington, 
mosquitoes  in  heated  houses  may  bite  in  December  and  January.  In 
localities  where  there  are  prolonged  dry  spells  and  where  heavy  rains  are 
to  be  expected  only  at  certain  seasons  of  the  year,  adult  mosquitoes  of  many 
species  live  through  the  dry  spells  and  lay  their  eggs  as  soon  as  the  rains 
come.  This  is  especially  the  case  in  tropical  regions  where  the  year  is 
Givided  into  wet  and  dry  seasons.  Certain  species  do  not  necessarily 
hibernate  as  adults  or  live  through  the  dry  seasons  as  adults.  There  are 
many  species  which  may  exist  for  a  long  time  in  the  egg  stage,  the  eggs 
being  laid  in  places  like  small  excavations,  sure  to  be  filled  with  water  when 
heavy  rains  occur,  and  others  hibernate  in  the  larval  state. 

Under  normal  summer  conditions  of  temperate  regions,  when  rains 
occur  more  or  less  frequently,  the  life  of  the  average  adult  mosquito  is 

*The  larv£e  of  Culex  dupreei  and  C.  discolor  offer  the  only  known  exceptions 
to  this  rule 

370 


MOSQUITOES  371 

short,  and  in  fact  the  term  of  the  life  of  the  adult  seems  to  be  dependent 
mainly  upon  the  opportunity  of  propagation  which  is  the  main  purpose 
of  the  adult.  The  adult  male  mosquito  does  not  necessarily  take  nourish- 
ment. It  will  sip  water  or  any  liquid  substance,  like  juices  of  fruits  and 
even  the  honey  of  flowers.  The  adult  female  does  not  necessarily  rely 
upon  the  blood  of  warm-blooded  animals;  they  are  plant  feeders,  and  very 
few  of  the  countless  millions  ever  get  an  opportunity  to  taste  the  blood  of  a 
warm-blooded  animal.  They  have  been  seen  puncturing  the  heads  of 
young  fish  and  swarming  about  turtles  when  the  latter  are  upon  land. 
They  also  have  been  seen  puncturing  the  chrysalis  of  a  butterfly. 

The  larvae,  on  the  contrary,  feed  upon  all  sorts  of  minute  organisms  float- 
ing upon  the  surface,  held  in  suspension  in  the  water,  or  resting  upon  the 
bottom  of  pools. 

Many  species  are  adapted  successfully  to  resist  extremely  low  tempera- 
tures. Arctic  travelers  speak  of  the  abundance  and  voracity  of  Arctic 
mosquitoes.  They  occur  in  enormous  swarms  during  the  short  summers 
of  Alaska,  Lapland  and  Greenland. 

Classification. — All  mosquitoes  belong  to  the  order  Diptera,  or  two- 

FlG.    11. 


wmmm 

Wing  of  a  mosquito,  sliowing  scales.     (Original.) 

winged  flies,  and  to  the  family  Culicidae.  The  species  of  the  family  Culi- 
eidse  may  at  once  be  distinguished  from  all  other  dipterous  insects  by  the 
fact  that  the  wing  veins  and  the  body  bear  flattened  scales.  There  are 
certain  other  insects  which  bear  a  close  general  resemblance  to  true  mos- 
quitoes, such  as  certain  crane-flies  of  the  family  Tipulidae,  and  especially 
of  the  genus  Geranomyia  in  which  the  insect  has  a  distinct  mosquito-like 
form  and  a  prolongation  of  the  mouth-parts  resembling  the  mosquito's 
proboscis,  but  when  examined  under  a  microscope  or  high  power  hand- 
lens  the  wing  veins  are  seen  to  be  naked — not  clothed  with  scales  or  hairs. 
The  family  Culicidse  has  been  divided  into  several  sub-families,  but  for 
the  purposes  of  this  work  it  is  only  necessary  to  consider  the  sub-families 
Culicinse  and  Corethrinae,  the  former  sub-family  including  all  true  biting 
mosquitoes  and  the  latter  those  forms  in  which  the  proboscis  is  short  and 
not  formed  for  piercing.  Certain  authors  have  split  up  the  biting  mos- 
quitoes into  several  sub-families,  and  have  even  given  some  of  them 
family  rank.  Such  a  classification  seems  premature  and  the  families  so 
created  do  not  seem  to  have  equal  classificatory  rank  or  to  be  founded 
upon  as  important  morphological  characters  as  the  other  accepted  famihes 
in  the  order  Diptera.  Considering,  therefore,  all  true  biting  mosqui- 
toes as  belonging  to  the  sub-family  CuUcinse,  the  principal  North  Ameri- 
can genera  will  readily  be  distinguished  by  the  following  table,  and  the 


372 


DISEASES  CAUSED  BY  PROTOZOA 


non-bitiiig  mosquitoes  of  tlie  sub-fumilj  Coivthriiuii  will  receive  no  further 
consideration  in  tliis  aeeount. 

Synoptic  Table  of  the  Principal  Genera  of  the  Biting  Mosquitoes  (Culicinse)  of 
the  United  States. 

1.  Palpi  in  the  male  at  least  nearly  as  long  as  the  proboscis;  in  the  female 

less  than  one  half  as  long 3 

Palpi  in  both  sexes  at  least  almost  as  long  as  the  proboscis 2 

Palpi  in  Ijoth  sexes  less  than  one-half  as  long  as  the  proboscis 7 

2.  Proboscis  straight  or   nearly  so,  colors    of   body  brown  and  yellow- 

ish  Anopheles 

Proboscis  very  strongly  curved,  colors  bluish  or  greenish.  .  .  .Megarhinus 

3.  Legs  bearing  many  nearly  erect  scales Psorophora 

Legs  destitute  of  such  scales 4 

4.  Back  of  head  bearing  many  narrow  scales 5 

Back  of  head  covered  with  broad,  appressed  scales Stegomyia 

5.  Feet  black,  the  hind  ones  in  part  snow-white J anthinosoma 

Feet  not  marked  like   this 6 

6.  Scales  in  outer  rows  on  sides  of  veins  of  wings  very  narrow,  scarcely 

tapering  at  tlie  base Culex 

Scales  in  outer  rows  on  sides  of  veins  in  basal  half  of  wings  very  narrow, 
many  of  those  in  apical  half  of  wings  rather  broad  and  distinctly 

tapering  at  the  base M elanoconion 

Scales  of  wings  very  broad,  strongly  tapering  at  the  base.  .  Tceniorhynchus 

7.  Upper  side  of  thorax  with  line  of  bluish  scales Uranotcenia 

Upper  side  of  thorax  not  marked  in  this  way 8 

8.  With  several  bristles  below  the  scutellum Wyeomyia 

Without   such    bristles Aedes 

Certain  additional  generic  names  are  used  in  connection  with  American 
mosquitoes,  especially  Grabhamia  and  Theobaldia.    Mr.  D.  W.  Coquil- 

FiG.  12 


Head  and  beak  of  a  mosquito,  showing  antennae,  palpi,  proboscis.     (Original.) 

lett,  who  is  responsible  for  the  preceding  synoptic  table,  is  not  yet  quite 
certain  of  the  status  of  these  two  genera  Certain  generic  names  have  also 
been  proposed  by  Felt  and  by  Dyar  in  which  the  genera  are  based  upon 


MOSQUITOES  373 

examinations  of  the  genitalia  of  the  male  sex.  While  it  is  quite  likely  that 
these  genera  may  be  valid,  more  must  be  known  about  them  bcd'ore  they 
are  introduced  into  a  work  of  this  character.  It  may  also  be  statfid  that 
just  as  this  article  is  being  completed  a  West  Indian  genus,  Deinocerites, 
has  been  taken  by  Dyar  at  Miami,  Florida.  D.  cancer,  the  sj;ecies  cap- 
tured, breeds  in  brackish  water  at  the  bottom  of  crab  holes  near  the  sea.^ 


MOSQUITOES  OF  THE  GENUS  CULEX. 

None  of  the  species  of  the  genus  Culex  have  been  definitely  and  ac- 
ceptably shown  to  be  responsible  for  the  carriage  of  disease  in  temperate 
or  subtropical  regions,  although  the  parasitic  worms  of  the  genus  Filaria, 
are  said  to  be  carried  and  transmitted  by  Culex  jatigans  as  well  as  by 
Stegomyia  calopus  and  Anopheles.  The  claim  that  dengue  fever  is  trans- 
mitted by  a  Culex  does  not  seem  as  yet  to  have  been  fully  substantiated. 
The  species  of  this  genus  may  be  recognized  by  the  more  or  less  erect 
forked  scales  on  the  head  and  the  slender  elongate  side  scales  of  the  wing 
veins.  Although  many  genera  have  been  split  off  from  the  genus  Culex 
as  it  was  understood  as  late  as  1900,  by  Theobald  and  other  writers,  the 
genus  still  remains  complex  and  is  likely  to  be  still  further  split  up. 
Although  the  adults  of  the  genus  as  at  present  understood  have  a  com- 
paratively uniform  structure  and  may  not  readily  be  divided  generically  by 
sound  morphological  characters,  the  larvee  differ  radically  among  them- 
selves, and  many  important  points  in  the  life  history  are  so  variable  among 
the  species  as  to  render  a  prophecy  as  to  future  generic  subdivision  prob- 
ably sound.  Many  of  the  individual  species  which  are  accepted  to-day 
have  two  or  more  distinct  types  of  larvse  from  which  are  bred  non-separ- 
able adults,  which  would  seem  to  indicate  the  necessity  for  new  species 
based  on  larval  characters. 

The  type  of  the  genus  has  always  been  considered  to  be  Culex  pipiens 
of  Linnaeus,  an  almost  perfectly  cosmopolitan  form  which  breeds  com- 
monly about  houses  in  all  parts  of  the  civilized  world  and  is,  in  temperate 
regions  especially,  the  commonest  inhabitant  of  rain  water  barrels.  This 
species  was  long  considered  as  perfectly  typical  of  the  genus  not  only  in 
structure  but  in  life-history;  but  the  extended  studies  of  other  species  have 
indicated  remarkable  differences  in  life-histories. 

The  eggs  of  Culex  pipiens  are  laid  in  an  irregular  raft-shaped  mass  on 
the  surface  of  the  water.  The  mass  is  usually  shaped  like  a  pointed 
ellipse,  somewhat  convex  below  and  concave  above,  all  the  eggs  standing 
on  end  and  closely  applied  side  by  side  in  from  six  to  thirteen  longitudinal 
rows,  and  from  three  or  four  to  forty  eggs  in  a  row.  The  number  in  each 
batch  varies  from  two  hundred  to  four  hundred.     Individual  eggs  are 

^  Since  this  article  was  put  in  tyi^je  there  has  been  great  activity  in  the  splitting 
up  of  the  old  genera  and  the  erection  of  new  genera  of  mosquitoes,  and  a  condition 
of  staple  equilibrium  has  not  yet  been  readied.  To  print  a  full  synopsis  of  these 
late  views  would  far  exceed  the  limits  of  this  work,  and  the  writer  therefore  re- 
fers readers  who  wish  to  carry  the  subject  of  classification  further,  to  Technical 
Bulletin  No.  11,  Bureau  of  Entomology,  U.  S.  Department  of  Agriculture,  entitled 
"A  Classification  of  the  Mosquitoes  of  North  and  Middle  America,"  by  D.  W. 
Coquillett,  Washington,  1906,  page  31,  1  figure,  which  will  be  sent  free  to  appli- 
cants. 


374 


DISEASES  CAUSED  BY  PROTOZOA 


.7  mm.  long  and  .IG  mm.  in  diameter  at  the  base.  The  entire  egg  mass  is 
about  one-fourth  of  an  inch  in  length.  In  summer  weather  the  eggs  hatch 
in  from  sixteen  to  twenty-four  hours.  The  hirvjie  issue  from  the  under- 
side of  the  egg  mass  and  are  very  active  at  birth.  They  come  frequently 
to  the  surface  to  breathe,  and  during  the  first  few  hours  of  their  life  may 


Culex  pipiens  :  egg-mass  and  enlarged  eggs.     (Author's  illustration.) 

remain  under  the  egg  mass  where  they  get  air  from  the  air  film  by  which 
the  mass  is  surrounded.  The  mouth  of  the  larva,  or  "wriggler"  as  it  is 
commonly  termed,  is  furnished  with  tufts  or  filaments  which  are  con- 
stantly in  vibration.  The  head  is  large,  the  antennse  long,  the  thorax 
somewhat  swollen,  and  the  abdomen  slender.  The  sides  of  the  body  are 
furnished  with  stiff  bristles.    There  is  a  long  breathing-tube  which  issues 

Fig.  14. 


Culex  pipiens:  full-grown  larva.     (Author's  illustration.) 

from  the  next  to  the  last  segment  of  the  abdomen,  and  this  tube  is  thrust 
through  the  surface  film  of  the  water  every  time  the  larva  rises  to  breathe. 
The  extremity  of  the  tube  is  furnished  with  a  spiracle  and  into  it  run  the 
two  main  tracheae  of  the  body.    The  true  end  of  the  body  is  furnished 


MOSQUITOES 


375 


with  four  jflat  flaps  which  in  young  larvae  probably  function  as  air-gills. 
The  specific  gravity  of  the  larva  is  somewhat  greater  than  water,  and  it 
wriggles  in  ascending  to  the  surface,  but  so  slight  is  this  difference  in  spe- 
cific gravity  that  the  tension  of  the  surface  film  of  the  water  is  sufficient 
to  maintain  it  without  exertion  while  breathing. 

In  warm  weather  about  seven  days  suffice  for  the  growth  of  the  larva? 
and  they  then  transform  to  pupaj.  In  this  stage  the  insect  breathes 
through  two  breathing  tubes,  one  issuing  from  either  side  of  the  thorax. 
These  are  trumpet-shaped.  The  pupa  is  lighter  than  water  and  main- 
tains its  position  at  the  surface  without  effort.  It  is  active,  and  to  escape 
its  natural  enemies  may  wriggle  actively  below  the  surface  of  the  water. 
Immediately  this  exertion  ceases,  it  rises  rapidly  to  the  top  where  it  re- 

FiG.  15. 


Culex  pipiens:  adult  male  and  details.     (Author's  illustration.) 

mains  most  of  the  time.  In  the  pupal  stage  the  insect  remains,  in  mid- 
summer, about  two  days.  A  minimum  generation  of  Culex  pipiens 
will,  therefore,  occupy  ten  days — egg,  sixteen  to  twenty-four  hours,  larva, 
seven  days,  and  pupa,  two  days.  In  colder  weather,  however,  the  duration 
of  this  development  may  be  indefinitely  suspended.  There  is  an  indefi- 
nite number  of  generations  each  year,  and  the  species  will  go  on  breeding 
so  long  as  the  temperature  is  favorable.  The  adult  as  a  rule  hibernates. 
In  the  neighborhood  of  two  hundred  species  of  the  genus  Culex  have 
been  described,  and  as  before  stated  there  is  considerable  variation  in 
the  habits  and  life-histories  of  the  different  forms. 

The  common  salt-marsh  mosquito  of  the  Atlantic  coast,  Culex  sollici- 
tans,  for  example,  according  to  the  observations  of  Smith,  does  not  lay  its 
eggs  in  water  or  on  the  surface  of  water.    The  eggs  must  be  dry,  or  not 


376 


DISEASES  CAUSED  BY  PROTOZOA 


water  covered,  for  at  least  twenty-four  hours  after  they  are  laid.  Other- 
wise they  will  not  iiatch.  They  may  remain  dry  for  three  months  or 
longer  without  losing  vitality,  and  if  at  any  time,  after  they  have  been  dry 
for  a  week  or  tvvo,  they  become  covered  with  water  they  hatch  at  once. 
It  seems  also  from  these  observations  that  not  all  of  the  eggs  hatch  the 
first  time  they  are  cpvered  with  water,  the  others  hatching  upon  the  second 
covering.  Eggs  are  laid  in  every  damp  space  on  the  salt  marsh  and  the 
country  immediately  adjoining  it.  They  are  not  laid  in  raft-shaped 
masses,  but  singly.  Culex  icEniorhynchufi,  also  a  salt  marsh  mosquito, 
lays  its  eggs  as  does  C.  .s-oJIicitans.  C.  perturbaiis,  on  the  contrary,  lays  a 
raft-shaped  mass,  as  docs  C.  pipicufi.  C.  squamirjer  has  apparently  but  one 
generation  each  year,  instead  of  many  as  with  C.  pipiens.    C.  piplens  bites 


Fig.  16. 


Culex  pipiens  :  adult  female.     (Author's  illustration.) 

mainly  at  night,  but  C.  soUicitans  flies  by  day  and  bites  when  opportunity 
offers.  The  common  woods  mosquito,  C.  sylvestris,  lays  its  eggs  singly  on  the 
surface  of  the  water,  when  they  sink  to  the  bottom,  or  they  may  be  placed 
upon  moist  mud  to  hatch  when  the  water  comes.  It  appears  to  hibernate 
in  the  egg  stage,  although  larvse  have  been  found  in  pools  late  m  the 
autumn  after  ice  has  formed.  A  species  commonly  found  in  woodland 
pools,  C.  canadensis,  as  with  several  others,  hibernates  in  the  egg  stage  and 
is  one  of  the  earliest  mosquitoes  to  bite  in  the  spring.  The  flight  of  the 
species  of  Culex  seems  to  vary  considerably.  C.  pipiens  is  not  a  strong 
flier,  and  is  in  no  sense  a  migratory  mosquito.  It  stays  about  houses  and 
flies  no  further  than  is  necessary  to  secure  food  and  lay  its  eggs.  C.  soUici- 
tans, on  the  other  hand,  is  said  by  Smith  to  fly  for  long  distances  inland 


MOSQUITOES 


377 


from  the  sea  coast  where  it  breeds.  He  finds  swarms  of  this  mosquito 
forty  miles  from  the  coast;  and  in  none  of  his  experiments  has  he  been 
able  to  breed  it  from  fresh  water.  It  is  perhaps  worthy  of  note  that  what 
is  apparently  this  species  has  been  bred  by  Mrs.  Hinds  in  Texas  and  by 
Dupree  in  Louisiana,  from  fresh  water;  but  this  is  probably  a  case  where 
we  have  adults  which  arc  specifically  indistinguishable  but  which  may 
really  be  specifically  distinct.  C.  territans,  a  rather  common  small  species, 
lays  its  eggs  in  rafts  smaller  than  those  of  C.  pipiens.  The  larva  is  very 
remarkable,  having  an  enormously  long,  slender  air-tube.  The  head  is 
very  broad  with  prominent  antennae  which  are  black  at  the  tip  and  have 
a  tuft  of  long  hairs  near  the  end.    It  seems  to  prefer  cold  water  rather  than 


Fig.  17. 


Culex  sollicitans:  adult  female.     (Author's  illustration.) 


warm,  stagnant  pools.  C  triseriatus  lays  its  eggs  singly  or  in  patches  at  the 
edge  just  below  the  surface  of  the  water  where  they  adhere  slightly  and 
remain  unhatched  until  spring.  This  species  is  probably  single  brooded. 
C.  dupreei  has  a  larva  which  seems  to  be  truly  aquatic  and  never  comes  to 
the  surface  of  the  water  to  breathe.  The  larva  of  C.  discolor  also  apparently 
rises  to  the  surface  very  seldom. 

No  such  extraordinary  variation  among  species  seems  to  occur  with 
other  genera  of  Culicidse,  and  the  generalizations  which  may  be  made 
concerning  the  life-history  of  Anopheles  are  much  more  perfect. 


378  DISEASES  CAUSED  BY  PROTOZOA 

MOSQUITOES  OF  THE  GENUS  ANOPHELES. 

As  indicated  in  the  synoptic  table,  the  principal  structural  difference 
between  the  adults  of  Anopheles  and  Culex  is  the  presence  of  long  jialpi 
in  the  female  of  Anopheles  and  of  very  short  palpi  in  the  female  of  Culex. 
AVith  Anopheles  the  ])alpi  in  both  sexes  are  about  as  long  as  the  proboscis. 
The  body  colors  arc  brown  and  yellow,  and  the  wings  are  usually  spotted. 
jNlembcrs  of  the  genus  Anopheles  may  rather  easily  be  recognized  when  at 
rest,  since  the  body,  head,  and  beak  are  held  in  practically  the  same 
plane,  whereas  there  is  a  marked  angle  between  the  body  and  the  head 
and  beak  in  most  other  mosquitoes.  It  is  the  habit  of  most  species  of 
Anopheles,  in  resting  upon  a  horizontal  wall  like  a  ceiling,  to  hold  the 
body  not  parallel  with  the  wall  but  at  a  distinct  angle  with  it — sometimes 
approximating  80°.  Frequently  with  some  species,  even  when  on  a  per- 
pendicular wall,  this  angle  of  rest  is  very  obvious. 

As  a  rule  the  Anopheles  mosquitoes  bite  only  after  nightfall,  but  an 
exception  must  be  made  in  the  case  of  A?iopheIes  crucians  which  will  bite 
durino-  the  day.  This  is  a  matter  of  importance,  since  it  has  heretofore 
been  believed"  that  shelter  from  mosquitoes  after  nightfall  obviates  all 
dano-er  from  malaria.  Even  Anopheles  punctipennis  has  been  seen  by 
Smith  in  the  afternoon  on  porches,  and  Dyar  has  known  it  to  bite  by  day. 
It  has  not  been  proven  definitely  that  this  species  will  carry  malaria,  and 
in  fact  its  presence  in  large  numbers  in  portions  of  New  Jersey  where 
malaria  is  unknown  and  yet  where  cases  of  malaria  must  frequently  be 
brought,  would  indicate  that  in  this  species  we  have  possibly  an  exception 
to  the  disease-bearing  function  of  the  genus. ^ 

The  Anopheles  mosquitoes  do  not  seem  to  be  strong  fliers,  and  there 
are  no  instances  on  record  known  to  the  writer  which  prove  a  longer 
flight  from  breeding  places  than  half  a  mile,  which  of  course  is  an  impor- 
tant point  in  the  problem  of  the  extermination  of  Anopheles  by  means  of 
the  abolition  of  breeding  places  or  their  treatment  with  insecticides. 

All  the  species  of  Anopheles,  differing  from  many  woodland  and  swamp 
mosquitoes,  make  every  effort  to  enter  houses.  Hibernation  is  almost 
uniformly  in  the  adult  stage,  and  in  regions  where  they  breed  abundantly, 
the  cellars  of  houses,  barns,  and  other  outbuildings  will  be  found  to  be 
favorite  places  of  hibernation.  They  are  often  found  thickly  massed  on 
the  inner  walls  of  outhouses,  and  have  been  seen  during  winter  on  the 
dark  underside  of  shelves  in  cellar  storerooms,  so  close  together  that 
their  bodies  touched,  for  a  space  of  several  feet.  There  are  a  few  recorded 
instances  of  the  hibernation  of  the  European  Anopheles  hifurcatus  in  the 
larval  condition,  the  most  marked  having  been  in  Switzerland  where  the 
larvEe  of  this  species  were  found  in  the  vicinity  of  Lausanne  hibernating 
beneath  the  ice  in  January,  February  and  March. 

The  life-histories  of  all  the  species  are  very  similar,  and  the  differences 
among  the  early  stages  of  the  different  forms  are  slight;  so  that  the  full 
life-history  of  a  single  species  may  in  a  measure  be  considered  typical  of 
the  genus.    Anopheles  maculipennis,  one  of  the  commonest  forms  in  the 

1  Since  this  was  written,  Dr.  J.W.  Dupree  of  Baton  Rouge,  La.,  has  sent  the 
writer  a  paper  in  which  he  states  that  he  has  discovered  the  malarial  relation  for 
this  species. 


MOSQUITOES 


379 


United  States,  has  a  wide  distribution,  occurring  also  in  Canada  and 
throughout  Europe.  It  has  not  as  yet  been  found  in  Asia  or  other  parts 
of  the  world,  and  it  is  quite  possible  that  it  was  introduced  from  Europe 
into  the  United  States;  in  fact,  it  is  possible  that  malaria  itself  was  so 
introduced,  although  the  recorded  prevalence  of  fevers  among  the  early 
settlers  of  Jamestown  and  other  portions  of  this  country  would  antagonize 
this  theory. 

Fig.  18. 


Anopheles  maculipennis :  adult  male  at  left,  female  at  right.     (Author's  illustration.) 

The  eggs  of  this  species  are  laid  singly  upon  the  surface  of  the  water, 
and  are  usually  found  in  little  groups.  Each  egg  is  boat-shaped  and  one 
end  is  slightly  deeper  and  fuller  than  the  other.  When  first  deposited 
they  are  white,  but  soon  darken.  The  upper  surface  is  marked  by  minute 
reticulations,  and  the  under  surface  by  much  larger  and  more  regular 
reticulations  dividing  it  into  hexagonal  areas.  The  rim  is  thickened  and 
regularly  ribbed.  Along  the  centre  of  each  side  the  rim  is  much  thickened 
and  the  ribbing  is  more  marked,  the  thickening  recalling  the  rounded 
float  which  runs  along  the  edge  of  a  life-boat.  It  is  composed  of  air- 
chambers  and  keeps  the  egg  with  its  flat  surface  uppermost.  Nuttall  and 
Shipley  have  called  attention  to  the  fact  that  when  the  egg  is  drawn,  by 
capillary  attraction,  a  little  way  up  from  the  water  upon  a  leaf  or  blade  of 
grass,  the  blunt  end  always  points  downward,  so  that  when  the  hatching 
takes  place  the  larva  emerges  into  the  water  and  not  into  the  air.  Each 
female  deposits  from  forty  to  a  hundred  eggs.  In  warm  weather  they 
hatch  in  from  three  to  four  days,  the  young  larva  issuing  from  a  circular 
split  near  the  blunt  end. 

During  the  early  part  of  its  life  the  larva  remains  habitually  at  the  sur- 
face of  the  water.    Its  breathing-tube  is  extremely  short,  and  the  body  is 


880 


DISEASES  CAUSED  BY  PROTOZOA 


held  parallel  with  the  surface  and  immediately  below  the  surface  film,  so 
that  portions  of  the  head  as  well  as  its  breathing-tul)e  are  ]M-actically  out 
of  the  water.  The  head  rotates  upon  the  neck  so  that  the  larva  can  turn 
it  around  with  the  utmost  ease  and  feetls  habitually  with  the  under  side  of 
the  head  toward  the  surface  of  the  water.  This  is  its  customary  feeding 
position.  The  long  fringes  of  the  mouth  parts  are  constantly  in  rapid 
motion,  causing  a  constant  current  toward  the  mouth-opening  so  that  all 
particles  floating  on  the  surface  of  the  Avater  gradually  converge  toward 
the  mouth  at  an  increasingly  rapid  rate  and  finally  enter  the  alimentary 
canal.  Spores  of  alga>  and  minute  particles  of  all  kinds,  organic  and  in- 
organic, floating  u])on  the  surface  of  the  water  follow  this  course  and 

Fig.  19. 


Anopheles  maculipennis  :  eggs,  greatly  enlarged.     (Author's  illustration.) 

enter  the  mouth  of  the  larva.  Seen  under  the  microscope,  those  objects 
which  are  dark  in  color  may  plainly  be  seen  to  pass  through  the  head  into 
the  thorax.  From  the  fact  that  it  feeds  upon  these  very  light  floating 
particles,  the  specific  gravity  of  the  body  of  the  larva  is  nearly  that  of  the 
water.  It  is  much  lighter  than  the  larva  of  Culex,  which  feeds  habitually 
upon  particles  held  in  suspension  at  a  lower  level,  and  the  Anopheles 
larva  maintains  itself  horizontally  just  below  the  surface  film  without 
apparent  effort.  The  tension  of  the  surface  film  itself  seems  to  afford  all 
needed  support. 

The  structural  characters  of  the  larva  are  very  distinct  and  at  once 
separate  it  from  the  larva  of  any  other  genus  of  mosquitoes.  The  head 
is  small;  the  respiratory  tube  is  extremely  short;  the  body  is  furnished 
with  very  long,  lateral,  branching  hairs,  and  upon  the  upper  surface  of 
each  of  five  of  the  abdominal  segments  there  is  a  pair  of  specialized  pal- 
mate hairs  each  with  a  stalk  and  a  conical  bundle  of  fine  hairs,  the  whole 
forming  a  little  cup;  and  it  is  thought  that  it  is  by  means  of  these  five  pairs 
of  palmate  hairs,  which  cling  to  the  surface  film,  that  the  larva  maintains 
its  horizontal  position  just  under  the  surface.  The  ninth  abdominal  seg- 
ment bears  below  a  fan-shaped  arrangement  of  long  hairs.  The  larvae  in 
moving  on  the  surface  swim  tail  foremost.  As  they  approach  full-growth, 
they  descend  frequently  to  the  bottom  of  shallow  pools,  and,  where  this 
is  covered  with  sand,  may  be  seen  mouthing  over  the  slimy  surface  of  the 


MOSQUITOES 


381 


sand  grains.    The  duration  of  the  larval  stage  is,  in  midsummer,  from 
sixteen  to  twenty  days. 

In  the  pupa]  condition  Anopheles  differs  less  markedly  from  other 
mosquitoes  than  in  the  larval  stage.  In  its  resting  position  at  the  surface 
of  the  vi^ater  it  is  less  perpendicular  than  the  pupa  of  Culex,  the  long  axis 
of  the  body  being  horizontal.  There  is  a  marked  difference  in  the  shape 
of  the  two  thoracic  respiratory  tubes,  those  of  Anopheh^s  b(;ing  short  and 
with  a  much  less  slender  base.  The  pupal  stage  lasts,  in  midsummer  from 
three  to  ten  days. 

Fig.  20. 


Anopheles  macuKpennis:  full-grown  larva,  with  head  reversed,  in  feeding  position. 
(Author's  illustration.) 

The  minimum  duration  of  a  generation  in  the  summer  time  in  the  lati- 
tude of  Washington  is  probably  about  twenty  days  or  perhaps  a  little  less. 
This  period  may  be  extended  indefinitely  by  cooler  weather. 

The  female  Anopheles  will  bite  a  number  of  times,  and  in  laboratory 
experimental  work  it  is  usually  found  necessary  to  give  a  female  Anoph- 
eles a  full  meal  of  blood  before  she  can  be  induced  to  deposit  her  eggs, 
although  Dupree  has  induced  fertile  oviposition  without  the  meal  of 
blood.  After  the  first  breeding,  no  further  sanguinary  diet  seems  to  be 
necessary  and  adults  may  be  kept  alive  for  some  time  by  feeding  them 
upon  bananas  or  other  fruit. 


382 


DISEASES  CAUSED  BY  PROTOZOA 


The  genus  is  one  of  wide  distribution,  and  tliis  distribution  corresponds 
fairly  well  with  the  distribution  of  malarial  diseases,  the  range  of  Anoph- 
eles nioscjuitoes,  however,  being  greater  than  the  range  of  the  disease 
since  there  are  very  many  localities  where  Anopheles  exist  in  numbers  and 


Fig.  21. 


Anopheles  larva  at  surface  of  water,  showing  resting  and  feeding  position. 
(Author's  illustration.) 


where  malaria  has  not  been  introduced.  Just  as  the  disease  itself  is  one 
of  low  altitudes,  so  the  mosquitoes  of  this  genus  prevail  in  low-lying  situa- 
tions. They  are  seldom  found  in  numbers  above  an  altitude  of  one  thou- 
sand feet,  although  in  the  tropics  they  are  found  at  a  considerably  higher 


Fig.  22. 


Mosquito  pupa  in  resting  positions  at  surface  of  water;    Culex  at  left,  Anopheles  at  right. 
(Author's  illustration.) 

altitude.  They  have  even  been  found  in  the  City  of  Mexico  at  an  altitude 
of  nearly  eight  thousand  feet,  although  they  are  comparatively  scarce  and 
malarial  diseases  are  practically  unknoAvn,  as  the  writer  is  informed  by 
health  authorities  resident  in  that  city.  No  s]w>cies  occurs  in  the  far  North, 
as  is  quite  to  be  expected  from  their  absence  at  considerable  clevationSt 


MOSQUITOES 


383 


In  the  number  of  species  the  genus  is  a  very  extensive  one,  although  its 
distinct  forms  are  not  so  numerous  as  the  species  of  the  genus  Culex.  In 
the  United  States  there  are  seven  recognized  species,  which  may  be  dis- 
tinguished by  the  following  synoptic  table: 


GENUS  ANOPHELES. 


1.  With  a  yelloys^ish-white  spot  near  three-fourths  the  length  of  the  first 

margin  of  the  wing 3 

Without  such  a  spot 2 

2.  Scales  of  the  last  vein  and  the  palpi  wholly  black 5 

Scales  of  the  last  vein  white,  marked  with  three  black  spots,  palpi 

marked  with  white  at  bases  of  last  four  joints crucians  Weid. 

3.  Hind  feet  wholly  brown 4 

Hind  feet  largely  snow-white  on  the  apical  half;  West  Indies,  Mexico, 

Central  and  South  America: 

Last  joint  of  hind  feet  wholly  white argyritarsis  Desv. 

Last  joint  black  at  base albipes  Theob. 

4.  Scales  of  last  vein  white,  those  at  each  end  black,  scales  of  third  vein 

black,  those  at  the  apex  white punctipennis  Say. 

Scales  of  last  vein  white,  those  toward  the  apex  black,  scales  of  third 

vein  white  and  with  two  patches  of  black  ones.  .  franciscanus  McCrack. 

5.  Wings  with  several  dark  spots maculipennis    Meig. 

Wings  unspotted barberi    Coq. 

Several  other  species  have  been  attributed  to  the  United  States.  Of 
these,  Anopheles  Jerruginosus  of  Wiedemann  is  probably  a  synonym  of 
crucians;  quadrimaculatus  of  Say  is  a  synonym  of  maculipemiis  of  IMeigen ; 
and  hiemalis  of  Fitch  is  a  synonym  of  punctipennis  of  Say.  A.  nigripes 
Staeger,  a  European  species  with  unspotted  wings,  is  said  to  occur  in 
northern  Europe  and  North  America,  but  the  locality  and  collector  are 
unknown  to  the  writer.    A.  pictus  of  Loew  was  described  from  Asia  ]\Ii- 

FiG.  23. 

Costal  cell  SiCbcostal  cell  First  vein      '   Marginal  cell 

Costal  vein        |    Axillary  vein    j    Second  vein         I  Third  vein      \  First  submarglnal  cell 

'  '    I  ''-       '- '         ^ 


ixillary  cell 

I 
Sixth  vein 


Piflh  vein 
Diagram  of  mosquito  wing,  with  names  of  veins  and  cells.     (After  Coquillett.) 


A-'-'Ulcell       /        Small  cross-vein    i        Second  siibjaarginal  cell 
Hind  cross-vein  Fourth  vein 


nor,  and  its  occurrence  in  the  North  American  fauna  is  very  doubtful. 
A.  walkeri  of  Theobald  also  has  unspotted  wings,  and  is  said  by  Theobald 
to  have  been  captured  at  Lake  Simcoe,  Ontario,  in  September.  It  is  now 
supposed  to  be  a  synonym  of  the  European  A.  bifurcatus. 

Probably  the  commonest   and  the  most  Avidely  distributed  of  these 
species  is  Anopheles  maculipennis.    It  is  not  a  striking  looking  form,  being 


3S4 


DISEASES  CAUSED  BY  PROTOZOA 


of  medium  size  and  of  general  insignificant  coloring.  The  wings  have  a 
slight  yellowish  cast,  and  bear  four  rather  small  dark  spots.  As  pointed 
out  in  the  synoptic  table,  the  scales  of  the  last  wing-vein  and  the  palpi  are 
entirely  black.  Its  Eiu'o])ean  distribution  has  already  been  referred  to, 
and  in  the  United  States  it  is  widespread.  It  occurs  abundantly  about 
New  York  City  and  on  Long  Island.  Felt  records  it  as  occurring  about 
Albany,  and  through  the  central  part  of  New  York  State  it  is  a  compara- 

Fiu.  24. 


Anopheles  punctipennis :    adult  femalo. 

tively  common  species.  In  New  Jersey,  Smith  finds  that  it  occurs  through- 
out the  state,  and,  although  in  general  it  is  less  numerous  than  A .  punc- 
tipennvi,  it  is  on  the  whole  more  plentiful  in  the  northern  and  hilly  sec- 
tions of  the  state.  It  is  found  about  Boston  and  in  other  parts  of  New 
England.  It  occurs  in  all  of  the  Atlantic  States  to  Florida,  in  all  of  the 
Gulf  States,  in  Ohio,  Wisconsin,  Minnesota,  Idaho,  California,  and  south 
into  Mexico.    It  also  occurs  in  Canada. 


MOSQUITOES 


385 


Anopheles  punctipennis  is  a  much  more  distinctive  looking  species. 
The  general  effect  of  the  wings  is  that  they  are  greatly  mottled,  and  there 
is  a  characteristic  and  distinctive  yellow^ish-white  marginal  spot  near  the 
apical  fourth  of  the  v^^ings.  It  is  of  medium  size  and  of  dark  brown  color, 
and  the  beak  and  legs  are  unhanded.  It  is  very  widely  distributed  through- 
out the  United  States,  and  occurs  also  in  Canada,  but  its  distribution  is 
northern  rather  than  southern.  It  is  found  in  the  New  England  States, 
New  York,  the  Atlantic  Coast  States  certainly  as  far  north  as  North  Caro- 
lina and  Louisiana,  the  Central  States  including  Minnesota.  It  has  been 
found  as  far  north  as  St.  John,  New  Brunswick,  and  as  far  southwest  as 
Salvatierra,  Mexico.     It  also  occurs  in  California. 

Fig.  25. 


Anopheles  crucians :  adult  female. 

Anopheles  crucians,  as  compared  with  the  preceding  species,  has  rather 
a  southern  than  a  northern  distribution  It  is  at  once  distinguished  from 
the  other  species  by  the  white  bases  of  the  last  four  segments  of  the  palpi, 
and  by  the  white  scales  on  the  last  wing-vein,  which,  however,  is  marked 
with  three  black  spots,  while  the  disk  of  the  wing  carries  several  black 
patches.    As  pointed  out  by  Smith,  this  species  flies  and  bites  freely  long 

25 


386  DISEASES  CAUSED  BY  PROTOZOA 

before  dusk  and  long  after  sunrise.  lie  finds  it  to  be  the  most  annoying 
indoor  form  at  Cape  ]\Iay  and  tliat  its  chief  brcetUng  phu-e  in  New  Jersey 
is  in  the  Cape  marsh.  The  species  also  occurs  rather  abundantly  on  the 
south  shore  of  Long  Island.  It  extends  down  the  Atlantic  coast  to  Miami, 
Florida,  and  is  also  found  in  Cuba.  It  occurs  in  the  Southern  States 
west  to  Texas. 

Anopheles  albipes  is  distinctly  a  tropical  and  sul)tro)iical  form.  It  oc- 
curs throughout  the  West  Indies  and  at  various  points  in  Central  America 
as  far  south  as  Panama.  It  has  been  taken  at  Key  West,  Florida,  and 
is  reported  to  occur  in  India.  It  is  a  striking  mosquito  in  general  appear- 
ance, and  is  distinguished  by  its  silvery-white  hind  tarsi,  the  last  joint 
only  being  black  at  the  base. 

Anopheles  franciscanus  is  sufficiently  characterized  in  the  synoptic 
table,  and  is  a  western  form  occurring  at  various  points  in  California. 
It  has  also  been  found  at  Laredo,  Texas,  and  at  Las  Vegas,  New  Mexico. 

The  American  Anopheles  with  unspotted  wings,  A.  barberi,  is  a  rare 
species,  and  breeds  in  hollow  trees  in  the  woods.  It  was  originally  found 
at  Plummers  Island,  ISIaryland,  and  has  since  been  taken  in  Virginia  and 
at  St.  Louis. 

Anopheles  argyriiarsis  is  a  form  of  tropical  and  subtropical  distribution, 
as  is  A.  albipes  from  which  it  may  at  once  be  distinguished  by  the  absence 
of  the  black  mark  at  the  base  of  the  last  tarsal  joint.  It  has  practically 
the  same  distribution  as  A.  albipes.  It  has  been  taken  at  New  Orleans 
and  may  breed  there,  although  the  constant  traffic  between  that  port  and 
Central  America  and  W^est  Indian  points  renders  the  introduction  of  the 
species  very  easy  and  its  capture  does  not  necessarily  mean  that  it  is  es- 
tablished in  Louisiana. 

Anopheles  albipes  and  Anopheles  argyriiarsis  have  been  placed  by 
Theobald  in  his  genus  Cellia,  which  is  distinguished  from  Anopheles  by 
the  dense  scaling  of  the  wings,  and  by  the  presence  of  nearly  erect 
clusters  of  scales  along  the  sides  of  the  abdomen.  The  habits  and  larval 
characteristics  are,  however,  those  of  Anopheles,  and  there  is  little  doubt, 
since  they  are  the  prevalent  species  of  the  Anopheles  group  in  malarial 
localities  in  the  West  Indies  and  Central  America,  that  they  are  malaria 
carriers.  In  fact  this  relation  has  been  proven  in  the  case  of  argyriiarsis 
by  Lutz,  and  in  the  other  by  Low. 


THE  GENUS  STEGOMYIA. 

The  genus  Stegomyia  was  separated  by  Theobald  from  Culex,  by  the 
fact  that  the  scales  of  the  head  and  scutellum  are  all  flat  and  broad, 
whereas  in  Culex  the  scales  of  the  head  are  narrow  and  curved  with  up- 
right forked  ones  and  flat  lateral  ones.  Sixteen  species  were  originally 
placed  by  him  under  this  genus  and  eight  were  later  described  and  trans- 
ferred to  this  genus,  but  certain  of  these  have  since  been  placed  in  other 
new  genera.  The  genus  itself  may  not  prove  to  be  a  stable  one.  Surely 
the  differing  life-histories  of  some  of  the  forms  would  indicate  further 
separations.  No  generalization  can  be  made  regarding  the  disease-bear- 
ing possibilities  of  the  genus,  since  only  a  single  species,  Stegomyia  calo- 
pus,  has  been  shown  to  carry  a  disease — yellow  fever. 


MOSQUITOES  387 

Stegomyia  calopus  has  a  wide  distribution.  In  general  terms  Theobald 
considered  it  as  ranging  from  38°  south  to  38°  north  latitude,  the  belt 
extending  around  the  world.  It  seems  to  have  a  general  distribution 
throughout  all  eastern  Australia,  western  Sumatra,  all  of  Java  and  farther 
India,  southern  Japan,  eastern  Hindostan,  the  Seychelles,  southern 
Africa,  Mashonaland,  Nigeria,  the  African  west  coast  inchuhng  Sene- 
gambia  and  Lagos,  all  of  Spain,  southern  Italy,  Palestine,  east  coast 
of  South  America  from  British  Guiana  to  Rio  de  la  Plata,  all  of  the  West 
Indies,  Argentina,  the  coast  regions  of  Central  America  on  both  the 
Pacific  and  Gulf  of  Mexico  sides.  It  is  also  found  at  Guayaquil  and 
Callao  and  will  undoubtedly  be  found  at  other  South  American  ports  in 
the  western  coast  as  far  south  as  Valparaiso.  It  it  also  found  in  the  Fiji 
Islands,  the  Hawaiian  Islands  and  the  Philippine  Islands. 

The  Central  American  distribution  of  the  species  is  of  especial  interest 
as  bearing  upon  the  possibilities  of  its  occurrence  at  high  elevations.  It 
is  stated  above  that  it  occurs  upon  both  the  east  and  west  coasts  of  Central 
America.  In  Mexico,  since  the  introduction  of  railroads  running  up 
from  the  coast,  it  has  been  extending  its  inland  and  upward  range.  It  has 
now  established  itself  at  Orizaba  on  the  Vera  Cruz  road  at  an  elevation  of 
4,200  feet,  and  at  Carasal  on  the  Interoceanic  Railroad  at  an  elevation  of 
3,000  feet.  It  occurs  abundantly  inland  in  North  INIexico,  having  followed 
up  the  valley  of  the  Rio  Grande,  and  occurs  at  all  points  on  the  railroad 
from  Tampico  to  Monterey  (altitude  1,630  feet).  It  has  been  found  in  the 
summer  time  at  Saltillo,  which  is  much  higher  than  Monterey. 

In  the  United  States  it  occurs  and  breeds  continuously  in  practically  all 
of  the  territory  which  has  been  marked  as  belonging  to  the  Lower  Austral 
life  Zone.  This  territory  includes  the  Atlantic  coastal  plain  from  the 
mouth  of  the  Potomac  River  southward,  and  all  of  the  Gulf  States  except 
the  high  regions  of  Georgia  and  Alabama  about  the  southern  end  of  the 
Appalachian  chain.  It  also  includes  the  valley  of  the  Mississippi  River 
for  some  little  distance  above  its  juncture  with  the  Ohio  River,  the  valley 
of  the  Ohio  River  to  nearly  the  middle  of  the  southern  border  of  Indiana, 
the  whole  of  Indian  Territory,  the  eastern  portion  of  Oklahoma,  a  small 
southeastern  strip  in  Kansas,  and  all  of  the  low-lying  eastern  and  southern 
portions  of  Arkansas.  The  dry  regions  of  western  Texas  do  not  furnish 
sufficient  moisture  to  propagate  many  mosquitoes,  but  in  the  water  supply 
of  ranches  in  such  dry  regions,  if  once  introduced,  the  yellow  fever  mos- 
quito will  probably  breed.  Although  found  on  the  Pacific  coast  of  Mexico, 
the  yellow  fever  mosquito  has  not  as  yet  been  authoritatively  recorded  from 
California,  although  the  coastal  region  from  Point  Vincent  south  to  Point 
Loma  offers  conditions  favorable  for  its  development.  Actual  collections 
of  mosquitoes  were  made  during  the  season  of  1904  through  a  large  part  of 
this  Lower  Austral  territory,  and  the  distribution  of  Stegomyia  calopus 
was  found  to  correspond  rather  exactly  with  the  lines  here  laid  down. 

The  northward  spread  of  this  species  is  interrupted  by  severe  winters. 
In  summer  time  it  is  constantly  being  carried  north  on  boats  up  the  Missis- 
sippi and  Ohio  Rivers  and  by  trains  coming  from  the  South.  Thus  it  has 
been  found  breeding,  in  the  summer  time,  at  points  considerably  north  of 
true  Lower  Austral  territory.  During  the  summer  of  1904  it  was  found 
breeding  at  St.  Louis  but  the  severe  winter  weather  precludes  the 
possibility  of  the  perfect  establishment  of  the  species  at  that  point. 


3SS  DISEASES  CAUSED  BY  PROTOZOA 

Siegomyia  calopus  is  a  rather  small  mosquito,  which  was  formerly  re- 
ferred to  in  literature  as  Cidcx  Jasciaius  and  as  Culcx  i(r>ti(iius.  Purists 
are  now  calling  it  Stecjomyia  calopus  jNIeigen,  since  fasciata  seems  to  be  a 
homonym.  It  is  a  very  handsome  species,  dark  in  color,  with  silvery  white 
bands  on  the  legs,  conspicuous  silvery  strijies  ujwn  its  thorax,  silvery  bands 
on  the  palpi,  and  silvery  spots  on  the  sides  of  the  thorax  and  abdomen. 
In  the  British  West  Indies  it  is  known  as  the  striped-legged  mosquito  and 
also  as  the  day  nios(|uitp.  It  bites  and  is  active  by  day,  but  may  also  bite 
at  night.  It  breeds  only  in  fresh  water  and  is  essentially  a  domestic  mos- 
quito— that  is  to  say,  it  is  seldom  found  far  from  human  habitations;  but 
about  houses  and  in  cities  and  towns  it  will  breed  in  any  chance  accumu- 
lation of  water.  It  is  a  long-lived  mosquito,  a  point  of  importance  when 
considering  the  interval  between  the  stamping  out  of  an  epidemic  and  a 
new  outbreak  without  the  introduction  of  a  new  case  from  a  distance. 
Guiteras  and  his  assistants  at  Las  Animas  Hospital  have  kept  an  adult 
female  alive  for  more  than  150  days;  and  in  the  dry  season  with  no  oppor- 
tunity to  oviposit  such  a  length  of  life  is  probably  of  frequent  occurrence. 
The  length  of  flight  has  not  definitely  been  determined.  It  does  not  seem 
I  to  be  an  especially  strong  flier,  but  its  possibilities  in  this  direction  are  of 
importance  as  determining  tlie  safe  anchorage  distance  of  vessels  from 
infected  ports.  Adult  mosquitoes  have  been  found  on  board  a  war  vessel 
recently  arrived  in  port  and  anchored  a  mile  from  shore,  under  conditions 
that  seem  to  show  that  the  mosquitoes  flew  aboard,  the  vessel  previously 
having  been  free,  and  the  possibility  of  the  carriage  of  the  mosquitoes 
from  shore  on  the  persons  of  individuals  in  boats  having  apparently  been 
eliminated.  This  is  on  the  evidence  (in  lit.)  of  Surgeon  A.  H.  Russel,  U. 
S.  N. 

The  eggs  are  deposited  singly,  each  egg  on  its  side,  and  preferably  in 
artificial  collections  of  water,  especially  in  rain-water  barrels  and  similar 
receptacles.  The  eggs  may  be  found  singly  or  in  groups  of  three  or  more 
arranged  in  parallel  rows  or  bunched  together.  They  are  black  in  color, 
cylindrical  in  shape,  with  conical  extremities,  of  which  one  is  blunter  than 
the  other.  Each  egg  is  .6  mm.  long  and  .16  mm.  broad.  The  female  may 
deposit  from  35  to  114  eggs  at  a  time,  the  average  being  about  fifty.  These 
eggs  will  withstand  desiccation,  and  are  very  resistant  to  external  influ- 
ences. Taylor  has  kept  thoroughly  dry  eggs  for  three  months,  which 
hatched  on  being  placed  in  water.  Normally  the  eggs  will  hatch  in  from 
twelve  hours  to  three  days,  depending  upon  the  temperature  of  the  water. 

The  larva  is  similar  to  that  of  Culex  pipiens,  but  it  is  more  slender  and 
the  respiratory  tube  is  shorter  and  is  swollen  in  the  middle  somewhat 
resembling  an  olive  in  shape.  The  growth  of  the  larva  is  very  rapid,  and 
in  Cuba  the  minimum  seems  to  be  about  sLx  days.  The  larvae  develop 
most  rapidly  in  foul,  stagnant  water,  and  the  development  may  be  hastened 
by  placing  a  certain  amount  of  faecal  matter  in  the  water. 

The  pupa  is  rather  dark  in  color,  with  more  elongate  thorax  and  a 
stouter  abdomen  than  Culex  pipiens.  The  minimum  duration  of  the 
pupal  stage  is  two  days,  and  the  mimimum  length  of  the  early  stages  is 
therefore  eight  and  a  half  days  (egg  twelve  hours,  larvse  six  days,  pupa 
two  days). 


MOSQUITOES  389 

REMEDIES   AGAINST    MOSQUITOES. 

The  very  best  remedy  against  mosquitoes  is  to  abolish  their  breeding 
places,  and  in  many  instances  this  may  readily  be  done  with  isolated 
country  houses  or  suburban  residences  or  in  villages  where  the  houses  are 
as  a  rule  well  separated  and  surrounded  by  gardens.  In  such  localities, 
barring  the  vicinity  of  extensive  swamp  lands,  and  outside  the  range  of 
flight  of  the  salt  marsh  mosquito,  every  property  holder  is  practically 
responsible  for  his  own  mosquitoes.  Every  effort  should  be  made  to 
clear  out  or  to  abolish  chance  breeding  places.  Disused  springs  and  wells 
should  be  cared  for,  and  every  possible  receptacle  for  standing  water 
should  be  abolished  or  filled  in.  Cesspools  should  be  covered  in  such  a 
way  as  to  render  mosquito  access  impossible  or  they  should  be  treated 
occasionally  with  kerosene.  About  a  country  place  or  suburban  house 
chance  breeding  places  are  apt  to  be  very  numerous.  Tin  cans  and  old 
bottles  in  a  rainy  summer  will  hold  sufficient  water  to  breed  hundreds  of 
mosquitoes.  The  water  pans  for  pet  animals  or  for  chickens  are  also 
breeding  places,  as  are  the  water  troughs  for  horses.  The  roof  gutters  of 
the  house  where  trees  overhang  are  apt  to  be  clogged  to  some  slight  extent 
and  thus  afford  enough  resting  water  to  breed  generations.  Rain  water 
barrels  and  tanks  should  be  carefully  screened.  All  depressions  in  the 
soil  in  which  surface  water  may  rest  for  even  so  short  a  period  as  a  week  in 
midsummer  should  be  filled  in.  The  banks  of  any  little  brooks  or  rivulets 
should  be  kept  clean  so  as  to  allow  no  opportunity  for  standing  water  or 
any  amount  of  aquatic  vegetation.  Ponds  which  cannot  be  drained 
should  be  treated  with  light  fuel-oil,  preferably  by  spraying.  Where  for 
one  reason  or  another  it  is  considered  impracticable  to  use  oil,  such  ponds 
should  be  stocked  with  fish.  Gold-fish,  silver-fish,  sun-fish,  top  minnows, 
killifish,  and  various  other  minnows  are  capital  mosquito  destroyers. 

In  localities  near  salt  marshes  or  fresh  water  swamps,  the  difficulty  is 
much  greater.  Even  in  such  places,  however,  strictly  local  work  will 
greatly  reduce  the  mosquito  supply,  and  large-scale  work  is  by  no  means 
impracticable.  The  recent  work  of  the  State  of  New  Jersey,  as  reported 
by  its  State  Entomologist,  Dr.  John  B,  Smith,  has  shown  that  the  diffi- 
culty of  draining  salt  marshes  is  not  very  great,  and  that  the  filling  in  of 
large  areas  is  perfectly  practicable.  Inland  the  drainage  of  most  swamps 
is  practicable.  For  example,  very  perfect  results  in  swamp  drainage  are 
shown  in  the  reclamation  of  the  Potomac  marshes  near  Washington. 

In  many  communities  the  work  of  mosquito  extermination  has  been 
undertaken  by  organizations  of  public-spirited  citizens,  but  with  proper 
legislation  and  with  the  proper  public  spirit  this  should  not  be  necessary. 
The  health-law  of  every  state  should  contain  a  clause  which  places  waters 
or  pools,  in  which  mosquitoes  breed,  among  the  nuisances  that  may  be 
abated  by  local  boards  of  health,  and  they,  after  due  notice  to  the  owners 
of  the  places,  should  be  empowered,  in  case  the  owners  fail  to  do  so,  to 
undertake  the  work  and  to  abate  the  nuisance,  the  cost  being  charged  to 
the  owners  of  the  property.  Such  legislation  is  in  effect  in  New  Jersey 
and  should  be  in  other  states. 


390  DISEASES  CAUSED  BY  PROTOZOA 


THE    COLLECTION   AND   BREEDING   OF    MOSQUITOES. 

Adult  mosquitoes  may  be  captured  in  a  small,  soft  net  or  more  easily  by 
placing  over  them  when  at  rest  a  small  inverted  vial.  They  are  readily 
stifled  by  tobacco  smoke  or  by  a  drojj  of  chloroform,  or  may  be  killed  in 
the  ordinary  cyanide  collecting-bottle  used  by  entomologists.  A  good 
collecting-bottle  may  be  made  by  soaking  a  few  rubber  bands  in  chloro- 
form and  placing  them  in  the  bottom  of  a  vial  with  a  layer  of  blotting 
paper  over  them.  They  will  give  off  enough  chloroform  fumes  for  a 
month  or  more  to  kill  mosquitoes  and  other  delicate  insects. 

For  permanent  preservation,  mosquitoes  may  be  gummed  with  white 
shellac  to  the  tips  of  small  cardboard  triangles,  and  the  triangles  pinned 
with  an  insect  pin  through  the  base. 

In  rearing  mosquitoes  the  rearings  should  be  isolated,  except  perhaps 
when  they  are  made  from  eggs  deposited  at  one  time  by  a  single  deter- 
mined female.  Even  here  it  is  well  to  isolate  the  larvae,  since  with  certain 
species  they  destroy  each  other.  Where  larvag  are  collected  in  a  pool,  isola- 
tion is  necessary  since  several  species  may  inhabit  the  same  pool  at  the 
same  time.  A  single  larva  should  be  reared  in  a  single  receptacle.  When 
the  larva  pupates,  the  cast  larval  skin  thould  be  saved  in  a  small  bottle  of 
formalin  or  alcohol  or  on  a  slide.  When  the  adult  emerges  the  pupal  skin 
should  be  added,  and  the  adult  and  skins  should  be  numbered  with  the 
same  number. 

Since  one  usually  has  an  insufficient  number  of  jars  to  isolate  all  or  a 
large  proportion  of  the  larv?e  in  each  culture,  it  is  well  first  to  put  them 
in  a  shallow  dish  and  isolate  those  that  appear  to  be  different.  The  rest 
should  be  left  in  a  general  culture  and  watched  closely  for  the  appearance 
of  forms  not  noticed  at  first.  Breed  all  of  the  larvae  to  adults,  unless 
reasonably  sure  that  the  culture  is  composed  entirely  of  one  species,  in 
which  case  the  remaining  larvae  can  be  preserved  in  formalin  or  alcohol. 
Mosquito  larvae  need  food,  and  if  they  are  small  the  water  must  be  re- 
newed, by  preference  from  the  original  source  with  some  of  the  bottom 
matter.  Too  much  fresh  matter  will  often  kill  the  larvae,  possibly  by  the 
over-development  of  bacteria.  Isolated  pupae  should  be  put  into  clean 
water  with  no  organic  matter.  The  larvae  should  not  be  crowded  after 
collection,  and  enough  air  space  should  be  left  at  the  top  of  the  jar  or  vial 
to  insert  a  cork  if  necessary. 

Anopheles  larvae,  being  surface-feeders,  need  a  broad,  shallow  pan, 
uncovered  and  preferably  placed  in  a  bright  light.  They  cannot  be  bred 
successfully  in  small,  deep  vessels  unless  full-grown  and  nearly  ready 
to  pupate. 

These  recommendations  are  based  upon  Dr.  H.  G.  Dyar's  extended 
exoerience  in  breeding  mosquitoes,  and  in  the  study  of  their  early  stages. 


List  of  Works  to  be  Consulted. 

1900.  Howard,  L.  O.,  Notes  on  the  Mosquitoes  of  the  United  States:  Giving  some 
Account  of  their  Structure  and  Biology,  loith  Remarks  on  Remedies. 
Bulletin  No.  25,  new  series,  Division  of  Entomology,  U.  S.  Depart- 
ment of  Agriculture,  p.  70,  fig.  22. 


MOSQUITOES  391 

1901.  Theobald,  Fred.  V.,  A  Monograph  of  the  Culicidce  or  Mosquitoefs;  Mainly 
Compiled  from  the  Collections  Received  at  the  British  Museum  from 
Various  Parts  of  the  World  in  Connection  with  the  Investigation  into  the 
Cause  of  Malaria  Conducted  by  the  Colonial  Office  and  the  Royal  Society; 
Printed  by  Order  of  the  Trustees.  Vol.  I.,  p.  424,  text  fig.  151 ;  Vol.  IL, 
p.  391,  text  fig.  318;   Vol.  III.,  (1903),  p.  359,  text  fig.  193,  pis.  XVI. 

1901-1903.  Nuttall,  G.  H.  F.,  and  Shipley,  A.  E.,  Studies  in  Relation  to  Malaria, 
II.;  "The  Structure  and  Biology  of  Anopheles,"  Journ.  Hyqiene, 
Vol.  I.,  pp.  45-74,  3  pis.;  269-276,  fig.  1.;  451-484,  4  pis.,  2  figs., 
1901;    Vol.  II.,  pp.  58-84,  1902;    Vol.  III.,  pp.  166-201,  5  pis.,  1903. 

1901.  Reed,  Walter,  and  Carroll,  James,  The  Prevention  of  Yellow  Fever,  re- 
printed from  the  Medical  Record,  Oct.  26,  1901,  p.  34,  fig.  10. 

1901.  Howard,  L.  O.,  Mosquitoes:    How  they  Live;    How  they  Carry  Disease; 

How  they  are  Classified;  How  they  may  be  Destroyed,  New  York,  Mc- 
Clure,  Phillips  &  Co.,  p.  241,  text  fig.  50,  pi.  I. 

1902.  Giles,  George  M.,  A  Handbook  of  the  Gnats  or  Mosquitoes,  giving  Anatomy 

and  Life-History  of  the  Culicidce,  together  with  Descriptions  of  all 
Species  noticed  up  to  the  present  date;  second  edition,  rewritten  and 
enlarged,  London,  John  Bale,  Sons  &  Danielsson,  Ltd.,  p.  530,  text 
fig.  51,  pi.  XVII. 

1902.  Ross,  Ronald,  Mosquito  Brigades  and  How  to  Organize  them,  London, 
Geo.  Philip  &  S^on,  32  Fleet  Street,  E.  C,  p.  98. 

1902.  Berkeley,  William  N.,  Laboratory  Work  with  Mosquitoes,  New  York, 
Pediatrics  Laboratory,  254  West  54th  St.,  p.  112,  fig.  61. 

1902.  North  Shore  Improvement  Association,  Report  on  Plans  for  the  Exter- 

mination of  Mosquitoes  on  the  North  Shore  of  Long  Island  between 
Hempstead  Harbor  and  Cold  Spring  Harbor,  New  York,  Styles  &  Cash, 
77  Eight  Av.,  p.  125,  fig.  7.  map. 

1903.  Taylor,  John  R.,  Observations  on  the  Mosquitoes  of  Havana,  Cuba,  re- 

print from  La  Revista  de  Medicina  Tropical,  June,  1903,  p.  27. 

1904.  Felt,  Ephraim  Porter,  Mosquitoes  or  Culicidce  of  New  York  State,  Bul- 

letin 79,  New  York  State  Museum,  Albany,  p.  243-400,  text  fig.  113, 

pi.  LVII. 
1904.  Smith,  John  B.,  Report  of  the  New  Jersey  State  Agricultural  Experiment 

Station  upon  the  Mosquitoes  occurring  within  the  State,  their  Habits, 

Life-history,  &c.,  Trenton,  N.  J.,  Mac  Crellish  &  Quigley,  state  printers 

p.  v.— 482,  fig.  136. 
1906.  Dyar  H.  G. ,  Key  to  the  Known  Larvce  of  Mosquitoes  of  the  United  States., 

U.  S.  Department  of  Agriculture,  Bureau  of  Entomology.      Circular 

No.  72,  p.  6,  fig;  1. 
1906.  Coquillet,  I).  W,  A  Classification  of  the  Mosquitoes  of  Middle  and  North 

America.  U.  S.  Department  of  Agriculture,  Bureau  of  Entomology, 

Technical  Series,  No.  11,  p.  31,  fig.  1. 


CHAPTER  XIX. 

THE  MALARIAL  FEVERS. 
By  CHARLES  F.  CRAIG,  M.  D. 

Synonyms. — ^^Vechselfiebcl■;  intermittent  and  remittent  fever;  tertian, 
quartan,  or  aestivo-autumnal  fever;  paludal;  climatic  fever;  swamp  or 
marsh  fevers;  ague;  paludal  fever;  hill  fever;  jungle  fever;  mountain 
fever  (in  some  localities);  coast  fever;  gnat  fever;  htemamoebiasis; 
Cameroon  fever;  febbre  intermittente;  paludisme;  maladies  palustres; 
fievre  paludeenne. 

Definition. — By  the  term  malarial  fevers  Ave  mean  a  group  of  specific 
infectious  fevers  due  to  infection  of  the  red  blood  corpuscles  of  man  by 
closely  related  animal  parasites  belonging  to  the  Sporozoa,  genus  PlaS' 
modium} 

These  fevers  occur  epidemically  or  endemically  and  are  accompanied 
by  a  sjTnptom  complex  which  is  more  or  less  characteristic  of  each  va- 
riety. Periodicity  is  one  of  the  most  marked  clinical  phenomena  and  is 
due  to  the  growth  and  multiplication  of  the  plasmodia.  Clinically,  these 
fevers  may  be  divided  into  intermittent,  remittent  and  continuous,  but 
such  a  classification  is  unscientific  as  it  does  not  indicate  disease  entities. 
All  malarial  infections  are  transmitted  by  mosquitoes  of  the  genus  Anoph- 
eles, and  so  far  as  is  known  at  the  present  time,  this  is  the  only  means  of 
transmission. 

Historical. — It  is  very  probable  that  the  ancient  Egyptians  had  some 
knowledge  of  what  we  now  term  the  "malarial  fevers,"  and  Groff  con- 
siders that  certain  inscriptions  upon  the  temple  at  Denderah  are  proof  of 
this  assumption.  Hippocrates  and  Celsus  described  very  accurately  the 
manifestations  of  the  various  forms.  Hippocrates  (406-377  B.  C.)  divided 
them  into  c[uotidian  and  tertian,  and  Celsus  (first  century,  A.  D.)  further 
distinguished  the  pernicious  forms. 

Morton^  was  the  first  to  associate  these  fevers  Avith  miasmatic  condi- 
tions, clearly  indicating  his  belief  that  they  were  due  to  noxious  gases 
arising  from  low  lands  and  swampy  districts. 

^The  malarial  parasites  belong  to  the  Sporozoa,  sub-order  Hoemosporidta, 
genus  Plasmodium.  The  name  Plasmodium  was  first  given  to  these  organisms  by 
Marchiafava  and  Celli,  and  is  very  unfortunate  from  a  biological  standpoint. 
Grassi  has  suggested  tiie  name  Hcemamoebce  for  the  jjarasites,  and  this  is  a  prei- 
erable  term  to  Plasmodium,  but  the  latter  term  will  have  to  be  retained  because 
of  the  law  of  priority.  The  same  objection  may  be  raised  to  the  name"  malaria," 
which  was  derived  from  tlie  Italian,  meaning  bad  air,  and  applied  to  these  fevers 
because  of  the  supposed  relation  of  miasmatic  conditions  to  tlieir  causation.  In 
the  light  of  our  present  knowledge  the  name  is  erroneous,  but  will  have  to  be  re- 
tained as  it  has  Decome  so  firmly  established  in  our  nomenclature. 

^  Pyretologia,  London,  1692. 

392 


THE  MALARIAL  FEVERS  393 

The  introduction  of  cinchona  into  Europe  by  th(!  Viceroy  Del  Cinchon 
in  1640  gave  an  impetus  to  the  study  of  mahiria,  as  it  thus  became  possible 
to  distinguish  malarial  fevers  from  other  infections  by  the  therapeutic  test. 
The  terra  "malarial"  was  not  applied  to  these  fevers  until  1712,  when 
Torti^  published  a  classical  description  of  the  pernicious  malarial  infec- 
tions and  distinguished  them  by  their  yielding  to  cinchona.  Meckel,  in 
1847,  and  Virchow,  in  1848,  first  described  the  melantemia  which  is  in- 
variably present  in  these  infections,  and  it  is  probable  that  they  actually 
saw,  without  recognizing  them,  the  malarial  parasites. 

It  was  not  until  1880,  however,  that  the  etiological  factor  in  the  pro- 
duction of  malaria  was  discovered.  Laveran,^  a  French  Army  Surgeon, 
stationed  at  Algeria,  after  careful  study  of  the  blood  of  many  cases  of 
malarial  fever,  announced  the  discovery  of  a  parasite  in  the  blood  which 
he  had  no  hesitation  in  claiming  to  be  the  veritable  cause  of  the  disease. 
At  first  his  researches  attracted  little  attention  but  they  were  soon  con- 
firmed by  many  observers,  and  his  claim  to  have  discovered  the  actual 
cause  of  malaria  abundantly  verified. 

Although  by  Laveran's  great  discovery  the  diagnosis  of  malaria  was 
placed  upon  a  scientific  basis,  but  little  was  known  regarding  the  means  of 
transmission  of  the  parasites,  and  it  remained  for  Ross,  in  1897,  to  clearly 
demonstrate  that  the  hsematozoa  of  birds  were  transmitted  by  a  certain 
species  of  mosquito.  Grassi  and  other  investigators  soon  confirmed  the 
investigations  of  Ptoss,  and  proved  that  all  varieties  of  the  malarial  fevers 
are  transmitted  from  man  to  man  by  mosquitoes  of  the  genus  Anopheles. 

Geographical  Distribution. — There  is  no  infectious  disease  which  can 
compare  with  the  malarial  fevers  in  the  extent  of  its  geographical  distri- 
bution. In  the  Eastern  hemisphere  malarial  infections  do  not  occur  above 
62°  N.  Latitude,  while  in  the  Western  hemisphere  they  are  very  rarely 
found  above  45°  N.  Latitude.  They  are  most  common  and  severe  in  Ioav- 
lying  coast  regions,  mountainous  countries  being  comparatively  exempt. 
The  deltas  of  large  rivers,  especially  the  rivers  of  tropical  countries,  are 
hot-beds  of  malarial  disease,  and  this  is  also  true  of  all  bodies  of  water 
situated  in  such  localities.  As  the  equator  is  approached  we  meet  less 
often  with  the  benign  forms  of  malarial  infection,  the  prevailing  types  be- 
ing the  severe  and  often  fatal  sestivo-autumnal  infections. 

The  most  important  malarial  localities  are  the  following: 

North  America. — In  North  America,  malaria  occurs  rarely  above  the 
forty-fifth  parallel,  but  is  often  frequent  and  fatal  in  the  Southern  states 
and  in  the  West  Indies,  especially  in  Cuba,  as  well  as  in  Central  America. 
In  the  New  England  and  Middle  Atlantic  states  the  benign  forms  are 
present,  but  are  comparatively  rare.  The  severe  forms  prevail  along  the 
low  regions  of  the  southern  coast  line,  and  especially  in  the  swampy  regions 
of  the  Gulf  states.  These  infections  are  common  and  severe  along  the 
Mississippi  River  and  its  southern  branches,  and  they  are  present  in 
many  of  the  Western  states,  especially  in  the  river  valleys  of  California 
where  severe  and  fatal  sestivo-autumnal  infections  are  not  uncommon. 
The  regions  about  thi  Great  Lakes  are  almost  free  from  malaria  except 
in  certain  localities  about  Lake  Michigan.  Canada  is  the  only  country 
in  North  America  which  appears  to  be  almost  entirely  free  from  malaria. 

^  Therapeutica  specialis  ad  febres  quasdam  perniciosas. 

^Bulletin  de  I'Academie  de  Medecine  de  Paris,  seance  de  23,  Nov.,  1880. 


394  DISEASES  CAUSED  BY  PROTOZOA 

South  America  — In  South  America,  severe  types  of  the  disease  are 
common,  esj)ecially  along  the  coast  regions  of  Colombia,  Venezuela, 
Guiana,  Brazil,  Ecuador,  Peru  and  Chile  The  whole  Atlantic  coast  line 
of  Central  America  is  severely  infected  with  festivo-autumnal  malaria,  and 
in  this  region  the  most  jiernicious  forms  are  common. 

Europe. — jNIalarial  fevers  occur  but  rarely  in  England,  Germany  and 
France.  In  Germany  they  occur  along  the  coast  of  the  Baltic,  especially 
in  Prussia,  and  they  are  not  imcommon  in  the  swamps  of  Hanover  and 
Westphalia,  and  along  the  Rhine;  in  France  these  infections  occur  along 
the  Loire  and  Rhone  on  the  west  coast;  in  Spain  the  valleys  of  the  Tago 
and  Guadahpiiver  are  infected,  and  pernicious  forms  occur  in  all  the 
countries  bordering  upon  the  INIediterranean ;  in  Greece,  Crete,  Italy, 
Sicily,  and  Turkey,  malaria  is  endemic;  in  Italy,  especially,  occur  the 
most  malignant  forms  in  the  regions  around  the  Roman  Campagna  and 
the  Pontine  marshes,  as  well  as  in  the  valley  of  the  Po;  in  Russia  malarial 
infections  are  present  in  the  valley  of  the  Volga,  Dniester,  and  Dnieper, 
and  they  are  also  common  in  the  regions  bordering  upon  the  Black  and 
Caspian  Seas. 

Asia. — India,  Ceylon,  portions  of  China  and  Arabia,  and  the  Islands 
of  the  Malay  Archipelago  are  infected  with  the  malarial  fevers.  This  is 
also  true  of  Asia  Minor  and  the  valleys  of  almost  all  the  great  rivers,  such 
as  the  Indus  and  Ganges.  In  Japan  the  benign  infections  are  common, 
and  even  upon  the  lofty  table  lands  near  the  Himalayas  malarial  infections 
are  often  met  with.  The  Philijipine  Islands,  until  very  recently  considered 
as  comparatively  free  from  malarial  disease,  have  been  proved  to  be  badly 
infected,  a  large  percentage  of  our  soldiers  returning  from  there  showing 
infection  with  the  tertian  and  a?stivo-autumnal  parasites. 

Africa. — In  Africa  are  some  of  the  most  dangerous  lurking  places  of 
malarial  infections,  the  worst  areas  being  those  along  the  west  coast  and 
the  Senegal,  Congo,  and  Niger  Rivers,  as  well  as  the  regions  around  the 
great  lakes  and  the  jungles  and  lake  shores  of  Abyssinia.  Madagascar,  Re- 
union, and  Mauritius  Islands  present  the  pernicious  varieties  of  the 
disease.  Around  Delagoa  Bay  and  along  the  east  coast  of  Africa,  sestivo- 
autumnal  fever  is  prevalent.  Lower  Egypt,  the  Soudan,  the  Nile  delta, 
Tripoli,  Tunis  and  Algeria,  all  harbor  these  infections. 

The  resume  given  indicates  the  most  important  localities  in  which 
malarial  infections  are  endemic,  but  there  are  numerous  districts  in  which 
a  few  sporadic  cases  occur  at  rare  intervals,  but  which  may  at  any  time 
become  endemic  foci,  provided  certain  species  of  mosquitoes  belonging 
to  the  genus  Anopheles  are  present,  together  with  individuals  harboring 
the  parasites.  A  knowledge  of  the  geographical  distribution  of  malarial 
infections  is,  therefore,  most  important,  as  localities  which  are  known  to  be 
infected  can  thus  be  avoided,  and  those  who  are  residents  of  such  locali- 
ties can  take  the  proper  precautions  to  avoid  infection. 


THE  MALARIAL  PARASITES. 

Etiology  — ^The  history  of  the  discovery  of  the  parasites  concerned 
in  the  etiology  of  the  malarial  fevers  furnishes  one  of  the  most  interest- 
ing chapters  in  the  annals  of  medicine.     The  theory  that  these  fevers 


THE  MALARIAL  FEVERS  395 

might  be  due  to  parasitic  infection  is  very  ancient,  dating  as  far  back  as 
118  B.  C,  but  little,  however,  was  known  concerning  this  subject  until 
1849,  when  J.  K.  Mitchell  ^  suggested  that  certain  spores  occurring  in 
marshy  districts  might  be  the  etiological  factor.  In  18G0,  Salisbury^ 
described  certain  small  vegetable  cells  which  he  claimed  to  have  found  in 
the  perspiration  and  urine  of  patients  sufi'ering  from  malaria,  and  which 
he  considered  to  be  the  causu,  and  for  a  time  his  views  were  widely  ac- 
cepted. In  1879,  Klebs  end  Tommasi  Crudeli^  found  in  the  soil  of 
malarial  districts,  certain  .:od-shaped  bacteria  which,  when  injected  into 
animals  in  pure  culture,  were  claimed  by  them  to  produce  the  symptoms 
of  the  disease.  Their  observations  were  never  confirmed  by  careful  observ- 
ers but  for  some  time  their  views  were  accepted  by  a  large  proportion  of 
the  scientific  world. 

The  bacterial  origin  of  the  malarial  infections  was  believed  in  for  a 
considerable  period  of  time,  although  in  1880  Laveran^  described  certain 
parasites  occurring  in  the  blood  which  he  considered  as  the  cause  of  the 
disease.  His  observations  were  soon  confirmed  by  Richard,  Marchiafava 
and  Celli,  Golgi,  Councilman,  Abbot,  Sternberg,  Osier  and  Dock.  In  his 
original  communication  Laveran  described  three  forms  of  the  parasite. 
The  first  consisted  of  oval  or  crescentic  bodies  with  hyaline  protoplasm 
containing  pigment,  arranged  either  in  clumps  or  in  a  wreath-like  arrange- 
ment. This  form  was  undoubtedly  the  crescentic  form  of  the  parasite 
causing  sestivo-autumnal  malaria.  The  second  form  described  consisted 
of  small  hyaline  bodies  containing  pigment;  and  from  these  bodies  there 
arose  occasionally  long,  thin,  hyaline  filaments  which  possessed  the  prop- 
erty of  motion.  This  form  was  undoubtedly  the  flagellated  form  of  the 
sestivo-autumnal  parasite.  The  third  form  described  by  him  consisted  of 
spherical,  slightly  granular  bodies,  with  motionless  pigment,  which  were 
evidently  degenerative  forms  of  the  two  foregoing  classes.  Richard^ 
later  described  the  intracorpuscular  hyaline  parasites  and  the  segment- 
ing bodies.  In  1885,  Marciafava  and  Celli®  described  carefully  the  hya- 
line and  intercorpuscular  parasites,  and  proposed  the  term  Plasmodium 
malarice  for  the  organism.  Biologically,  this  term  is  very  inaccurate  and 
should  be  abandoned,  as  the  parasites  belong  to  the  sporozoa,  but  the  name 
is  so  firmly  fixed  in  our  nomenclature  that  it  will  probably  have  to  be 
retained.  In  the  same  year,  Golgi^  proved  that  quartan  fever  depended 
upon  a  specific  form  of  the  malarial  parasite,  and  shortly  afterward  he 
also  differentiated  and  described  the  parasite  causing  tertian  fever.  To 
him  we  also  owe  the  discovery  that  the  malarial  paroxysm  always  co- 
incides with  the  segmentation  or  sporulation  of  a  group  of  parasites. 
Occurring  every  forty-eight  hours,  this  segmentation  produces  tertian 
fever,  while  if  it  occurs  every  seventy-two  hours  quartan  fever  is  the  t}^e 
present.  In  1885,  Golgi  also  called  attention  to  the  probably  distinct 
type  of  the  crescentic  and  ovoid  forms  of  the  organism,  and  Councilman 

^On  the  Cryptogamous  Origin  of  Malarious  and  Epidemic  Fevers,  Philadel- 
phia, 1849. 

^American  Journal  of  the  Medical  Sciences,  January,  1866. 
^Arch.  f.  exp.  Path.  u.  Pharmak.,  1879,  XI,  311. 

^Gaz.  Med.  de  Par.,  1882,  252. 

^ Fortschritte  der  Med.,  1885,  III,  No.  24,  787. 

''Arch,  per  le  sciens,  Med.^  X,  1886,  109-135. 


39G  DISEASES  CAUSED  BY  PROTOZOA 

first  called  attention  to  the  diagnostic  value  of  the  various  forms  which 
are  observed  in  the  l)lood.  In  18S9,  Goigi  further  added  to  his  studies 
concerning  the  development  of  the  crescents,  showing  that  they  arose  from 
the  small,  cellular  rings,  and  that  this  parasite  was  associated  with  fevers 
of  remittent  character.  To  him  belongs  the  credit,  therefore,  of  first 
clearly  differentiating  the  Jiestivo-autumnal  parasite.  In  the  same  year, 
Marchiafava  and  Celli  added  to  Golgi's  observations  and  gave  a  most 
accurate  description  of  the  a^stivo-autumnal  plasmodium. 

Classification. — The  classification  of  the  jxirasites  causing  malaria  has 
occuined  the  attention  of  zoologists  for  many  years,  and  a  great  many 
difl'crent  o{)inions  have  been  advancetl  reganling  their  exact  position.  At 
the  present  time  it  is  conceded  by  all  that  they  belong  to  the  Sporozoa,  and 
the  classification  of  Schaudinn,  adopted  at  ])rescnt  by  nearly  all  authori- 
ties, is  the  one  which  will  be  followed  in  this  contribution.  He  places  the 
organisms  imder  the  sub-order  Ilcemosporidia,  and  gives  three  varieties, 
as  follows:  Plasmodium  vivax  (tertian  parasite),  Plasmodium  malarioe 
(quartan  parasite),  and  Plasmodium  immacidahim^  (i:estivo-autumnal 
parasite).  The  Italian  authorities,  together  with  nearly  every  investigator 
who  has  studied  malaria  in  the  tropics,  have  made  a  subdivision  of  the 
sestivo-auturanal  parasite  into  two  varieties,  the  quotidian  and  tertian.  A 
large  amount  of  labor  has  been  expended  in  differentiating  these  varieties 
of  the  testivo-autumnal  parasite,  and  it  is  undoubtedly  true  that  they  can 
be  differentiated  when  the  material  is  available  for  study.  From  personal 
experience,  the  writer  is  satisfied  that  the  quotidian  and  tertian  restivo- 
autumnal  parasites  can  be  as  easily  differentiated  as  the  tertian  and 
quartan. 

The  malarial  plasmodia  are  found  in  man  within  the  red  blood  cor- 
puscles and  are  essentially  parasites  living  upon  and  within  these  cells. 
In  this  situation  they  destroy  the  red  corpuscles  and  produce  the  well- 
known  anaemia  peculiar  to  malarial  fever,  together  with  the  pigmentation, 
or  melantemia  which  is  due  to  the  destruction  of  the  haemoglobin  of  the  red 
cell.  In  describing  these  parasites  in  the  light  of  our  present  knowledge, 
two  life-cycles  must  be  considered:  first,  the  human  cycle,  schizogony 
or  asexual  cycle,  occurring  within  the  infected  individual,  and  second, 
the  mosquito  cycle,  sporogony,  or  sexual  cycle,  occurring  within  the  in- 
fected mosquito.  As  has  been  stated,  the  only  known  method  of  trans- 
mission of  malarial  fevers  is  by  the  aid  of  certain  mosc(uitoes  belonging  to 
the  genus  Anopheles.  These  fevers  are  not  infectious  from  patient  to 
patient  except  through  the  intermediation  of  certain  mosquitoes. 

Plasmodium  Vivax — (The  Tertian  Parasite) — (Schizogony,  Human 
Cycle). — The  tertian  parasite,  or  Plasviodium  vivax,  appears  first  within 
the  red  cell  in  schizogony  as  a  small  actively  amoeboid  hyaline  body,  the 
schizont,  of  various  shapes,  the  difference  in  outline  being  due  to  the 
rapidity  and  extent  of  the  amoeboid  movement.  At  first  the  outline  of  the 
organism  is  very  indistinct  and  careful  examination  is  needed  to  dis- 
tinguish it.  As  the  organism  grows  older  and  becomes  pigmented  it  is 
much  more  easily  distinguished.    The  hyaline  stage  is  quickly  followed 

*  The  name  "P.  immaculatum"  is  not  correct.  Blanchard  has  shown  that  Grassi 
previously  used  the  terms  "  immaculatum"  and  "  prajcox  "  for  parasites  occurring 
m  birds,  which  prevents  their  use  for  the  human  parasite.  This  makes  Welch's 
term,  "  falciparum,"  the  proper  one. — ^Editor. 


PLATE  J 

Fig.  1.— Tertian  Malarial  Plasmodium. 

1.  Hyaline  form.  7.   SegmentinK  forms.  9.   Kon-flagellalo  form.   (Macro- 

2  Pigmented  ring  form.  8.    I'laffellate   form.       (Microga-  gameto.; 

3  to  6.   Pigmented  forms.  metocyte.)  10.   Segmei>ting    form    after    <le- 

*=  slriiot'on  of  rod  corpuscle. 

Fig.  2.  — Quartan  Malarial  Plasmodium. 

1     Hyaline  forms  S.   Segmenting  forms   after   llie         0.    I'lagellale   form.      (Microga- 

2 'to  .5.   Pigmented  forms.  destruction  of  re. I  corpus-  metocyte.) 

6  and  7.   Segmenting  forms.  '"'■  !"■   '^' g^^fefj'f ""  ^"'■'"-   ^^'=^''''^'- 

Fig.  3.— Tertian  ^^stivo-autumnal  Malarial  Plasmodium. 

1  and  4.   Hyaline  ring  form.  8.   Young  intracorpuscularcres-       10.    Magellate    form.      (Microga- 

2,  .3  and  7.  Pigmented  ring  form.  cent.  metocyte.) 

5  and  6.  Pigmented  forms.  9-   Segmenting  forms.  11  to  14.   Crescentic  forms. 

Fig.  4.— Quotidian  ..^stivo-autumnal  Malarial  Plasnnodium. 

1  to  4.   Hyaline  ring  forms.    Some  8.   Segmenting  forms.     Segmen-  10,    11,    13    and    l.j.    Cre.scentic 

cells   show  infection   with  tation  complete  within  in-                    forms, 

more  than  one  organism.  fected  red  blood  corpuscle.  ]2.   Ovoid  form. 

5  to  7.   Pigmented    forms.      In   G  9.   Flagellate    form.      (Microga-  14    Non-flagellate    forms.     (Ma- 
one  hyaline  form.  metocyte.)                                                    crogamefe.) 

Note. — Mark  the  larger  size  and  greater  amount  of  pigment  in  the  tertian  x'stivo-autumnal  Plasmodium. 


PLATE   IL 

Fig.  1. — Tertian  Malarial    Plasmodium.     Stained  by  Oliver's 
Modification  of  Wright's  Stain. 

1  to  4.    Ring    forms  of    tertian       11  to  14.  Nearly  full-grown  forms,       18.   Segmenting   forms  after  de- 
parasite,  showing  diffusion    of    the  struction  of  red  corpuscle. 

5  Ring     form.        (Conjugation  chromatin.  19_    Flagellum.     (Microgamete.) 

form  of  Ewing.)  15    to    17.       Segmenting     forms      OQ.   Sporozoite. 

6  to  10.   Pigmented  organisms.  ^it^m  red  corpuscle. 

Fig.  2.— Quartan  Malarial  Plasmodium.     Stained  by  Oliver's 
Modification  of  Wright's  Stain. 

1  to  4    Ring    forms  of  quartan       10  to  12.   Segmenting     forms    of       13.   Segmenting    stage    after   de- 
parasite,  quartan  parasite.  struction  of  red  corpuscle. 
5,  6,  7,  8,  9.    Pigmented  parasites. 

Note. — Chromatin  of  nucleus  stained  red  ;   protoplasm  stained  blue  ;   vesicular  portion  of 

nucleus  unstained. 

PLATE    ITL 

v^stlvo-autumnal  Malarial  Plasmodia.     (Tertian.)     Oliver's 
Modification  of  Wright's  Stain. 

1,  3,  4,  5,  0,  7,  8-,  9,  10  and  1.5.        12.    Red    corpuscle    showing    in-      2.5  to  36.     Crescentic     forms     of 

Ring     forms     of      tertian  fection    with     two     "  ring                     a^stivo-autumnal    plasmo- 

testivo-autumnal    plasmo-  forms."                                                       dium  (tertian), 

dium.  IS  and  19.  Pigmented  forms,  just  29.    Ovoid  form. 

2.  Intracellular  form.  prior  to  segmentation.  37.   Segmenting  form. 
11,  13,  14,  16  and  17.   Pigmented  20,  21,  23  and  24.     Round      and  33.   Sporozoites. 

ring  forms.  ovoid     forms     developed        a.  Segmenting  form    of    quotid- 

from  crescents.  ian   sestivo-autumnal    plas- 

22.   Macrogamete.  modium. 

Note. — In  this  plate  the  tertian  cestivo-autumnal  Plasmodium  is  shown.     The  staining  reactions  of 
the  quotidian  Plasmodium  are  exactly  similar. 


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THE  MALARIAL  FEVERS  '.i'Jl 

by  the  appearance  of  a  few  minute  granules  of  nnldish-brown  pigment 
situated  within  it  and  showing  active  movement.  This  movement  is  due 
to  protoplasmic  currents  which  are  present  within  the  parasite.  In  the 
beginning,  occupying  but  a  minute  portion  of  the  red  cell,  as  it  continues 
to  grow,  the  parasite  encroaches  more  and  more  upon  the  infected  cor- 
puscle, until  when  full-grown  it  fills  the  entire  cell.  The  growth  of  the 
parasite  is  gradual,  covering  forty-eight  hours.  The  full-grown  para- 
sites have  a  rather  distinct  outline  and  the  red  cells  containing  them  are 
greatly  swollen,  sometimes  to  almost  double  the  size  of  the  normal  red 
blood  corpuscle.  Toward  the  end  of  thirty-six  hours  the  organism  has 
approached  nearly  to  its  full  growth,  only  a  narrow  rim  of  the  red  cell 
showing  around  it.  Amoeboid  motion  has  become  almost  entirely  lost, 
the  parasite  being  circular  in  shape,  well  defined,  the  pigment  more  or  less 
motile  and  much  increased  in  quantity,  still  however,  finely  granular  in 
appearance  and  reddish-brown  in  color,  At  the  end  of  forty-eight  hours 
segmentation  takes  place,  the  pigment  becomes  collected  at  the  centre  or 
to  one  side  of  the  organism  in  the  form  of  a  compact  clump  and  fine  radial 
divisions  are  noticed  branching  from  the  centre  toward  the  periphery  of 
the  organism,  thus  dividing  the  parasite  into  small  ovoid  segments.  As  a 
rule,  there  are  two  rows  of  these  segments,  one  row  surrounding  the 
centre,  and  another  surrounding  the  first  row,  but  very  often  the  seg- 
ments are  irregularly  arranged,  and  they  are  always  devoid  of  pigment. 
They  vary  in  number  from  twelve  to  twenty-four,  the  average  being 
about  sixteen,  and  are  known  as  merozoites.  At  the  time  that  segmenta- 
tion occurs  the  infected  red  cell  has  apparently  disappeared,  being  en- 
tirely destroyed  by  the  invading  parasite.  The  destruction  of  the  red 
cell,  which  is  complete  at  the  time  of  segmentation,  liberates  the  segments, 
or  merozoites,  which,  are  again  capable  of  infecting  new  corpuscles,  and  thus 
the  human  life-cycle  or  schizogony  continues.  The  pigment  which  is  not 
present  at  the  beginning  of  the  life-cycle  in  the  red  blood  corpuscle, 
gradually  increases  as  the  degeneration  of  the  red  cell  continues,  being 
derived  from  the  destroyed  hsemoglobin  of  the  cell.  In  all  the  pigmented 
forms  of  the  tertian  parasite  the  pigment  is  generally  motile,  the  move- 
ment being  due  to  the  protoplasmic  currents  which  have  been  mentioned. 
In  examining  blood  from  tertian  cases  it  will  be  noticed  that  a  certain 
proportion  of  the  full-grown  parasites  do  not  segment,  and  it  is  these 
which  are  intended  to  commence  the  life-cycle  of  the  organism  in  the 
mosquito,  which  will  be  described  later. 

Plasmodium  Malarias — (The  Quartan  Parasite) — (Schizogony,  Human 
Cycle). — Like  the  tertian  parasite,  the  organism  causing  quartan  malarial 
infection  appears  at  first  within  the  red  corpuscle  as  a  small  actively  amoe- 
boid hyaline  body  without  pigment,  the  schizont.  It  will  be  noticed  that 
the  amoeboid  motion  is  less  marked  than  in  the  case  of  the  tertian  or- 
ganism. The  quartan  parasite  rapidly  becomes  pigmented,  the  pigment 
being  collected  in  larger  granules  than  is  the  case  in  the  tertian  parasite, 
being  less  motile  and  arranged  around  the  periphery  of  the  organism, 
whereas  in  the  tertian  parasite  the  pigment  is  distributed  throughout  the 
protoplasm.  The  outline  of  the  organism  is  also  much  more  distinct 
than  is  the  case  in  the  tertian  parasite  during  all  stages  of  its  gro^i;h.  In- 
stead of  the  swollen  decolorized  red  cell  seen  in  the  tertian  infection,  the 
infected  corpuscle  in  quartan  fever  is  normal  in  size  and  often  sUghtly 


398  DISEASES  CAUSED  BY  PROTOZOA 

below  normal,  and  darker  green  in  color,  instead  of  pale.  This  difference 
in  the  appearance  of  the  infected  red  cell  serves  at  once  to  distinguish  the 
two  varieties  upon  microscopic  examination  of  the  blood.  The  para- 
site slowly  increases  in  size,  and  in  doing  so  becomes  less  amoeboid.  The 
pigment  increases  in  quantity  and  becomes  collected  at  the  extreme  per- 
iphery of  the  organism  and  is  absolutely  immotile.  The  granules  of  pig- 
ment are  considerably  larger  than  in  the  tertian  parasite,  darker  in  color, 
and  at  no  stage  of  the  growth  of  the  organism  do  they  collect  in  small 
clumps  throughout  the  protoplasm,  as  is  common  in  the  tertian  form. 
As  growth  increases  the  parasite  tends  more  and  more  to  fill  the  infected 
red  cell,  and  when  full-grown — that  is,  at  the  end  of  seventy-two  hours, 
it  almost  fills  the  cell,  a  small  greenish  rim  of  hemoglobin  still  being  visible 
around  the  organism.  At  this  stage  of  its  growth  the  parasite  is  very  dis- 
tinctly outlined  and  is  much  more  refractive  than  is  the  tertian  variety; 
the  pigment  is  absolutely  motionless  and  collected  around  the  periphery; 
the  shape  is  circular  and  amoeboid  motion  has  entirely  ceased.  At  the 
end  of  seventy-two  hours  segmentation  occurs,  the  pigment  becoming 
collected  at  the  centre  or  in  a  star-like  arrangement  distributed  from  the 
centre.  Radial  striations  appear  dividing  the  organism  into  from  eight 
to  twelve  segments,  or  vierozoites.  The  segments  are  generally  arranged 
in  a  perfectly  symmetrical  manner  around  the  central  pigment,  giving  the 
so-called  daisy  or  "Marguerite"  appearance  to  the  parasite  at  this  stage. 
When  segmentation  is  complete,  each  merozoite  becomes  free  in  the 
blood  plasma  and,  in  the  human  life-cycle,  again  invades  the  red  corpuscles, 
undergoing  the  changes  which  have  been  described.  As  in  the  tertian 
form,  certain  parasites  do  not  undergo  segmentation,  and  these  are  the 
ones  intended  to  carry  on  the  life-cycle  in  the  mosquito. 

Plasmodium  Falciparum — (^stivo-Autumnal  Parasite) — Quotidian 
Form — (Schizogony,  Human  Cycle). — As  has  been  stated,  the  writer  be- 
lieves with  Marchiafava  and  Bignami  that  there  are  two  distinct  varieties 
of  the  festivo-autumnal  parasite,  the  quotidian  and  tertian.  These  are 
distinguishable  microscopically  and  the  symptoms  produced  by  them  are 
characteristic  and  easily  differentiated  clinically.  In  previous  contri- 
butions^ the  differential  points  between  these  tAvo  varieties  of  the  testivo- 
autumnal  parasite  and  also  the  clinical  phenomena  which  are  produced 
by  them  have  been  described. 

The  quotidian  parasite  appears  at  first  in  the  infected  red  cell  as  a  very 
minute  ring-shaped  or  round  hyaline  body,  the  schizont,  which  upon  close 
inspection  shows  very  active  amoeboid  motion.  The  outline  of  the  organ- 
ism at  first  is  indistinct  but  gradually  becomes  more  distinct  and  when 
full-grown  it  is  very  clear-cut  and  refractive.  The  round  forms  are  per- 
fectly hyaline  in  apjjearance  but  the  ring  form,  which  is  most  common, 
consists  of  a  narrow  hyaline  body  enclosing  a  small  area  which  shows  the 
normal  greenish-yellow  color  of  the  infected  corpuscle.  This  appearance 
is  considered  by  most  authorities  to  be  due  to  the  fact  that  the  centre  of 
the  parasite  is  much  thinner  than  the  periphery,  thus  allowing  the  normal 
color  of  the  corpuscle  to  show  through.  Careful  observation  of  these 
ring  forms,  however,  will  show  that  they  often  become  perfectly  hyaline 

^The  Philadelphia  Medical  Journal,  April  7,  1900;  also,  Journal  Am.  Med. 
Association,  Nov.  3,  1900,  The  ^stivo- Autumnal  (Remittent)  Malarial  Fevers, 
Wm.  Wood  &  Co.,  1901;  International  Clinics,  vol.  Ill,  13th  series,  Oct.,  1903. 


THE  MALARIAL  FEVERS  399 

and  in  so  doing  the  protoplasm  of  the  organism  flows  in  from  the  edge  of 
the  ring,  thus  tending  to  prove  that  no  protoplasm  existed  in  this  greenish- 
colored  area.    The  amoeboid  motion  is  very  active,  but  the  organism  has 
to  be  carefully  watched  in  order  to  distinguish  it.    The  infected  red  cor- 
puscle is  generally  smaller  in  size  than  the  normal  corpuscle  and  darker 
green  in  color.    It  is  very  apt  to  be  crenated.    In  many  instances  double 
or  triple  infections  of  the  corpuscle  may  be  observed.    In  the  peripheral 
blood  the  hyaline,  round  or  ring-shaped  organisms  are  those  which  are 
most  commonly  observed,  although  a  certain  number  of  pigmented  forms 
are  not  uncommon.    The  pigmentation  is  never  as  marked  as  in  the  ter- 
tian or  quartan  parasite,  the  pigment  consisting  of  a  small,  solid  block, 
almost  black  in  color,  situated  at  some  portion  of  the  edge  of  the  parasite 
or  at  the  centre;  it  is  never  motile.    Very  rarely  the  pigment  consists  of 
fine  granules,  but  these  granules  never  number  more  than  three  or  four. 
The  segmenting  forms  are  but  very  seldom  observed  in  the  peripheral 
blood,  although  blood  from  the  spleen  taken  at  the  proper  time  in  well 
marked   cases   presents   numerous   parasites   undergoing  this    process. 
Segmentation    occurs  at  the  end  of   twenty-four  hours.     Just   before 
segmentation  the  parasite  occupies  about  one-fourth  of  the  red  blood  cor- 
puscle, thus  distinguishing  it  from  the  quartan  and  tertian  varieties  which  fill 
the  corpuscle.    The  pigment  does  not  show  any  decided  increase  in  amount 
and  is  absolutely  immotile.     At  the  time  of  segmentation  this  pigment 
becomes  collected  at  the  centre  of  the  parasite  and  radial  striations  can 
be  detected,  starting  from  the  centre  and  dividing  it  into  from  six  to  eight 
very  minute  round  or  oval  segments,  or  merozoites.    While  in  the  tertian 
and  quartan  forms  it  is  often  impossible  to  distinguish  the  remains  of  the 
red  corpuscle  when  segmentation  occurs,  in  this  variety  it  can  be  plainly 
seen  that  segmentation  occurs  within  the  infected  red  cell.    The  mero- 
zoites are  liberated  by  the  entire  destruction  of  the  red  corpuscle;   each 
merozoite  is  capable  of  again  infecting  the  red  cell  and  the  human  cycle 
is  thus  repeated. 

In  this  variety,  as  well  as  in  the  tertian  form,  peculiar  bodies  occur 
which  are  developed  within  the  red  blood  corpuscle,  but  which  do  not 
undergo  segmentation.  These  are  the  so-called  crescents,  which  are  so 
characteristic  of  sestivo-autumnal  infections,  and  which  will  be  described 
in  considering  the  mosquito-cycle  of  this  parasite. 

Plasmodium  Falciparum — (iSstivo-Autumnal  Parasite) — Tertian  Form 
(Schizogony,  Human  Cycle). — Like  the  quotidian,  the  tertian  testivo- 
autumnal  parasite  appears  first  within  the  infected  red  cell  as  a  round 
hyaline  ring  or  disk.  The  infected  corpuscle  is  greenish  in  color,  smaller 
than  the  normal  corpuscle  surrounding  it  and  generally  crenated.  The 
young  parasites  are  considerably  larger  than  the  quotidian  parasite,  occu- 
pying from  one-fourth  to  one-third  of  the  total  area  of  the  infected  cell. 
The  ring  forms  are  irregular  in  outline,  one  portion  of  the  ring  being 
larger  than  the  rest,  giving  it  the  so-called  "signet-ring"  appearance.  The 
organism  is  very  highly  refractive  and  sharply  outlined,  appearing  as 
though  it  had  been  cut  into  the  corpuscle  with  a  punch.  Amoeboid  motion 
is  present,  although  it  is  less  rapid  than  in  the  quotidian  form,  and  only 
very  rarely  is  more  than  a  single  parasite  seen  within  one  corpuscle.  In 
the  course  of  from  twenty  to  twenty-four  hours  the  hyaline  forms  become 
pigmented,  the  pigment  occurring  in  the  form  of  very  fine,  reddish-brown 


400  DISEASES  CAUSED  BY  PROTOZOA 

granules  somewhat  resembling  those  found  in  the  tertian  parasite.  The 
pigment  is  in  larger  amount  than  in  the  quotidian  parasite  and  is  generally 
motile.  As  growth  inereases  anurboid  motion  becomes  lost,  and  this  is 
also  true  of  the  peculiar  ring-shape  which  is  so  characteristic  of  this  form 
of  the  parasite.  At  the  time  of  segmentation,  which  occurs  in  forty-eight 
hours,  the  organism-occupies  about  one-half  of  the  infected  red  cell.  The 
pigment  is  collected  at  the  centre  and  radial  striations  start  from  this 
point  and  divide  the  ])arasite  into  ten  or  fifteen  segments,  or  merozoifes. 
In  some  instances  as  high  as  twenty-four  merozo^tes  have  been  counted. 
Segmentation  occurs  within  the  red  blood  corpuscles  but  its  situation  is 
not  so  easy  to  distinguish  in  this  form  as  in  the  quotidian.  The  segment- 
ing forms  occur  but  seldom  in  the  peripheral  blood,  although  they  are 
very  numerous  in  certain  cases  in  blood  collected  from  the  s])leen.  The 
young  segments  are  liberated  in  the  blood  plasma  and  again  infect  the 
red  cell;  thus  the  human  cycle  is  repeated. 

So  far,  wc  have  considered  the  human  cycle  of  the  malarial  plasmodia, 
which  consists,  briefly,  in  the  infection  of  the  red  blood  corpuscles  by  the 
merozoites  which  are  derived  from  the  segmenting  bodies.  The  mosquito- 
cycle,  which  is  more  complex,  will  now  be  considered. 

Development  of  the  Malarial  Plasmodia  Within  the  Mosquito— 
(Sporogony,  Sexual  or  Mosquito-Cycle). — Historical. — That  malaria 
is  transmitted  by  insects  is  by  no  means  a  modern  conception.  Nearly  two 
thousand  years  ago,  Varro  and  Columella  mentioned  the  possibility  that 
these  diseases  were  transmitted  in  this  way.  In  1848,  Nott^  considered 
the  subject  as  already  proven,  but  King,^  of  Washington,  in  1882,  was 
the  first  to  advocate  it  vigorously  and  give  evidence  in  favor  of  this 
method  of  transmission.  In  1884,  Laveran^  considered  the  subject  and 
suggested  that  this  was  probably  the  way  that  malarial  disease  was 
transmitted.  In  1894,  Manson^  elaborated  the  theory  and  stated  it 
as  his  belief  that  malarial  disease  w^as  transmitted  probably  by  mosqui- 
toes In  1895,  Ross,^  of  the  Indian  Army  Medical  Service,  studied  the 
development  of  the  parasites  of  sestivo-autumnal  malaria  in  mosqui- 
toes, and  proved  that  the  crescents  underw^ent  definite  changes  wdthin 
the  body  of  the  insect.  In  1896,  Bignami®  advocated  the  theory  that 
the  malarial  diseases  were  transmitted  by  the  inoculation  of  man  by 
the  bite  of  the  mosquito,  comparing  this  process  of  infection  to  the  one 
already  proved  in  the  production  of  Texas  cattle-fever  by  the  tick.  In 
1897,  Ross^  further  elaborated  his  experiments  and  was  able  to  observe 
the  development  of  the  crescentic  form  of  the  jestivo-autumnal  parasite  in 
the  mosquito.  A  great  advance  wr.s  made  when  MacCallum^  observed 
that  the  full-grown  extracellular  halteridium,  a  parasite  causing  avian 
malaria,  consisted  of  two  forms,  one  of  which  is  flagellated  and  the  oth^* 

^New  Orleans  Medical  and  Surgical  Journal,  1848,  IV,  563,  601. 

^  Transactions  of  the  Philosophical  Society  of  Washington,  February  10,  1882. 

^  Traite  des  Fihrcs  Palustres.  Paris,  1884,  pp.  457-458. 

^  British  Medical  Journal,  December  8,  1894. 

^Proceedings  of  South  Indian  Branch  British  Medical  Association,  December  1 
1895. 

"Lancet,  November  14  and  21,  1896. 

^  British  Medical  Journal,  December  18,  1897. 

'Bulletin  of  Johns  Hopkins  Hospital,  November  1897;  also  Journal  of  Ex- 
perimental Medicine,  January,  1S9S 


THE  MALARIAL  FEVERS  401 

non-flagellated.  He  observed  that  the  flagella,  breaking  away  from  the 
flagellated  form,  penetrated  the  non-flagellated  organisms,  and  after 
penetration  a  motile  body  resulted  which  moved  about  among  the  blood 
corpuscles,  and  which  was  capable  of  penetrating  and  destroying  them. 
Later  he  observed  the  same  phenomena  in  studying  the  iestivo-autumnai 
parasites,  and  considered  that  this  process  was  one  of  fertihzation. 

In  1898,  Bignami  performed  some  inoculation  experiments  upon  man 
with  mosquitoes  which  had  bitten  individuals  suft'ering  from  malaria,  but 
these  experiments  were  unsuccessful,  due  to  the  fact  that  he  did  not  em- 
ploy the  right  species  of  mosquito.  Later  Bignami'  was  successful  in 
producing  an  attack  of  sestivo-autumnal  malaria  in  man  by  allowing 
mosquitoes  which  had  bitten  an  infected  individual  to  bite  a  patient  who 
had  never  had  malaria.  In  the  same  year,  Bastianelli,  Bignami,  and 
Grassi^  were  successful  in  producing  a  double  tertian  infection  in  man 
by  the  bites  of  infected  Anoflieles.  In  February,  1899,  they  were,  for  the 
first  time,  successful  in  infecting  the  Anopheles  maculipennis  with  quartan 
parasites,  and  traced  the  developmental  stages  of  this  organism  in  the 
mosquito.  They  were  also  successful  in  producing  sestivo-autumnal 
malaria  by  the  bites  of  infected  mosquitoes. 

Description  of  Forms  Occurring  in  the  Mosquito  Cycle. — As  has  al- 
ready been  mentioned,  in  tertian  and  quartan  infections  there  occur 
certain  organisms  which  do  not  undergo  segmentation.  This  is  also  true 
of  the  aestivo-autumnal  infections,  in  which  occurs  a  peculiar  body  known 
as  the  crescent,  intended  to  continue  the  life-cycle  of  the  parasite  within 
the  mosquito. 

Tertian  and  Quartan  Forms. — In  tertian  and  quartan  infections,  in 
blood  which  has  been  removed  from  the  body  for  some  time,  there  occur 
peculiar  bodies  known  as  flagellated  organisms.  It  will  be  noticed  that 
these  bodies  are  of  two  kinds,  which  the  writer  designated  in  a  previous 
contribution^  as  active  and  passive  flagellated  organisms.  The  active 
flagellated  organism,  or  the  microgametocyte,  is  spherical  in  shape  and 
filled  with  actively  motile  pigment.  This  pigment  is  in  the  form  of  small 
granules  which  are  distributed  throughout  the  protoplasm  of  the  organism. 
It  will  be  noticed  that  in  such  round  bodies  the  pigment  becomes  more  and 
more  active,  until  finally  three  or  more  serpentine  prolongations  of  the 
protoplasm  appear  at  the  circumference  of  the  organism.  These  prolonga- 
tions of  the  protoplasm  are,frQjiijy3jreeJo_foJir.  timesjhe_^  of  the 
parasite  and  are  possessed  of  a  very  active  lashing  movement,  antTare 
known  as  flagella,  or  microgametes.  Together  with  this  form  of  the  organ- 
ism there  occur  round  bodies  in  which  the  pigment  is  collected  in  larger 
clumps  and  generally  arranged  around  the  circumference  in  the  form  of 
a  perfect  ring,  while  there  is  no  evidence  of  motility.  These  are  the  pas- 
sive flagellated  organisms,  or  macrogametes,  and  never  present  the  process 
of  flagellation  as  seen  in  the  microgametocyte,  or  active  body.  The  flagella 
from  the  microgametocyte  eventually  become  free  in  the  blood  plasma  and 
sometimes  can  be  seen  attached  to  the  bodies  which  have  just  been  des- 
cribed ,  I.e.,  the  macrogametes.  This  process,  however,  takes  place  in  nature 

^Lancet,  December  3  and  10,  1898. 
^R.  Acad   dei  Lancei,  vol.  VII,  Dec.  4,  1898. 
^New  York  Medical  Journal.  December  23,  1889. 
26 


402  DISEASES  CAUSED  BY  PROTOZOA 

in  the  middle  intestine  of  tl;e  mosquito.  A  distinct  difference  has  been 
demonstrated  in  the  structure  of  the  female  viacrogametes  and  the  male 
microgametocijies.  In  the  macrogamete  the  nucleus  is  of  good  size  and 
situated  at  one  side  of  the  centre  of  the  organism,  containing  little  chro- 
matin. In  the  microgamcioci/ie  the  nucleus  is  always  situated  at  the  centre 
of  the  organism  arid  contains  a  large  amount  of  chromatin.  When  the 
flagella,  ov  microgamctr.^-,  develoj)  from  the  microgcunciocgte,  it  has  been 
demonstrated  that  the  chromatin  passes  into  them  and  forms  an  essential 
portion  of  their  structun\ 

iEstivo-Autumnal  Infections. — There  occur  in  the  blood  in  irstivo- 
autumnal  infections  peculiar  forms  of  the  parasite  knoM'n  as  crescents. 
These  forms  are  developed  within  the  red  blood  corpuscle  and  are  typi- 
cally crescentic  in  shape.  They  are  very  refractive,  having  a  more  or  less 
granular  protoplasm,  and  contain  A\ithin  them,  generally  at  the  centre,  but 
sometimes  at  one  or  the  other  pole,  a  clump  of  i)igment  arranged  in  the 
form  of  slender  rods  or  minute  dots.  In  the  very  young  crescents  the  pig- 
ment is  distributed  throughout  the  protoplasm,  but  as  the  crescent 
matiu'cs  it  collects  at  the  centre  or  at  one  end.  The  border  of  the  crescent 
is  sharply  cut  and  is  represented  by  a  single  or  double  line,  having  a  pecu- 
liar greenish  color.  In  most  crescents,  when  full-grown,  careful  examina- 
tion Avill  show  a  dim  line  upon  the  concave  side  of  the  organism,  which  has 
a  peculiar  greenish  color.  This  represents  the  remainder  of  the  red  blood 
corpuscles  in  which  the  crescent  was  developed. 

In  tertian  ?estivo-autumnal  infections  the  crescent  is  much  more  slender 
and  has  pointed  extremities.  It  very  seldom  shoAvs  a  double  outline; 
the  protoplasm  is  finely  granular  and  the  pigment  is  large  in  amount  and 
in  the  form  of  slender  rods.  In  the  quotidian  a^stivo-autumnal  infections 
the  crescent  is  generally  much  shorter  and  plumper  than  in  the  tertian. 
Its  extremities  are  rounded  and  it  always  presents  a  distinct  double  out- 
line. The  protoplasm  is  less  granular  and  the  pigment  is  smaller  in 
amount  and  in  the  form  of  dots.  Normally  in  the  mosquito,  and  also  in 
the  blood  which  has  been  removed  for  some  time  from  the  body,  these 
crescents  undergo  a  series  of  changes,  first  becoming  oval  in  shape  and 
finally  round.  The  spherical  bodies  represent,  in  the  jestivo-autumnal 
infections,  the  macrogametes  and  microgavietocytes  of  the  tertian  and  quar- 
tan infections  and  undergo  similar  changes  in  the  stomach  or  middle 
intestine  of  the  mosquito;  that  is,  the  male  elements,  or  microgametocytes, 
become  flagellated,  the  flagella,  or  micro  gametes,  becoming  free  and 
fertilizing  the  female  elements,  or  macrogametes. 

Cycle  of  Development. — Having  considered  the  bodies  w^hich  enter 
into  the  mosquito-cycle,  and  which  may  be  observed  at  times  in  human 
blood  which  has  been  removed  from  the  body  for  a  short  time,  we  will  now 
take  up  the  cycle  of  development  which  these  bodies  undergo  in  the 
mosquito,  bearing  in  mind  that  it  is  essentially  the  same  in  all  varieties  of  the 
Plasmodia.  The  process  of  flagellation  and  the  fertilization  of  the  macro- 
gamete,  the  female  orgamism,  by  the  microgaviete,  or  flagellum,  which  occurs 
normally  in  the  middle  intestine  of  the  mosquito  after  biting  an  infected 
individual,  has  been  described.  The  result  of  this  fertilization  is  known  as 
the  sporont.  After  a  certain  period  of  time  the  sporont  becomes  elongated  and 
finally  motile,  and  it  is  then  known  as  the  ookinete.  The  ookinete  penetrates 
the  wall  of  the  middle  intestine  and  eventually  becomes  situated  on  the  outer 


THE  MALARIAL  FEVERS  403 

side  of  the  epithelium  and  the  basement  membrane  of  the  intestine  between 
the  adipose  tissue  and  the  muscular  wall.  Here  the  organism  becomes 
spherical  in  shape  and  forms  a  cyst  known  as  the  oocyst.  At  this  stage  the 
protoplasm  is  granular  and  reticular  in  appearance,  the  pigment  is  reduced 
in  amount,  and  the  entire  organism  is  enclosed  within  a  well-defined 
capsule.  The  oocyst  is  formed  at  about  the  third  or  fourth  day  after  infec- 
tion of  the  mosquito.  About  the  fifth  or  sixth  day  the  oocyst  enlarges  and 
within  it  are  formed  spherical  refractive  bodies  known  as  sporolAasts.  At 
this  stage  the  organism  is  increased  so  much  in  size  that  it  projects  from 
the  intestinal  wall.  Besides  the  sporoblasts,  the  cyst  contains  some  pigment 
and  minute  granules  which  resemble  fat.  At  the  end  of  a  week  the  sporo- 
blasts have  produced  a  large  number  of  delicate  filaments  having  pointed 
extremities  and  containing  a  small  amount  of  nuclear  chromatin. 
These  filaments  are  the  sporozoites.  They  are  about  14/i  in  length  and 
are  arranged  in  a  ray-like  formation  about  a  central  mass  which  may  con- 
tain pigment.  At  this  stage  the  capsule  of  the  cyst- is  very  distinct.  The 
sporozoites  are  finally  liberated  by  the  rupture  of  the  cyst  and  make  their 
way  to  the  tubules  of  the  salivary  glands.  At  this  time  the  infected  mos- 
quito, when  biting  a  man,  will  inoculate  the  sporozoites,  which,  penetrat- 
ing the  red  blood  cells,  develop  into  merozoites,  and  the  human  cycle  of  the 
organism  begins.  The  entire  cycle  of  development  in  the  mosquito  is 
about  fourteen  days  in  duration. 

Briefly  stated,  the  cycle  of  development  of  the  malarial  plasmodium  in  the 
mosquito  may  be  summed  up  as  follows : 

1.  Macrogamete,  in  tertian  and  quartan  infections,  the  female  spherical 
bodies,  and  in  festivo-autumnal  infections  the  female  crescent. 

2.  Microgametocyte,  in  tertian  and  quartan  infections  the  male  spherical 
bodies  and  in  sestivo-autumnal  infections  the  male  crescent. 

3.  Microgamete,  the  liberated  flagellum  of  the  microgametocyte. 

4.  Sporont,  the  result  of  the  fertilization  of  the  macrogamete  by  the 
microgamete. 

5.  OoJdnete,  the  motile  stage  of  the  sporont. 

6.  Oocyst,  the  cystic  stage  of  the  sporont. 

7.  Sporoblasts,  developed  within  the  oocyst. 

8.  Sporozoites,  developed  within  the  sporoblasts  and  liberated  by  the 
rupture  of  the  oocyst,  and  which  are  introduced  into  man  by  the  mosquito 
and  are  capable  of  beginning  the  human  life-cycle  by  infecting  the  red 
blood  corpuscles. 

It  may  be  stated  that  this  cycle  of  development  has  been  demonstrated 
in  the  mosquito  in  all  varieties  of  the  malarial  plasmodia,  and  that  infec- 
tion of  man  by  the  mosquito  has  also  been  demonstrated  with  all  varieties 
of  the  Plasmodia. 

The  Malarial  Mosquitoes.— The  structure  and  habits  of  the  mos- 
quitoes which  transmit  malaria  have  been  considered  in  another  portion 
of  this  work.  It  may  not  be  amiss  to  give  a  list  of  those  mosquitoes 
which  have  been  proved  to  transmit  malarial  disease.  Only  one  genus,  so 
far  as  we  know,  is  capable  of  transmitting  malaria,  the  Anopheles.  Of 
the  fifty  or  more  described  species  belonging  to  this  genus,  the  foUoA^ing 
have  been  shown  experimentally  to  transmit  the  disease; 


404  DISEASES  CAUSED  BY  PROTOZOA 

In  Africa,  the  A.  costalis,  A.  paludi^,  A.  junestus. 

In  India,  A.  sinensis,  A   Rossii,  A.  culicifacis,  A.  Theobaldi,  A.  barbirostis. 

In  Europe,  .4.  superpictus,  A.  maculipennis,  A.  bijurcaius. 

In  America,  .1.  tnaculipennis ,  A.  argijrotarsus. 

Staining  Reactions  of  the  Malarial  Plasmodia. — Under  the  division 

of  this  suhjcc't  dcahng-  with  diagnosis,  the  staining  methods  which  are  of 
greatest  practical  nse  will  be  fully  discussed.  While  the  examination 
of  the  fresh  blood  is  of  the  greatest  imi)ortance  in  studying  certain  j^hases 
of  the  life-cycle  of  the  malarial  plasmodia,  the  staining  reactions  exhibited 
by  these  organisms  illustrate  more  fully  the  exact  morphological  structure. 
It  may  be  stated  that  the  staining  reactions  are  similar  in  all  varieties,  and 
that  they  prove  that  the  organism  is  composed  of  a  nucleus  and  proto- 
plasm. The  chromatin  is  the  only  portion  of  the  nucleus  which  takes  the 
stain,  and  by  Wright's  method  it  stains  a  very  brilliant  red  and  lies,  appar- 
ently, within  a  vesicular  nucleus,  the  protoplasm  of  w^iich  does  not 
stain.  Surrounding  the  nucleus  in  the  young  forms  is  a  small  amount  of 
protoplasm  which  stains  a  delicate  blue  color,  and  imbedded  in  which  is 
the  pigment.  In  all  the  forms,  as  the  parasite  matures,  the  chromatin 
becomes  distributed  throughout  the  protoplasm,  and  in  the  full-grown 
parasites  a  distinct  nucleus  cannot  be  demonstrated,  while  the  protoplasm 
stains  uniformly  throughout.  As  segmentation  approaches,  the  pigment 
becomes  collected  more  or  less  toward  the  centre  of  the  organism,  and  the 
chromatin  which  has  been  distributed  diffusely  throughout  the  protoplasm 
collects  into  small  clumps,  forming  a  portion  of  the  young  segments. 
At  the  time  of  segmentation  the  chromatin  is  compactly  collected  in 
clumps  lying  within  a  minute  unstained  area,  the  vesicular  portion  of  the 
nucleus,  and  surrounded  by  a  small  ring  of  protoplasm,  staining  very 
intensely.  In  the  pestivo-autumnal  infections  the  crescents  are  composed, 
as  shown  by  the  staining  reactions,  of  a  large  amount  of  protoplasm  and  a 
compact  clump  of  chromatin  situated  at  the  centre  or  at  one  pole  of  the 
crescent.  The  flagellated  organisms  stain  similarly  to  the  full-grown 
parasites  with  the  exception  that  a  narrow  thread  of  chromatin  can  be 
detected  within  each  flagellum.  This  chromatin  gradually  becomes  col- 
lected toward  the  centre  of  the  flagellum  before  it  becomes  free  from  the 
parent  body,  the  remainder  of  the  flagellum  staining  a  uniform  blue,  the 
chromatin  being  bright  red  in  color.  There  are  many  exceptions  to  this 
general  rule  regarding  the  staining  properties  of  the  plasmodia,  but  these 
are  probably  due  to  external  factors. 

In  all  varieties  of  the  malarial  parasite  the  first  stage  seen  within  the 
red  cell  in  stained  specimens  is  ring-shaped,  consisting  of  a  small  dot  of 
chromatin  surrounded  by  an  unstained  area,  and  this  again  surrounded  by 
a  small  amount  of  protoplasm. 

Contributing  Factors  in  Etiology.— While  the  malarial  parasites,  or 
hosmosporidia,  are  the  direct  cause  of  the  malarial  infections,  and  while 
the  transmission  of  the  disease  depends  entirely,  so  far  as  we  at  present 
know,  upon  moscjuitoes  of  the  genus  Anopheles,  there  are  certain  factors 
which  enter  indirectly  into  the  etiology  of  the  disease.  These  factors  favor 
the  development  of  the  parasites  within  the  body  or  indirectly  aid  in  in- 
fection.   Among  them  may  be  mentioned  the  following: 

Locality. — This  subject  has  already  been  considered  under  the  geo- 
graphical distribution  of  malaria  but  it  has  a  decided  influence  upon  the 


THE  MALARIAL  FEVERS  405 

character  of  the  infection.  The  mild  tertian  and  quartan  infections, 
especially  the  tertian,  are  of  almost  world-wide  distribution,  but  the  more 
severe  sestivo-autumnal  types  are  much  more  limited  as  regards  locality, 
being  very  uncommon  in  northern  latitudes  and  becoming  more  and  more 
common  as  the  tropics  are  approached. 

Climate. — As  stated  in  the  foregoing,  climate  has  a  decided  influence  as 
regards  the  distribution  of  certain  types  of  malarial  infection.  These 
infections  are  most  common  and  pernicious  in  tropical  climates,  so  that 
heat  may  be  considered  as  an  essential  predisposing  cause  of  the  malarial 
fevers.  Even  in  temperate  climates,  the  sestivo-autumnal  fevers  prevail 
mostly  during  the  summer  and  autumn  months,  while  in  the  tropics  they 
prevail  throughout  the  year.  Thayer  and  Hewetson^  call  attention  to 
the  seasonal  variation  of  these  diseases  as  observed  in  Baltimore.  The 
smallest  number  of  cases  occurred  during  the  months  of  December,  Janu- 
ary and  February;  during  the  spring  months  the  cases  increased  until 
May,  and  then  decreased  until  July,  when  they  again  increased  and 
reached  the  maximum  in  September.  The  observations  of  these  author- 
ities have  been  borne  out  by  those  of  numerous  investigators,  and  there 
can  be  no  doubt  that  the  season  has  a  most  marked  influence  as  regards 
the  number  of  cases  observed  in  any  locality.  This,  of  course,  is  probably 
due  to  the  fact  that  mosquitoes,  especially  in  temperate  climates,  are  much 
more  numerous  during  the  spring,  summer,  and  autumn  months. 

Time  of  Day. — It  has  always  been  observed  that  there  is  much  more 
danger  of  contracting  malaria  at  night  than  during  the  day.  In  the  light 
of  our  present  knowledge  that  these  diseases  are  due  to  inoculation  by  the 
bite  of  the  mosquito,  this  fact  is  easily  explained,  for  it  is  during  the  night 
that  mosquitoes  mostly  bite. 

Altitude. — These  diseases  occur  especially  in  low-lands  along  the  coast 
and  rivers  of  warm  countries.  This  is  a  fact  which  has  been  observed 
since  the  very  earliest  study  of  malarial  infections.  Mountainous  regions 
are  generally  free  from  malaria,  although  this  is  not  always  so,  for  in  the 
Philippine  Islands  certain  valleys  are  almost  free  from  malaria,  while  the 
hills  in  the  vicinity  are  notoriously  infected.  It  has  also  been  observed  that 
persons  living  in  the  tropics  and  sleeping  in  the  lower  stories  of  houses  are 
more  apt  to  become  infected  with  malaria  than  those  in  the  upper  stories. 
For  a  long  time  this  was  held  to  be  due  to  low-lying  noxious  vapors  which 
penetrated  the  lower  floors  but  did  not  rise  to  the  upper  stories  of  dwell- 
ings. The  true  explanation  is  that,  as  a  rule,  mosquitoes  do  not  fly  to 
any  great  height. 

Moisture. — Marshes  and  low-lying  damp  regions  are  usually  condu- 
cive to  malaria,  and  moisture  is  a  most  important  factor  in  the  distribution 
of  the  disease.  This  is  again  explained  by  the  fact  that  mosquitoes  are 
most  numerous  and  breed  most  abundantly  in  moist  regions. 

Soil.— It  was  long  ago  observed  that  the  sailors  upon  ships  cruising  in 
tropical  regions  did  not  contract  malaria  unless  they  went  on  shore,  and 
it  was  supposed  that  the  miasmatic  gases  arising  from  swamps  and  moist 
soil  led  to  the  production  of  the  disease,  and  for  a  long  time  it  was  be- 
lieved that  the  upturning  of  the  soil  in  certain  regions  led  to  an  outbreak. 
Tropical  jungles,  low  marshy  islands,  or  lands  covered  with  pools  of  stag- 

^  Johns  Hopkins  Hospital  Reports,  Vol.  V,  1895,  pp.  5-215. 


406  DISEASES  CAUSED  BY  PROTOZOA 

nant  water  have  always  been  regarded  as  conducive  to  nialariul  infection. 
The  fact  remains,  however,  that  the  soil  per  se  has  nothing  to  do  with  the 
production  of  malarial  disease  except  in  so  far  as  it  favors  the  breeding  of 
mosquitoes.  A  moist  soil  favors  the  spread  of  the  disease  as  it  brings  about- 
the  conditions  favorable  for  the  development  of  the  mosquito  larv;ie;  this 
is  also  true  of  thosc-instances  in  which  malarial  epidemics  have  followed 
the  upturning  of  soil  in  certain  localities,  thus  favoring  the  formation  of 
stagnant  })ools  in  which  the  larv;ic  of  the  mosquito  develop. 

Rain. — Rain  favors  the  production  of  malaria  because  it  favors  the 
breeding  of  the  mosquito.  Ailded  to  this,  continued  rainy  weather,  by 
diminishing  the  resisting  powers  of  the  individual,  favors  the  development 
of  the  disease  after  he  has  become  infected  by  the  mosquito. 

Race. — According  to  Thayer  and  Hewetson,  the  negro  is  less  liable  to 
contract  malaria  than  the  white  man.  This  subject  has  attracted  the 
attention  of  a  great  many  investigators,  and  it  has  been  found  that  the 
native  negro  races  acquire  a  more  or  less  complete  immunity  in  early  life 
from  malarial  disease.  A  very  large  percentage  of  negro  children  in  in- 
fected localities  are  found  to  harbor  the  malarial  plasmodia,  but  this  is  not 
true  of  the  adult.  There  is  probably  no  racial  immunity  against  malaria, 
but  it  is  imdoubtedly  true  that  an  acquired  immunity  is  present  among 
many  people  Avho  inhabit  malarial  regions. 

Age. — Children  are  more  susceptible  to  malarial  infection  than  adults, 
and,  as  has  been  suggested  by  INIarchiaf ava,  this  is  probably  due  to  the  fact 
that  mosquitoes  bite  children  in  preference  to  adults. 

Sex. — When  equally  exposed,  both  sexes  have  the  same  ratio  of  infec- 
tion, but,  as  a  matter  of  fact,  malaria  is  more  common  in  men  than  in 
women,  as  the  latter  are  not  as  often  exposed  to  the  bites  of  the  mosc[uito. 

Occupation. — The  occupation  of  man  becomes  a  predisposing  factor 
in  the  production  of  the  disease  in  proportion  to  the  chances  that  occupa- 
tion gives  him  of  infection  by  the  nioscpiito.  Laborers  working  at  ditch- 
ing, railway  building,  and  other  occupations  wdiich  necessitate  the  turning 
up  of  the  soil  and  exposure  to  night  air,  and  therefore  to  the  bites  of  mos- 
quitoes, are  especially  liable  to  contract  the  malarial  fevers.  An  instance 
of  this  was  the  terrific  mortality  from  eestivo-autumnal  malaria  during  the 
early  work  upon  the  Panama  canal. 

There  are  numerous  other  factors  which  contribute  to  the  production  of 
malarial  fevers,  among  which  may  be  mentioned  those  which  lower  the 
individual's  resisting  powers,  such  as  exposure,  dissipation,  over-eating, 
over-work,  whether  mental  or  physical,  and,  in  short,  anything  which 
interferes  with  the  normal  physiological  processes.  There  can  be  no 
doubt  that  an  infection  with  a  small  number  of  malarial  parasites  is  over- 
come, in  a  great  many  instances,  by  the  healthy  individual,  but  should  the 
normal  resisting  poAvers  be  lowered  such  an  infection  would  result  in  the 
symptoms  of  the  disease. 

Cultivation. — No  one,  as  yet,  has  been  able  to  cultivate  the  malarial 
Plasmodia  in  artific?al  media,  outside  of  the  human  body.  The  only  in- 
vestigator who  has  ever  claimed  to  have  done  so  is  Coronado,^  but  his 
experiments  have  been  repeated  by  other  observers,  none  of  whom  has 
been  able  to  confirm  them.    While  cultivation  of  these  organisms  has  not 

^Cronica  Medici  Suirurgica  de  la  Habana,  November,  1892. 


THE  MALARIAL  FEVERS  407 

been  successful,  the  sestivo-autumnal  parasites  have  been  kept  ahve  out- 
side of  the  human  body  for  some  (hiys.  Sakharov  was  the  first  to  perfcjrrn 
such  experiments  and  he  was  able  to  keep  the  parasites  alive  in  blood, 
obtained  by  leeches  from  the  human  subject,  for  a  week.  No  reproduc- 
tive changes,  however,  were  observed.  Hamburger  and  Mitchell,  as 
quoted  by  Thayer,^  performed  similar  experiments  and  were  able  to 
keep  the  pestivo-autumnal  parasites  alive  for  a  period  of  eight  days. 

Inoculation  Experiments. — ^The  malarial  fevers  may  be  transmitted  by 
direct  inoculation  from  man  to  man.  It  would  be  unprofitable  here  to 
detail  the  experiments  which  have  been  performed  along  this  line,  but  the 
disease  has  been  successfully  reproduced  in  this  way  by  Gerhardt,  Mari- 
otti,  Marchiafava,  Celli,  Bignami,  Bastianelli,  Baccelli,  Sakharov,  Elting, 
and  many  others.  It  has  invariably  been  found  that  the  type  of  parasite 
inhabiting  the  blood  injected  is  found  again  in  the  blood  of  the  individual 
infected,  and  is  followed  by  the  clinical  symptoms  of  the  variety  of  malaria 
produced  by  the  type  of  parasite  injected.  Thus,  for  instance,  the  inocu- 
lation of  blood  from  a  patient  suffering  from  tertian  fever  is  always  fol- 
lowed by  tertian  fever  in  the  inoculated  individual. 

Immunity. — ^Tliis  may  be  considered  under  the  following  heads, 
racial,  congenital,  and  acquired  immunity.  Natural  immunity  may 
occur,  but  it  is  undoubtedly  rare. 

Racial  Immunity. — Certain  races  of  mankind  have  been  considered 
immune  to  the  malarial  fevers.  This  statement,  however,  rests  upon  but 
very  little  proof,  and  cannot  be  substantiated  by  facts.  While  this  is  so, 
it  is  a  well-recognized  fact  that  some  races  are  more  resistant  to  malaria 
than  others.  For  instances,  the  black  races  are  more  resistant  in  adult 
life,  but  the  immunity  which  exists  is  possibly  acquired.  In  other  words, 
in  those  races  which  live  in  malarial  localities  the  disease  is  acquired  in 
very  early  life  and  a  natural  immunity  is  established  so  that  the  adult 
individuals  are  resistant  to  the  infection.  It  may  be  stated  as  a  fact  that 
no  people  inhabiting  the  world  are,  as  a  race,  immune  to  the  malarial 
fevers. 

Congenital  Immunity. — ^There  exist  people,  living  in  the  most  malari- 
ous localities,  who  have  never  suffered  from  the  disease.  This  immunity 
is,  in  all  probability,  congenital,  and  in  a  few  instances  has  been  proven  to 
be  a  family  characteristic. 

Acquired  Immunity. — ^Long  residence  in  malarious  country  may,  if 
the  individual  survives,  confer  upon  him  a  relative  immunity  to  the 
disease.  Repeated  attacks  of  malaria  will  in  time  render  the  individual 
less  liable  to  further  attacks.  We  can  explain  this  in  only  one  way:  that 
the  malarial  poison  produces  certain  changes  in  the  human  organism 
which  render  it  at  least  partially  immune  to  future  attacks.  The  histoi'y 
of  acquired  immunity  is  simply  that  of  repeated  attacks  of  malarial  fever, 
each  one  a  little  less  severe  than  the  preceding,  until  at  last  a  spontaneous 
permanent  cure  is  affected.  Such  immunity  may  be  lasting,  but  as  a  rule 
hardship,  privation,  ill-health,  or  removal  to  a  new  locality  will  destroy  it. 

Pathology.- — Primarily,  malarial  infections  exert  the  most  marked 
eflfect  upon  the  blood,  as  the  plasmodia  live  at  the  expense  of  the  red  blood 
corpuscles,  arid  probably  elaborate  toxins  which  materially  affect  all  the  ele- 

^Lectures  on  the  Malarial  Fevers,  1897,  p.  27. 


408  DISEASES  CAUSED  BY  PROTOZOA 

ments  of  this  fluid.  In  1847,  Meckel  discovered  granules  of  pigment  in  the 
blood,  and  ever  .since  then  the  condition  of  nielana'niia  has  been  recognized 
as  one  of  the  nio.st  characteri.stic  features  of  malarial  di.sea.se.  It  may  be 
stated  that  the  patholojiical  changes  which  occur  in  the  blood  are  the 
result  of  primaiT  and  .secondary  causes,  the  i)rinuiry  cause  being  the  infec- 
tion of  the  retl  cells  by  the  parasites  and  the  changes  brought  about  by 
such  infection;  the  secondary,  the  anaemic  condition  which  is  the  inevi- 
table result  of  malarial  infection. 

Changes  in  the  form  of  tlie  red  corpuscles  are  alwavs  present,  as  in  tertian 
infections,  where  the  cor])uscles  are  swollen  and  mu(  h  larger  than  normal, 
while  in  the  a\stivo-autumnal  infections  they  are  smaller,  the  color  is  much 
darker  and  the  corpuscles  appear  greenish  or  brassy  in  color.  Many  of 
the  infected  red  corpuscles,  especially  in  the  a^stivo-autumnal  infections, 
show  a  retraction  of  the  ha?moglobin,  small  areas  being  thus  rendered 
colorless.  The  infected  red  cells  are  gradually  destroyed  by  the  growth  of 
the  parasite  within  them,  but  even  in  those  which  are  not  infected  a 
marked  difference  is  noted  in  the  color  index  and  in  the  form. 

There  occur  in  the  blood  macrophages,  containing  much  pigment, 
and  in  the  restivo-autumnal  infections  especially,  numerous  plasmodia. 
Together  with  these  there  occurs  either  free  or  within  many  of  the 
leukocytes,  brown,  black,  or  brownish-yellow  pigment,  occurring  as 
blocks,  granules,  rods,  grains,  and  irregular  clumps.  The  occurrence  of 
this  pigment  is  one  of  the  most  characteristic  conditions  found  in  the 
blood  of  malaria.  The  pigment  occurs  in  two  forms,  melanin  and 
h(Emosiderin.  The  first  gives  no  reaction  for  iron,  while  the  second 
does.    As  regard  the  origin  of  the  two  varieties  Bignami  has  well  said: 

"The  melansemia,  index  of  an  acute  infection,  is  derived  only  from  the 
direct  transformation  of  hfcmoglobin  into  melanin  through  the  action  of 
the  parasites  within  the  red  blood  corpuscles;  the  melanosis  of  the  viscera, 
spleen,  liver,  bone-marrow,  etc.,  index  of  a  previous  infection,  has  a 
double  origin.  In  chief  part  it  is  derived  from  the  melansemia;  that  is, 
from  the  deposition  in  the  viscera  of  the  black  pigment  {melanin)  formed 
during  the  acute  infection  in  the  circulating  blood;  in  part  it  has  a  local 
origin,  that  is,  it  is  derived  from  the  slow  transformation  of  the  blocks  of 
yellow-colored  pigment  (JioBmosiderin) ,  which  are  deposited  or  formed  in 
the  spleen  and  in  the  other  viscera  from  the  enormous  quantity  of  altered 
red  blood  corpuscles,  which,  in  grave  infections,  die  before  the  direct 
action  of  the  parasites  has  transformed  their  haemoglobin  into  black 
pigment." 

Besides  the  occurrence  of  changes  in  the  form  and  color  of  the  red 
blood  corpuscles,  as  well  as  the  occurrence  in  the  blood  of  pigmented 
leukocytes  and  j)igment,  in  all  forms  of  malarial  fever  there  is  a  reduction 
in  both  the  red  and  white  corpuscles.  This  reduction  is  very  often  more 
marked  in  tertian  and  quartan  malaria  than  in  restivo-autumnal  and  is  due 
to  the  action  of  the  parasites  upon  the  corpuscles  containing  them,  the 
action  of  the  poisonous  material  elaborated  and  set  free  by  the  parasites, 
and  to  inhibited  function  of  the  blood-producing  glands. 

Most  valuable  observations  upon  the  reduction  of  the  red  cells  have 
been  made  by  Kelsch,^  who   found    that    a  reduction  followed  every 

^Archives  de  physiologic,  1875,  690. 


THE  MALARIAL  FEVERS  409 

paroxysm  of  the  fever.  This  reduction  may  be  very  great;  some  cases 
have  been  observed  in  which  only  500,000  red  cells  were  present  to  the 
cubic  millimeter.  In  ordinary  cases,  after  the  infection  has  persisted  for  a 
few  days,  it  will  be  found  that  the  red  cells  have  fallen  to  2,000,000,  or 
slightly  less,  per  cubic  millimeter.  This  marked  reduction,  however,  is 
not  persistent,  for  in  long-continued  infections  it  will  be  found  that  after  a 
certain  amount  of  anaemia  has  been  produced  fhcro  is  no  further  fall,  and 
even  in  most  cases  a  slight  gain  over  the  lowest  point  reached  during  the 
acute  infection.  In  the  pernicious  forms  the  red  cells  may  fall  to  1,000,000 
or  less  per  cubic  millimeter  within  twenty-four  hours,  but  if  the  patient 
has  suffered  from  repeated  attacks  such  a  marked  decrease  is  but  seldom 
observed.  The  return  to  the  normal  number  of  red  cells  is  generally 
rapid  after  the  mild,  and  in  some  cases  after  severe  infections  which  have 
been  promptly  stopped  by  treatment;  but  in  cases  which  have  been  treated 
improperly  or  where  many  relapses  have  occurred  a  chronic  and  persistent 
anaemia  is  produced  which  is  one  of  the  most  marked  characteristics  of 
chronic  malarial  infection. 

As  regards  the  white  corpuscles,  it  may  be  said  in  general  that  the  re- 
duction in  their  number  corresponds  with  that  of  the  red  cells.  During 
the  paroxysm  there  is  often  a  leukocytosis,  while  between  the  paroxysms 
the  leukocytes  are  markedly  reduced  in  number.  This  is,  in  general,  true 
of  all  forms  of  malarial  fever,  but  in  some  cases  of  fatal  pernicious  malaria 
a  leukocytosis  is  observed,  which  is  a  strong  argument  against  the  theory 
of  Metchnikoflf  that  the  leukocytes  play  the  most  important  part  in  the 
spontaneous  cure  of  these  infections.  Recently  much  attention  has  been 
paid  to  the  relative  increase  in  the  mononuclear  leukocytes  as  being  of 
diagnostic  importance  in  malarial  infection.  While  probably  in  a  major- 
ity of  instances  there  is  a  considerable  increase  in  this  type  of  cell,  it  has 
not  been  the  writer's  experience  that  very  much  weight  can  be  given  in 
diagnosis  to  a  mononuclear  increase  in  malarial  infection. 

Besides  the  reduction  in  the  red  and  white  corpuscles  there  is  generally 
a  marked  reduction  in  the  haemoglobin,  especially  in  the  sestivo-autumnal 
infections.  This  reduction  may  be  very  rapid,  the  haemoglobin  falling 
from  10  to  40  per  cent,  within  two  or  three  days.  But  little  weight  can, 
however,  be  given  to  the  reduction  of  the  haemoglobin  as  regards  the  prog- 
nosis of  individual  cases.  In  some  of  the  most  pernicious  forms  of  ma- 
laria there  may  be  but  a  slight  reduction  in  haemoglobin,  while  in  many 
benign  tertian  infections  there  is  often  a  very  marked  reduction. 

Summing  up  our  knowledge  as  regards  the  changes  in  the  blood  in  the 
malarial  fevers,  it  may  be  briefly  stated  as  follows:  A  marked  reduction 
of  the  red  cells  both  by  parasitic  infection  and  as  the  result  of  poisons 
elaborated  by  the  parasites,  as  well  as  changes  brought  about  by  these 
poisons  in  the  blood-forming  glands;  a  corresponding  reduction  in  the 
number  of  white  cells,  with,  in  most  cases,  a  relative  increase  in  the  mono- 
nuclear leukocytes;  a  marked  reduction  in  the  haemoglobin,  and  the 
presence  in  the  blood  of  more  or  less  black  and  brownish-yellow  pigment. 

The  chief  changes  in  the  blood  of  patients  who  have  suffered  from  re- 
peated attacks  of  malaria  consist  in  a  greater  or  less  degree  of  anaemia, 
the  red  blood  cells  seldom  numbering  more  than  3,000,000  per  cubic 
millimeter,  often  not  over  1,500,000,  and  a  reduction  in  haemoglobin  and 
the  leukocytes. 


410  DISEASES  CAUSED  BY  PROTOZOA 

In  severe  cases  nucleated  red  cells  are  sometimes  seen  and  poikiloey- 
tosis  is  almost  invariably  present.  In  such  cases  the  polymorphonuclear 
leukocytes  are  decreased  while  the  mononuclear  are  increased. 

The  Urine, — In  many  cases  of  benign  tertian  and  quartan  malarial 
infections  there  is  but  little  change  in  the  urine,  but  in  the  more  severe 
jestivo-autumnal  infections  there  is  often  a  marked  reduction  in  the 
amount  tluring  the  ajn'rexial  stage,  while  during  the  paroxysms  the 
amount  is  increased.  Pohjuria  is  often  marked  during  the  convalescence 
from  tertian  and  cpiartan  fevers  but  is  not  so  common  in  the  aestivo- 
autumnal  infections.  Sometimes  the  polyuria  is  very  excessive.  One 
patient  observed  by  the  writer,  after  a  tertian  oestivo-autumnal  attack, 
passed  from  20,000  to  25,000  Cc.  of  urine  per  day.  The  color  of  the  urine 
is  generally  dark  amber  or  reddish,  as  in  other  febrile  diseases,  and  the 
acidiiij  is  increased  when  the  urine  is  diminished  in  amount.  The  specific 
gravity  is  increased  during  the  attack,  but  in  cases  showing  polyuria  it  is 
generally  very  low,  being  from  1.005  to  1.010.  The  total  solids  are  in- 
creased. The  amount  of  urea  excreted  in  twenty-four  hours  is  increased, 
especially  during  the  paroxysm,  l^ut  in  cases  showing  polyuria  the  amount 
is  generally  decreased.  The  chlorides  are  not  increased  as  a  rule.  Albu- 
min a])pears  in  a  certain  ]iro})ortion  of  very  severe  tertian  and  quartan 
infections  and  in  the  majority  of  jestivo-autumnal  infections.  In  the 
latter  class  of  cases  hyaline  and  granular  casts  are  often  observed,  and  it 
can  be  stated  as  a  rule  that  all  fatal  cases  of  malaria  show  albuminous 
urine  containing  casts  prior  to  death.  Personal  observations  suggest 
that  indican  is  almost  invariably  increased  in  the  urine  of  patients 
suffering  from  festivo-autumnal  infections. 

The  Viscera. — The  pathological  changes  occurring  in  the  viscera  have 
been  thoroughly  studied  by  many  observers,  among  whom  may  be  men- 
tioned Bignami,  Laveran,  Councilman,  Bastianelli,  Dock,  Thayer, 
Barker  and  Ewing.  From  the  observations  of  these  authorities,  we  have 
come  to  realize  better  the  extensive  pathological  ravages  of  malarial  in- 
fections. It  should  be  understood  that  any  of  the  malarial  parasites 
may  cause  pernicious  infections  leading  to  the  death  of  the  patient,  and 
the  pathological  changes  produced  by  them  do  not  differ  markedly  one 
from  the  other. 

A  patient  dead  of  malarial  fever  presents  a  peculiar  brown  or  grajdsh 
hue  of  the  slcin.  The  degree  of  emaciation  depends  upon  the  duration  of 
the  infection.  Rigor  mortis  is  moderate,  and  postmortem  discoloration 
occurs  early  and  may  be  very  intense.  As  most  cases  of  pernicious  ma- 
laria die  from  cerebral  complications,  the  brain  presents  most  marked 
pathological  lesions.  Externally  the  bloodvessels  are  much  congested, 
the  entire  organ  appearing  hyperffimic.  Small  capillary  hemorrhages  are 
often  observed  and  oedema  is  the  rule.  In  cases  where  no  brain  symptoms 
have  been  exhibited  during  life,  the  organ  externally  shows  but  little 
hyperemia.  The  changes  in  the  brain  consist  in  congestion  of  the  capil- 
laries and  the  presence  of  minute  hemorrhages  within  the  substance  of  the 
organ.  The  congestion  and  hemorrhages  are  due  to  blocking  of  the  capil- 
laries by  malarial  parasites,  which  may  be  observed  in  various  stages  of 
development  within  the  red  cells,  together  with  an  immense  amount  of 
pigment  and  numerous  pigmented  leukoc}^es.  Very  often  the  pigment 
is  present  in  such  large  amount  that  the  organ  appears  pigmented  upon 


THE  MALARIAL  FEVERS  411 

naked-eye  Inspection.  The  parasites  may  be  so  numerous  that  there  are 
hardly  any  uninvadcd  corpuscles  seen,  or  they  may  be  few  in  number. 
Microscopically,  it  may  be  found  that  many  of  the  capillaries  in  the  severe 
infections  are  entirely  filled  with  red  cells  containing  parasites,  and  often 
thrombi  are  formed,  composed  of  such  corpuscles,  together  with  pigment 
and  pigmented  leukocytes.  Besides  the  infected  blood  corpuscles  free 
parasites  may  be  observed,  as  well  as  macrophages,  free  pigment,  i)ig- 
mented  leukocytes,  and  endothelial  cells.  To  the  observations  of  Mar- 
chiafava  and  Monti  we  are  indebted  for  valuable  information  upon  the 
changes  taking  place  in  the  nerve  cells  as  the  result  of  eestivo-autumnal 
infection.  The  changes  occur  both  in  the  protoplasm  and  nucleus  of  the 
nerve  cell  and  lead  to  a  complete  degeneration  and  consequent  destruc- 
tion of  the  diseased  tissue. 

Guarnieri  has  contributed  a  valuable  research  regarding  the  changes 
occurring  in  the  retina  in  pernicious  malaria,  finding  that  they  consist  in 
hemorrhages  and  congestion  of  the  capillaries,  thus  leading  to  impair- 
ment of  function. 

The  changes  in  the  lungs  are  not  at  all  characteristic,  varying  con- 
siderably according  to  the  stage  of  the  disease,  and  being  those  usually 
found  in  severe  fever.  A  microscopic  examination  of  sections  in  certain 
cases  shows  congestion  of  the  alveoli,  which  contain  large  numbers  of  pig- 
mented, parasite-laden,  white  cells,  and  infected  red  blood  corpuscles. 
In  those  cases  in  which  bronchopneumonia  has  occurred,  the  exudation 
in  the  alveoli  is  mostly  composed  of  polymorphonuclear  leukocytes,  to- 
gether with  numerous  infected  red  blood  corpuscles  and  pigment,  although 
the  free  pigment  is  generally  small  in  amount.  A  pneumonia  complicating 
a  fatal  attack  of  malarial  infection,  is  without  doubt  due  to  a  double  infec- 
tion by  the  diplococcus  of  pneumonia  and  the  malarial  plasmodium. 

No  changes  which  are  characteristic  are  observed  in  the  heart  muscle. 

There  has  been  considerable  discussion  regarding  the  changes  occurring 
in  the  stomach  and  intestine  in  pernicious  malaria.  In  certain  cases  in 
which  diarrhoea  has  been  marked  some  time  before  death,  the  mucous 
membrane  of  these  organs  is  more  or  less  pigmented  and  there  is  marked 
hypersemia,  and  even  necrosis  and  ulceration.  The  Peyer's  patches,  as 
well  as  the  solitary  glands,  are  often  swollen.  Upon  microscopic 
examination,  sections  of  the  stomach  and  intestine  show  that  the  capil- 
laries of  the  mucous  folds  are  often  crowded  with  parasite-invaded  cor- 
puscles and  these  may  occlude  the  capillaries,  resulting  in  necrosis  and 
ulceration  of  the  mucous  membrane.  The  epithelial  lining  of  the  mucous 
membrane  is  often  necrotic,  and  there  may  be  present  a  general  super- 
ficial necrosis  of  this  portion  of  the  membrane. 

The  liver  is  generally  enlarged  and  markedly  pigmented  and  in  some 
cases  it  is  almost  black  in  color.  Upon  section,  the  cut  surface  is  often 
very  much  pigmented  and  generally  greatly  congested.  Microscopically 
the  most  marked  changes  are  found  in  the  capillaries  and  liver  cells. 
The  capillaries  show  many  very  large  phagocytes  containing  much  pig- 
ment and  sometimes  infected  red  blood  corpuscles,  as  well  as  malarial 
parasites.  The  epithelial  cells  are  greatly  swollen  and  may  contain  free 
pigment  and  degenerated  organisms.  Free  pigment  is  often  obsen^ed  in 
large  lumps  within  the  liver  capillaries,  while  the  stellate  cells  of  Kupfer 
present  marked  pigmentation.    The  liver  cells  are  atrophied,  undergoing 


412  DISEASES  CAUSED  BY  PROTOZOA 

fatty  degeneration,  necrosis  and  pigmentation.  The  })igmentation,  how- 
ever, in  the  Hver  cells,  is  not  due  to  the  malarial  pigment  but  to  })igment 
derived  from  degenerated  red  blood  corpuscles  and  is  not  characteristic 
of  malaria,  as  it  occurs  in  many  other  diseases.  One  of  the  most  char- 
acteristic and  important  changes  occurring  in  the  liver  are  areas  of  focal 
necrosis,  which  are  believed  by  Flexner  to  be  due  to  the  presence  of  some 
circulating  toxic  substance. 

The  organ  A\liich  i)resents  probably  the  most  marked  changes  in  mala- 
rial infections  is  the  spleen.  It  is  aln.iost  invariably  enlarged,  some- 
times enormously  so.  It  is  of  a  dark  blue  or  almost  black  color  externally, 
the  capsule  being  smooth,  while  upon  section  the  cut  surface  is  of  a  choc- 
olate, slate  or  almost  black  color,  the  consistence  being  very  greatly 
decreased.  The  INlalpighian  corpuscles  are  almost  invisible.  Upon 
microscopic  examination  the  capillaries  are  found  greatly  congested 
by  multitudes  of  red  blood  corpuscles,  most  of  them  containing  parasites. 
This  is  not  always  true,  as  there  are  numerous  cases  in  which  few 
infected  red  blood  corpuscles  are  demonstrable  in  the  spleen.  The 
intense  congestion  of  the  capillaries  pushes  apart  the  cells  of  the  splenic 
pulp,  and  in  some  cases  large  areas  are  destroyed  by  hemorrhagic  exuda- 
tion. In  the  spleen  the  red  cells  contain  parasites  in  all  stages  of  devel- 
opment, but  the  pigmented  forms  and  the  segmenting  bodies  are  most 
commonly  observed,  as  well  as  the  crescents  in  Eestivo-autumnal  infec- 
tions. Besides  the  infected  red  blood  corpuscles,  sections  of  the  spleen 
show  an  immense  number  of  phagocytes.  These  leukocytes  consist  of 
small  cells  which  resemble  lymphocytes,  and  larger  cells  known  as  ma- 
crophages. The  macrophages  contain  clumps  of  pigment,  red  blood 
corpuscles  containing  parasites,  free  parasites,  degenerated  red  blood 
corpuscles,  and  even  the  small  phagocytic  cells  which  have  been  mentioned. 
The  Malpighian  bodies  do  not  become  pigmented  but  the  fibrous  trabecu- 
Ife  always  present  marked  pigmentation.  The  free  pigment  is  present  in 
the  form  of  small  rods  or  granules.  Here,  as  in  the  liver,  two  forms  of 
pigmentation  occur,  the  dark  brown  or  nearly  black  melanin,  the  malarial 
pigment,  and  the  golden  yellow  pigment,  or  hsemosiderin,  derived  from 
degenerated  red  blood  corpuscles. 

The  kidneys  in  pernicious  malaria  present  very  marked  lesions  which 
have  been  studied  especially  by  Ewing  and  Dock,  who  have  contributed 
very  valuable  work  upon  this  subject.  The  condition  produced  is  gener- 
ally that  of  an  acute  nephritis,  presenting  all  the  typical  lesions  of  this 
disease,  together  with  the  pecidiar  lesions  due  to  malarial  infection.  As 
in  the  liver  and  spleen,  microscopically  the  most  marked  change  is  the 
great  congestion  of  the  capillaries  of  the  Malpighian  tufts  and  the  inter- 
tubular  capillaries.  These  vessels  are  filled  with  infected  red  blood  cor- 
puscles, free  pigment  and  pigmented  leukocytes.  There  is  also  present  a 
marked  pigmentation  of  the  endothelial  and  epithelial  cells,  as  well  as 
those  linifig  the  tubules.  Free  parasites  are  often  observed  and  may  be 
seen  occasionally  within  the  glomerular  capillaries.  The  epithelium  of 
Bowman's  capsule  is  undergoing  marked  proliferation  and  the  capillary 
space  may  be  entirely  occluded.  The  epithelium  of  the  tubules  presents 
marked  degenerative  changes,  consisting  of  fatty  and  albuminoid  degen- 
eration and  necrosis.  The  straight  tubules  often  contain  hyaline,  epithe- 
lial or  granular  casts.    It  should  be  remembered  that  there  is  not  a  marked 


THE  MALARIAL  FEVJJRS  413 

pathological  condition  of  the  kidneys  [)resent  in  every  case,  but  it  is  safe 
to  say  that  most  cases  of  pernicious  malaria  are  accompanied  by  an  acute 
parenchymatous  nephritis  presenting  the  peculiar  lesi*  iis  which  have 
been  described. 

In  certain  cases  the  bone  marrow  presents  very  marked  changes.  Micro- 
scopically, unless  the  malarial  infection  has  persisted  for  a  long  time, 
there  is  but  little  change.  If  weeks  or  months  have  elapsed,  however, 
the  color  of  the  bone  marrow  changes  from  the  normal  yellow  to  red  or 
dull  black.  The  capillary  vessels  are  found  to  contain  numerous  endo- 
corpuscular  parasites  in  various  stages  of  development,  and  in  festivo- 
autumnal  infections,  crescentic  bodies.  They  also  contain  numerous 
macrophages,  and  in  the  marrow-pulp  are  found  free  parasites  in  various 
stages  of  development,  as  well  as  macrophages,  nucleated  red  blood  cor- 
puscles, and  pigmented  medullary  cells. 

In  considering  the  pathology  of  malarial  infections  it  should  be  remem- 
bered that  all  the  changes  described  are  not  presented,  as  a  rule,  in  every 
case.  Some  cases  will  present  marked  changes  in  the  spleen  and  liver, 
while  the  brain  and  kidneys  are  but  slightly  affected,  and  in  others  all  the 
chief  viscera  of  the  body  will  show  marked  lesions.  The  pathology  of 
chronic  malarial  infections,  or  malarial  cachexia,  is  characteristic.  As  has 
been  stated,  there  is  always  a  marked  anaemia,  the  spleen  is  greatly  enlarged, 
sometimes  weighing  ten  or  more  pounds,  and  presents  marked  pig- 
mentation. The  liver  is  also  enlarged  but  not  in  proportion  to  the  enlarge- 
ment of  the  spleen.  This  organ  also  appears  pigmented.  The  kidneys  are 
enlarged,  and  grayish  in  color,  due  to  deposits  of  malarial  pigment.  This  is 
also  true  of  the  brain  cortex,  and  upon  section  of  the  brain  there  is  marked 
congestion  of  the  capillaries,  which  contain  numerous  infected  red  blood 
corpuscles,  pigmented  leukocytes  and  free  pigment.  The  condition  pres- 
ent is  characterized  by  the  marked  pigmentation  of  all  the  viscera,  to 
which  the  name  melanosis  may  well  apply. 

Pathology  of  Latent  Malarial  Infection. — The  pathology  of  acute 
and  chronic  malarial  infection  having  been  considered,  it  remains  to  discuss 
the  pathology  of  latent  infections.  By  this  term  we  mean  those  cases  in 
which  no  symptoms  of  malaria  are  presented,  but  which  have  died  from 
some  other  disease.  During  the  last  three  years  at  the  U.  S.  Anny  General 
Hospital,  Presidio  of  San  Francisco,  California,  seven  cases  have  been 
observed  in  which  the  autopsy  showed  latent  malarial  infection;  during 
life  no  symptoms  of  such  infection  had  been  presented.  In  three  of  these 
the  infection  was  tertian  in  character,  and  in  four,  sestivo-autumnal. 
The  pathology  of  these  cases  is  interesting  in  that  during  life  they  pre- 
sented no  symptoms  of  malaria,  and  as  showing  the  lesions  produced 
before  the  disease  could  be  diagnosed.  The  pathological  lesions  found 
were  confined  entirely  to  the  spleen  and  liver.  The  spleen  in  the  tertian 
infections  was  considerably  enlarged  and  somewhat  pigmented.  INIicro- 
scopically  the  sections  showed  intense  congestion  of  the  sinuses,  together 
with  pigmentation,  especially  marked  along  the  edges  of  the  iMalpighian 
bodies  and  the  fibrous  trabeculse.  Many  of  the  cells  of  the  splenic  pulp 
were  pigmented.  In  the  splenic  sinuses  and  in  the  capillaries  there  were 
numerous  parasite-infected  red  cells  and  pigmented  leukocytes,  but  such 
cells  were  not  nearly  as  numerous  as  in  acute  infections.  The  parasites 
were  characteristic  of  those  occurring  in  the  peripheral  blood  and  were  all 


414  DISEASES  CAUSED  BY  PROTOZOA 

in  about  tlic  same  stage  of  development  in  each  case.  While  this  was  so, 
it  hai)ponc(l  that  the  patients  (hod  at  such  intervals  that  the  entire  human 
cvfle  of  the  tertian  ixvraslte  could  be  worked  out  from  an  examination  of 
sections  of  the  spleen,  and  the  chief  point  of  importance  in  the  pathology 
of  latent  infections,  as  observed  in  these  cases,  is  that  the  entire  human 
cycle  of  the  parasite  .can  be  followed  in  the  s})leen  when  no  parasites  are 
demonstrable  elsewhere  in  the  body,  thus  proving  conclusively  that  the 
seat  of  the  initial  malarial  infection  is  in  the  spleen.  The  capillaries  also 
contain  numerous  pigmented  leukocytes  and  macroi)hages. 

The  liver  in  the  tertian  infections  did  not  differ  in  appearance  from 
that  of  the  normal  organ,  but  upon  section,  the  cai)illaries  showed  within 
them  a  few  j)igmcnted  leukocytes,  some  containing  what  appeared  to  be 
degenerated  malarial  organisms.     No  infected  red  cells  were  observed. 

In  the  tiestivo-autumnal  infections  the  pathological  lesions  were  the 
same  and  the  life-cycle  of  the  parasite  could  be  traced  from  the  earliest 
hyaline  organism  to  the  segmenting  bodies,  but  no  crescents  could  be 
demonstrated.  The  only  explanation  of  this  fact  is  that  the  parasites  had 
not  advanced  as  yet  to  the  stage  in  which  crescent  formation  was  possible. 

The  pathology  of  latent  malarial  infections  can  be  summed  up  by 
saying  that  before  demonstrable  clinical  symptoms  of  malaria  are  present 
the  malarial  plasmodia  are  undergoing  their  human  life-cycle  within  the 
sjileen  and  can  be  demonstrated  in  this  organ  after  death.  The  changes 
produced  are  the  same  in  character  as  occur  in  acute  infections,  but  of 
course  not  so  marked  in  extent. 

It  is  obvious  that  puncture  of  the  spleen  as  a  diagnostic  measure  in 
these  cases  would  result  in  the  discovery  of  the  malarial  infection. 


SYMPTOMS. 

Incubation. — The  incubation  period  of  malaria  has  received  a  great 
deal  of  attention,  but  at  the  present  time  there  is  considerable  confusion 
regarding  it.  Marchiafava  and  Bignami  have  contributed  a  valuable  study 
of  this  subject,  in  which  they  found  that  the  incubation  period,  from  the 
time  the  patient  was  bitten  by  the  mosquitoes  until  the  first  symptoms 
appeared,  varied  from  nine  to  ten  days.  Osier  states  that  in  the  irregular 
fevers  the  incubation  period  varies  from  three  to  five  days,  while  in  the 
regular  it  varies  from  ten  to  twelve.  From  inoculation  experiments,  Bas- 
tianelli  and  Bignami  found  that  in  ?estivo-autumnal  infections  the  maxi- 
mum period  of  infection  was  five  days,  the  minimum  two,  and  the  mean 
three  days.  Mannaberg  in  seven  cases  found  the  period  of  incubation 
to  vary  from  three  to  fourteen  days,  while  Marchiafava  and  Bignami 
found  the  maximum  to  be  fourteen  days  and  the  minimum  two.  As  re- 
gards the  data  obtained  from  inoculation  experiments,  it  may  be  stated 
that  the  disease  was  inoculated  in  an  unnatural  manner,  and  that  for  this 
reason  the  data  may  be  unreliable.  In  inoculation  of  blood  containing 
only  the  forms  of  the  parasite  belonging  to  the  human  cycle  it  is  reason- 
able to  suppose  that  the  period  of  incubation  will  be  shorter  than  is  the 
case  when  the  mosquito  transmits  the  sporozoites  to  man,  and  this  has 
been  proven  experimentally,  for  Marchiafava  and  Bignami  have  found 
that  in  an  individual  stung  by  the  mosquito  which  had  sucked  blood  con- 


THE  MALARIAL  FEVERS  415 

taining  crescents,  festivo-autumnal  fever  developed  in  from  nine  to  twelve 
days,  whereas  in  the  inoculation  experiments  of  all  the  authorities  quoted 
the  mean  was  six  days.  But  though  the  period  of  incubation  of  these 
fevers  is  doubtless  in  the  majority  of  cases  from  nine  to  twelve  days, 
numerous  instances  do  occur  which  show  a  much  longer  period  of  incu- 
bation, sometimes  weeks  or  months.  Sternberg  quotes  the  instance 
of  certain  sailors  who  were  infected  while  their  ship  lay  for  two  days 
in  port  and  developed  the  disease,  one  after  forty-eight,  and  one  after 
one  hundred  and  four  days  after  leaving  the  port.  The  period  of  incu- 
bation may  be  very  much  prolonged,  and  in  authentic  instances  jjcrsonally 
observed  the  first  symptoms  of  malaria  did  not  appear  until  from  seven  to 
ten  months  after  exposure.  These  were  in  the  person  of  officers  and  en- 
listed men  of  the  army  serving  in  a  tropical  climate,  exposed  to  eestivo- 
autumnal  fever  and  who  immediately  afterward  were  stationed  in 
localities  in  which  there  were  no  Anopheles  mosquitoes  and  no  endemic 
foci  of  malaria.  As  Osier  says,  "A  patient  may  dwell  for  years  in  an 
infected  region  without  having  paroxysms,  or  indeed  fever  of  any  sort, 
and  he  may  then  come  under  observation  for  the  first  time  with  ansemia 
and  a  greatly  enlarged  spleen  and  liver." 

The  explanation  of  these  long  periods  of  incubation  is  made  clear  by 
the  theory  advanced  by  Thayer;  i.  e.,  that  the  parasites  multiply  and  un- 
dergo their  life-cycle,  but  in  such  small  numbers  that  they  give  rise  to  no 
observable  clinical  signs. 

Although  many  individuals  in  malarial  localities  do  not  present  symp- 
toms of  malaria  for  long  periods  of  time,  it  is  without  doubt  true  that  in  the 
great  majority  of  instances  an  individual  exposed  to  infection  will  acquire 
the  disease  in  from  three  weeks  to  two  months. '  This  was  well  illustrated 
in  the  case  of  our  soldiers  in  Cuba,  almost  ninety-five  per  cent,  of  whom 
gave  a  history  of  being  there  from  two  to  six  weeks  before  the  onset  of 
malarial  fever.  One  month  was  the  most  common  period  given  by  the 
men  as  intervening  between  landing  in  Cuba  and  the  first  chill. 

The  length  of  the  period  of  incubation  will  vary,  of  course,  with  the 
amount  of  the  infecting  agent,  the  physical  condition  of  the  infected  in- 
dividual and  his  surroundings  as  regards  exposure,  heat  and  cold,  in- 
sufficient nourishment,  etc. 

Classification, — It  is  extremely  difficult  to  classify  the  malarial  fevers 
from  a  clinical  standpoint.  A  division  into  intermittent,  remittent  and 
continuous  fevers,  while  useful,  is  at  best  but  a  rough  classification  which 
does  not  signify  disease  entities  and  which  is  confusing  in  many  ways. 
It  may  be  stated  that  any  malarial  fever  may  be  intermittent,  remittent  or 
continuous.  For  instance,  while  a  single  tertian  infection  is  undoubtedly 
intermittent,  we  can  conceive  of  a  tertian  infection  in  which  several  genera 
lions  of  parasites  may  mature  at  various  times,  giving  rise  to  a  remittent  or 
even  continuous  temperature  curve.  The  same  is  true  of  quartan,  and 
especially  of  the  eestivo-autumnal  infections.  It  is  also  trvie  that  infection 
with  one  generation  of  any  of  the  malarial  plasmodia  will  always  result  in 
a  typical  intermittent  fever.  In  other  words,  all  malarial  infections  are 
intermittent  in  character  and  only  become  remittent  or  continuous  when 
more  than  one  generation  of  the  plasmodium  matures  at  different  inter- 
vals of  time.  While  the  term  remittent  malaria  is  generally  applied  to 
infections  due  to  the  sestivo-autumnal  parasites,  the  name  is  a  misnomer, 


416 


DISEASES  CAUSED  BY  PROTOZOA 


as  the  .Tstivo-autumnal  infections  are  as  truly  intermittent  as  are  the 
tertian  and  quartan.  For  this  reason  it  seems  better,  in  considering  the 
symptomatology  to  classify  the  malarial  fevers  frona  an  etiological  stand- 
point;   /.  ('  ,  tt-rtian,  (|iiartan  and  a^stivo-autumnal. 

Sjrmptoms  of  Tertian  Malaria. — The  i)aroxysms  of  fever  in  tertian 
malaria  occur  every  forty-eight  hours  and  are  due  to  the  segmentation 
of  the  tertian  malarial  piasmodium.  The  time  of  the  paroxysm  can  be 
accurately  judgetl  by  the  stage  of  growth  of  the  organism  as  seen  in  the 
peripheral  "blood.  The  onset  of  the  paroxysm  always  occurs  during  the 
segmentation  of  the  organism,  and  c|uotidian  paroxysms  are  caused  by 
double  infections  with  the  tertian  ]iarasite. 

This,  the  most  connnon  and  mildest  form  of  malarial  fever,  occurs 
both  in  tropical  and  tem])erate  climates,  and  when  uncomplicated,  presents 
a  typical  temperature  curve,  showing  in  single  infections  a  rise  of  tem- 
perature every  second  day,  while  infections  with  numerous  groups  of 


Fig.  26. 


Tertian  Malarial  Fever. 


tertian  oro-anisms  may  give  rise  to  a  remittent  or  sub-continued  fever. 
In  cases  which  present  quotidian  paroxysms  it  is  often  possible  to  destroy 
one  o-roup  of  parasites  by  small  doses  of  quinine,  and,  when  this  is  done, 
the  regular  tertian  paroxysm  will  reappear .^ 

The  paroxysm,  when  typical,  is  divided  into  three  stages,  chill,  fever, 
and  sweating.  The  'prodromal  symptoms  are  generally  malaise,  loss  of 
appetite  and  more  or  less  dull  headache.  After  these  symptoms  have 
persisted  for  a  few  days  the  patient  is  seized  with  a  severe  chill,  but 
althouo-h  he  feels  extremely  cold  the  temperature  continues  to  rise  and  at 
the  acme  of  the  chill  has  reached  103°,  104°,  or  even  106°  F.  The  chill 
is  immediately  followed  by  a  pronounced  sense  of  heat,  and  in  a  short 
period  of  time  the  patient  will  complain  as  bitterly  of  this  as  he  previously 
had  of  the  cold.  During  the  stage  of  fever,  delirium  is  often  present, 
accompanied  by  severe  headache.  During  the  onset  of  the  chill,  nausea 
and  vomiting  are  common,  but  they  do  not  persist,  as  a  rule,  during  the 
stage  of  fever.  After  the  fever  has  lasted  for  a  few  hours,  it  rapidly 
declines  to  normal,  accompanied  by  very  severe  sweating,  the  entire  skin 
being  bedewed  with  moisture,  often  so  pronounced  that  the  bed- 
clothing  is  saturated. 


THE  MALARIAL  FEVERS  417 

The  Cold  Stage. — As  has  been  mentioned,  there  are  generally  some 
prodromal  symptoms  of  the  approaching  malarial  chill,  as  evidenced  by 
yawning,  a  general  sense  of  discomfort,  headache,  and  often  nausea  and 
vomiting.  The  feeling  of  cold  usually  commences  at  the  feet  and  gradually 
progresses  upward,  although  very  often  the  first  chilly  sensations  are  felt 
along  the  spine.  In  this  form  of  infection  the  chill  is  severe,  the  patient 
shaking  very  vigorously,  but,  it  is  not  so  severe  as  in  the  quartan  infections. 
In  certain  mild  cases  the  chill  may  be  absent,  the  patient  complaining  only 
of  chilly  sensations.  The  facial  expression  of  the  patient  during  the  chill  is 
one  of  cyanosis,  the  lips  being  blue  and  the  skin  bluish-red  in  color.  The 
extremities  are  cyanotic  and  the  skin  presents  the  well-known  condition 
characterized  as  "goose  flesh."  The  jDulse  is  rapid,  generally  rather 
diminished  in  volume  and  often  irregular.  Headache  is  very  often  intense. 
During  the  chill  the  temperature  rises  very  rapidly,  reaching  104°  F. 
or  more,  but  careful  examination  will  demonstrate  that  it  has  begun  to 
rise  before  the  onset  of  the  chill.  The  urine  is  increased  in  quantity 
and  lowered  in  specific  gravity.  The  duration  of  this  stage  varies  from 
one  quarter  of  an  hour  to  two  hours  in  the  most  severe  cases. 

The  Hot  Stage. — At  the  commencement  of  the  hot  stage  the  patient 
complains  of  flushings  of  heat,  rapidly  succeeded  by  cold  sensations.  Soon 
the  sensations  of  cold  are  entirely  lost  and  the  patient  complains  bitterly 
of  the  intense  heat  occasioned  by  this  high  temperature.  The  facial 
appearance  is  that  of  congestion,  the  conjunctiva  being  injected  and  the 
skin  red,  while  the  entire  surface  of  the  body  is  reddened  and  the  con- 
gestion is  especially  marked  in  the  hands.  The  pulse  is  full,  bounding  and 
often  dicrotic.  The  respirations  are  often  rapid  and  hurried,  and  there 
may  be  more  or  less  cough,  denoting  congestion  of  the  lungs.  The  head- 
ache increases  and  may  become  very  intense  and  of  a  throbbing  character. 
Epistaxis  occurs  in  a  small  proportion  of  the  cases.  In  the  milder  tertians 
there  are  no  nervous  symptoms  present  beyond  a  severe  headache,  but  in 
the  severe  cases  there  may  be  marked  delirium  or  a  drowsy  condition 
merging  into  a  semicoma.  This  condition  is  almost  always  present  in 
those  rare  cases  of  tertian  infection  which  become  pernicious.  The  chief 
symptoms  complained  of  by  the  patient  during  the  hot  stage  are  the  severe 
headache  and  the  intense  heat.  The  temperature  may  reach  its  extreme 
height  during  this  stage  but  very  often  the  height  of  the  fever  is  reached  at 
the  end  of  the  cold  stage.  It  is  not  uncommon  during  the  hot  stage  to 
observe  cutaneous  eruptions.  Herpes  is  very  frequently  seen,  especially 
on  the  lips,  and  urticaria  and  a  general  erythema  not  infrequently  occur. 
These  eruptions  sometimes  lead  to  a  suspicion  of  some  eruptive  disease 
being  the  cause  of  the  chill.  Herpes  of  the  penis  may  occur  during  the  hot 
stage  of  the  paroxysm  The  duration  of  this  stage  varies  somewhat,  but 
is  generally  from  four  to  six  hours. 

The  Sweating  Stage. — ^As  the  fever  begins  to  decline,  it  will  be  noticed 
that  the  perspiration  appears  first  on  the  forehead  and  face,  and  the 
patient  at  once  begins  to  feel  better,  the  decrease  in  the  unpleasant 
symptoms  being  proportionate  to  the  severity  of  the  sweating.  Com- 
mencing, as  has  been  said,  on  the  face,  the  perspiration  rapidly  involves 
the  entire  body  and  is  often  so  severe  that  water  may  be  seen  trickling  from 
the  skin  of  the  arms,  thighs,  and  legs.  The  sweating  stage  lasts,  as  a  rule 
from  two  to  three  hours,  at  the  end  of  which  time  the  temperature  has 

27 


418 


DISEASES  CAUSED  BY  PROTOZOA 


declined  to  normal,  all  of  the  impleasant  symptoms  have  disappeared,  and 
the  patient  generally  sleeps  for  some  time.  As  a  rule,  the  temperature 
goes  somewhat  below  normal  and  the  decline  is  accompanied  by  con- 
siderable weakness  of  the  circulation,  the  pulse  being  slow  and  weak  In 
very  rare  cases  this  stage  may  be  accompanied  by  collapse,  and  m  one 
case  of  pernicious  tertian  infection  observed  by  the  writer  this  collapse 
proved  fatal.  During  the  cold  stage  an  excessive  amount  of  urine  is  often 
voided,  i)olyuria  being  a  most  fre(]uent  symptom. 

The  average  duration  of  the  entire  tertian  paroxysm  is  from  eleven  to 
fourteen  hours,  but  it  must  be  remembered  that  there  are  paroxysms  so 
slight  as  to  be  hardly  recognized,  especially  in  chiklrcn,  while,  on  the  other 
hand,  the  length  of  the  paroxysm  may  be  prolonged  to  twenty-four  hours. 
In  children  the  onset  of  the  malarial  paroxysms  is  often  accompanied  by 
convulsions. 

Physical  examination  of  the  patient  will  generally  show  an  enlarged 
spleeii,  but  this  sign  cannot  be  thoroughly  relied  upon  except  in  those 
cases  which  have  severe  and  re])eatcd  infections.  Albuminuria  is  present 
in  a  considerable  proportion  of  the  cases.  Of  over  1,000  cases  of  ter- 
tian infection  personally  observed  nearly  400  showed  albumin  in  the 
urine,  and  86  showed  the  presence  of  a  few^  granular  and  epithelial  casts. 

Symptoms  of  Quartan  Infections. — The  quartan  paroxysms  occur 
every  seventy-two  hours,  but  here,  again,  we  may  have  double  infections 
in  which  the  segmentation  of  the  parasites  occurs  at  irregular  intervals, 
thus  giving  an  irregular  temperature  curve  which  may  be  misleading  from 
a  diagnostic  standpoint.  It  is  not  necessary  to  detail  the  symptoms  occur- 
ring with  quartan  paroxysms,  as  they  differ  in  no  way  from  those  occur- 
ring in  tertian  infections  except  that,  as  a  rule,  they  are  more  severe  and 


Fig.  27. 


Quartan  malarial  fever. 


these  infections  are  more  apt  to  become  pernicious.  There  are  the  same 
stages  of  chill,  fever,  and  sweating  as  are  seen  in  the  tertian  infection.  The 
nervous  symptoms  are  very  much  more  pronounced,  the  headache  being 
more  severe,  and  slight  delirium  being  almost  always  present.  The 
quartan  paroxysm  is  not  as  prolonged  as  the  tertian,  seldom  covers 
more  than  ten  hours,  and  is  due  to  the  segmentation  of  the  quartan 
parasites. 


THE  MALARIAL  FEVERS  419 

Symptoms  of  -ffilstivo- Autumnal  Infections.— Clinically,  all  sestivo- 

autumnal  infections  should  be  classed  as  severe  infections,  in  contra- 
distinction to  the  quartan  and  tertian  infections,  which  are  usually 
considered  as  mild  infections.  It  should  be  thoroughly  understood,  how- 
ever, that  a  quartan  or  tertian  infection  may  become  pernicious,  although 
such  instances  are  rare.  The  old  idea  that  there  is  a  malarial  parasite 
peculiar  to  the  pernicious  infections  is  no  longer  tenable,  for  it  is  now 
recognized  that  any  of  the  malarial  parasites  may  induce  pernicious 
symptoms,  and  that  the  parasites  accompanying  such  infections  do  not 
diflFer  in  any  respect  from  those  accompanying  the  mildest  infections. 

The  sestivo-autumnal  infections  occur  in  temperate  regions  most 
frequently  during  the  months  of  July,  August,  September,  and  October, 
but  in  the  tropics  they  persist  throughout  the  year,  and  are  not  character- 
ized by  any  marked  seasonal  prevalence. 

As  has  been  stated,  the  writer  believes  that  these  infections  are  caused 
by  two  distinct  varieties  of  the  sestivo-autumnal  parasite,  one  completing 
its  cycle  of  development  in  the  human  body  in  twenty-four  hours,  and  the 
other  in  forty-eight  hours.  Either  of  these  parasites  is  capable  of  caus- 
ing pernicious  infections,  but  personal  observations  suggest  that  the 
tertian  sestivo-autumnal  parasite  is  the  one  most  commonly  concerned. 
From  personal  observations  embracing  nearly  2,000  cases  of  sestivo- 
autumnal  fever  in  which  the  parasites  were  demonstrated  in  the  blood,  75 
per  cent,  were  due  to  the  tertian  sestivo-autumnal  variety. 

The  sestivo-autumnal  infections  have  long  been  distinguished  by  the 
term  remittent,  it  being  supposed  that  in  these  infections  the  temperature 
curve,  instead  of  presenting  the  marked  intermittency  observed  in  tertian 
and  quartan  infections,  was  remittent  or  irregular  in  character.  This 
is,  however,  not  always  correct,  for  these  infections,  when  uncomplicated 
or  uninfluenced  in  any  way  by  treatment,  may  be  as  truly  intermittent  as 
are  the  tertian  and  quartan  infections.  It  is  undeniable,  however,  that 
remittency  and  irregularities  in  the  temperature  curve  are  more  common 
in  the  astivo-autumnal  infections,  but  too  much  stress  should  not  be  laid 
upon  this  point  in  diagnosis. 

Symptoms  of  Tertian  .ffistivo- Autumnal  Fever. — Patients  suffering 
from  this  variety  of  malarial  infection  will  present,  as  a  rule,  the  following 
symptoms : 

Prodromal. — The  prodromal  symptoms  are  loss  of  appetite,  slight 
headache,  evanescent  pains  in  the  back  and  legs,  nervousness,  increased 
urination,  and  a  general  feeling  of  malaise.  As  in  the  tertian  and  quartan 
infections,  three  stages  may  be  distinguished. 

The  Cold  Stage. — This  commences  with  yawning  and  the  patient 
complains  of  headache,  slight  nausea,  perhaps  accompanied  with  vomit- 
ing, and  often  intense  nervousness.  In  a  majority  of  cases  there  are  no 
distinct  chills,  but  the  patient  complains  of  creeping  sensations  along  the 
spinal  column  and  slight  flushings  of  cold  especially  noticeable  along  the 
posterior  portion  of  the  buttocks  and  thighs.  At  the  same  time  the  head- 
ache increases  and  there  is  generally  profound  mental  depression.  The 
mucous  membranes  are  cyanosed  and  the  extremities  cold.  There  is 
severe  pain  in  the  legs  and  back,  greatest,  as  a  rule,  in  the  lumbar  region. 
The  pulse  is  generally  weak  and  increased  in  frequency  and  may  be  very 
irregular.    The  respirations  are  rapid  and  rather  shallow,     During  this 


420 


DISEASES  CAUSED  BY  PROTOZOA 


stage  the  temperature  is  elevated  and  may  reach  103°  F.  or  more.  This 
portion  of  the  attack  doea  not  hist  over  half  an  hour  in  a  majority  of  the 
cases. 

Hot  Stage. — The  patient  next  experiences  a  sense  of  heat  which  comes 
first  as  localized  flushings,  but  soon  becomes  general.  The  facial  expres- 
sion is  that  common  to  fever,  the  eyes  being  suffused  and  brilliant,  the  face 
red,  and  the  skin  hot  ap.d  dry.  Headache  is  intense  and  there  is  present 
'.  either  great  mental  depression  or  nervous  excitement.  The  pain  in  the 
back  and  limbs  is  often  agonizing  in  character,  and  in  some  instances 

Fig.  2S. 


Tertian  jestivo-autiunnal  fever. 


there  is  severe  pain  over  the  abdomen.  The  temperature  is  elevated  and 
the  curve  very  characteristic.  Nausea  and  vomiting  are  often  present, 
vomiting  being  sometimes  very  severe.  The  urine  is  increased  in  quantity 
and  is  generally  albuminous.  Diarrhoea  is  a  common  complication.  The 
pulse  is  rapid  and  dicrotic  in  character,  the  respiration  rapid,  and  there 
may  be  severe  dyspnoea.  This  stage  lasts  for  several  hours,  often  from 
sixteen  to  eighteen  or  twenty,  and  is  succeeded  by  a  stage  of  remission. 
During  this  time  the  symptoms  gradually  decline  in  severity  and  finally 
disappear,  the  temperature  returns  to  normal,  generally  going  a  degree 
or  degree  and  a  half  below  normal.  A  slight  sweating  occurs  but  this  is 
not  nearly  so  marked  as  in  the  tertian  and  quartan  paroxysms.  The 
intermission  may  last  only  two  or  three  hours  when  another  paroxysm 
ensues.  As  a  rule,  attacks  of  this  fever  occur  toward  evening,  extend 
throughout  the  next  day,  and  subside  during  the  first  hours  of  the  third 
day,  the  entire  paroxysm  thus  lasting  thirty-sLx  hours  or  more  and  occur- 
ring every  forty-eight  hours. 

While  the  symptoms  described  are  often  more  severe  than  they  are  in 
the  tertian  and  quartan  infections,  there  is  nothing  diagnostic  about  them 
except  the  temperature  curve.  In  uncomplicated  eases  the  behavior  of 
the  temperature  is  absolutely  characteristic,  and  the  temperature  curve  is 
one  that  is  not  met  with  in  any  other  disease.  This  peculiarity  of  tertian 
festivo-autumnal  infection  Avas  first  pointed  out  by  Marchiafava  and 
Bignami,  and  the  writer  has  confirmed  their  observations  in  every 
uncomplicated  case  of  such  infection.  At  the  onset  of  the  fever  the  tem- 
perature rises  suddenly  to  103°  or  104°  F.    Following  the  sudden  rise 


THE  MALARIAL  FEVERS 


421 


there  occur  slight  oscillations  which  cover  several  hours,  during  which 
time  the  temperature  falls  from  one-half  to  one  degree.  This  period  of 
oscillation  is  followed  by  a  distinct  fall  or  pseudo-crisis,  the  temperature 
dropping  from  one  and  one-half  to  two,  or  even  three  degrees.  This  fall 
of  temperature  is  often  considered  by  the  physician  as  the  true  crisis  of 
the  paroxysm.  On  the  contrary,  however,  the  fever  again  rises  to  a  point 
higher  than  before  attained  and  then  falls  rapidly.  This  is  the  true  crisis, 
as  the  temperature  goes  considerably  below  normal.  This  peculiar 
temperature  curve  can  be  divided  into  five  stages:  (1)  the  initial  rise;  (2) 
the  period  of  slight  remissions;  (3)  the  pseudo-crisis;  (4)  the  precritical 
stage;    (5)  the  true  crisis. 

Another  point  of  value  in  diagnosis  between  this  type  of  fever  and  the 
mild  tertian  and  quartan  types  is  the  length  of  time  during  which  the  fever 
lasts.  This  varies,  but  generally  the  temperature  remains  elevated  over 
twenty-four  hours,  and  often  from  thirty-eight  to  forty;  in  other  words, 
the  paroxysm  really  covers  two  days,  while  the  period  of  intermission  is 
very  short. 

While  this  peculiar  temperature  curve  will  be  observed  in  a  very  large 
proportion  of  cases  of  tertian  sestivo-autumnal  malaria,  there  may  be 
many  deviations  from  it  due  to  several  factors,  among  the  most  important 
being  improper  medication;  double  infections,  or  infection  with  more 
than  one  variety  of  malarial  parasite;  anticipation  of  the  attacks  or 
retardation,  which  are  especially  common  in  the  pernicious  forms;  and 
slight  elevations  of  the  temperature  occurring  between  the  paroxysms. 
The  ordinary  temperature  chart  which  shows  only  the  morning  and 
evening  temperature  is  worse  than  useless  as  a  guide  in  studying  this  form 
of  fever.  The  temperature  should  be  taken  at  least  every  four  hours  and 
better  every  three. 

S3nnptoms  of  Quotidian  -ffistivo-Autumnal  Infections.— The  quo- 
tidian infection,  which  depends  for  its  etiology  upon  the  quotidian  form 

Fig.  29. 


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Quotidian  sestivo-autumnal  fever. 


of  the  sestivo-autumnal  parasite,  varies  but  slightly  in  its  symptomatology 
from  the  tertian,  except  that  the  paroxysms  occur  every  twenty-four  hours. 
As  a  rule,  in  the  quotidian  cases  the  chilly  sensations  are  more  severe  and 


422  DISEASES  CAUSED  BY  PROTOZOA 

there  is  often  a  distinct  chill.  Sweatingis  also  more  pronounced  but  is  not  so 
marked  as  in  the  simple  tertian  and  quartan  fevers.  The  temperature 
curve  is  entirely  different.  It  consists  in  the  abrupt  rise  of  the  temperature 
to  103°  F.  or  more,  succeeded  by  as  abrupt  a  fall.  The  attack  lasts  as  a  rule 
only  about  eight  or  ten  hours.  The  tem})erature  curve  seldom  remains  reg- 
ular for  long  at  a  timie,  for  the  attacks  tend  to  run  into  one  another,  thus  giv- 
ing rise  to  a  continuous  fever.  This  is  especially  true  of  those  cases  of  a 
pernicious  type.  The  temperature  curve  in  the  quotidian  form  is  not  char- 
acteristic as  it  resembles  very  closely  that  of  double  tertian  infection,  and  we 
must  therefore  dejiend  upon  the  microscope  in  making  our  diagnosis.  There 
is  no  greater  proof  of  the  value  of  a  microscopic  examination  of  the  blood 
than  is  founcl  in  the  ease  with  which  the  various  forms  of  malarial  fever 
may  be  diagnosed  and  differentiated  by  it,  and  such  an  examination  is 
often  instrumental  in  saving  life. 

Pernicious  Malarial  Infections. — Any  one  of  the  malarial  plasraodia 
may  give  rise  to  pernicious  symptoms,  but  the  vast  majority  of  fatal  cases 
of  malarial  fever  are  due  to  the  R\stivo-autumnal  parasites.  The  tertian 
sestivo-autumnal  parasite  is  more  often  concerned  in  such  infections  than  is 
the  quotidian,  but  it  should  be  remembered  that  tertian  infections  are  very 
much  more  numerous  than  are  the  cjuotidian.  It  is  very  important  in 
treatins:  cases  of  jestivo-autumnal  malaria  to  remember  that  there  is 
always  an  element  of  danger  in  that  they  may  at  any  time  develop 
pernicious  symptoms  which  may  cause  the  death  of  the  patient,  and  it 
should  be  distinctly  understood  that  the  pernicious  forms  of  malaria 
depend  for  their  etiology  upon  the  same  organisms  as  do  the  mildest 
forms. 

The  great  majority  of  pernicious  attacks  of  malaria  occur  in  northern 
latitudes  in  the  summer  and  autumn  and  are  rare,  while  in  the  tropics  they 
occur  throughout  the  year  and  are  very  common.  The  most  pernicious 
attacks  occur  in  patients  who  have  suffered  repeatedly  from  malarial 
paroxysms  which  have  not  been  properly  treated,  and  the  pernicious 
symptoms  often  develop  during  such  a  paroxysm.  The  causes  of  the 
pernicious  symptoms  are  not  very  clearly  understood.  Bastianelli  and 
Bignami  considered  that  the  chief  causes  for  the  development  of  the 
pernicious  symptoms  rest  in  the  localization  of  the  parasites  in  the  brain 
or  in  other  important  organs,  and  also  in  the  number  of  parasites  present. 
While  these  reasons  undoubtedly  have  much  to  do  with  the  development 
of  pernicious  symptoms,  it  is  probable  that  the  amount  of  toxins  secreted 
by  the  parasites  have  much  to  do  with  the  development  of  these  symptoms, 
as  well  as  the  physical  condition  of  the  infected  individual  and  his  sur- 
roundings as  regards  climate,  food,  hardships,  etc. 

The  pernicious  forms  of  malaria  may  be  classified  in  two  ways;  i.e., 
from  the  character  of  the  temperature  curve,  and  from  the  most  prominent 
symptoms  which  are  present.  Under  the  first  classification  we  may  have 
tertian,  quartan,  remittent  or  larval  pernicious  malaria.  Under  the  second 
classification  we  may  have  comatose,  delirious,  tetanic,  eclamptic,  hemi- 
plegic,  dysenteric,  choleraic,  algid,  cardialgic,  hemorrhagic,  jrtiemnonic 
and  bilious  pernicious  malaria  fevers.  Only  a  few  of  the  most  common 
varieties  will  be  described  and  it  should  be  remembered  that  these  are 
not  disease  entities,  but  only  take  their  name  from  the  clinical  symptoms 
which  are  present. 


THE  MALARIAL  FEVERS  423 

The  Comatose  Form. — This  is  the  most  frequent  form  of  pernicious 
malarial  fever  and  occurs  in  two  ways,  cither  as  a  sudden  attack  of  coma 
or  a  gradually  developing  comatose  condition  during  a  paroxysm  o'f  fever. 
The  sudden  development  of  coma  is  rare  and,  unless  at  once  recognized 
and  treated,  invariably  fatal.  In  this  form  the  patient,  who  may  have 
suffei-ed  from  repeated  attacks  of  malaria  and  who  has  not  felt  well  for 
some  time,  is  suddenly  stricken  with  profound  coma,  falls  to  the  ground 
and,  in  the  fatal  cases,  does  not  again  regain  consciousness.  This  form 
is  apt  to  be  mistaken  for  apoplexy.  The  face  is  suffused,  the  pupils  con- 
tracted, the  pulse  at  first  full  and  bounding,  later  soft,  rapid  and  thready, 
the  respirations  hurried  and  sometimes  stertorous.  The  temperature  is 
irregular,  seldom  reaching  103°  F.,  and  is  often  subnormal.  Death 
generally  occurs  within  two  days.  The  most  common  form  of  comatose 
malaria  is  that  in  which  coma  develops  more  or  less  gradually  during  an 
attack  of  the  fever.  The  symptomatology  of  the  attack  is  the  same  as  in 
the  ordinary  paroxysm,  but  the  nervous  symptoms  such  as  restlessness 
and  delirium  may  be  more  marked.  As  a  rule  the  patient  is  restless  and 
mentally  depressed.  Following  this  there  develops  a  tendency  to  somno- 
lence, which  deepens  into  stupor  and  finally  coma.  Unconsciousness  is 
complete,  the  patient  lying  perfectly  quiet,  or  there  may  be  restless  move- 
ments of  the  arms  and  legs.  The  skin  is  often  somewhat  icteric  in  hue, 
and  hot  and  dry;  the  pupils  are  generally  equally  contracted  but  may  be 
unequal  or  equally  dilated.  The  icteric  hue,  which  is  often  present  in  the 
conjunctivfe,  has  led  to  a  diagnosis  of  yellow  fever  in  infected  regions. 
The  face  may  be  cyanotic  but  in  old  infections  it  is  generally  pale.  Slight 
spasms  of  the  muscles  of  the  face  are  not  infrequent.  The  tongue  is 
tremulous,  dr}'-,  and  thickly  coated,  and  slight  hemorrhages  into  the  skin 
are  sometimes  observed.  There  may  be  hemiplegia  present  or  total 
paralysis.  The  respirations  are  slow  and  quiet,  but  may  be  irregular, 
rapid  and  stertorous.  The  pulse  is  generally  slow  and  full  and  incom- 
pressible at  first,  but  becomes  rapid  and  weak  as  the  paroxysm  pro- 
gresses. The  faeces  and  urine  are  passed  involuntarily,  and  retention  of 
urine  may  occur.  In  cases  having  a  fatal  termination  the  pulse  becomes 
thready,  rapid  and  intermittent;  the  respirations  irregular,  labored  or 
shallow;  the  skin  pale  and  bedewed  with  cold  perspiration,  and  death 
occurs  by  collapse.  In  cases  which  recover,  the  temperature  falls,  accom- 
panied by  perspiration,  the  consciousness  is  slowly  regained,  but  in  many 
of  these  cases  the  improvement  is  only  apparent  and  the  patient  relapses 
in  the  course  of  a  few  hours  into  a  second  paroxysm,  and  perhaps  into  a 
third,  which  usually  results  fatally.  Between  the  paroxysms  the  mental 
condition  is  one  of  torpor  or  great  mental  depression  accompanied  by 
severe  headache.  The  duration  of  the  coma  is  variable,  lasting  from  a 
few  hours  to  three  or  four  days,  but  it  generally  does  not  persist  longer  than 
twenty-four  to  twenty-six  hours. 

As  regards  the  course  of  the  temperature  in  this  form  of  pernicious 
malaria,  it  may  be  stated  that  it  is  irregular.  Some  cases  present  high 
temperature  throughout,  between  103°  and  104°  F.,  while  in  others  the 
temperature  may  remain  slightly  above  normal,  or  even  below  normal. 
In  fatal  cases  the  fever  if  present,  declines,  as  a  rvile,  some  hours  before 
death,  but  it  may  ascend.  Manson  cites  temperatures  of  101°  and  112°  F. 
In  a  fatal  case  observed  by  the  writer  the  temperature  never  went  above 


424  DISEASES  CAUSED  BY  PROTOZOA 

101°  F,  until  a  few  hours  before  death,  wlien  it  rose  to  103°,  the  entire 
attack  hasting  six  days.  In  this  case  the  disease  was  not  recognized  by 
the  attending  physician  until  a  few  hours  before  deatii,  when  a  blood 
examination  was  asked  for,  and  large  numbers  of  (jiiotidian  a^stivo- 
autumnal  parasites  were  found. 

Besides  the  comatose  form  of  pernicious  malaria  there  are  other  cere- 
bral forms,  among  which  may  be  mentioned  the  dcliriou.f  form  in  which 
the  patient  has  hallucinations,  followed  by  violent  excitement;  the  eclamp- 
tic form,  which  is  common  in  children,  in  wliich  the  sym))toms  are  similar 
to  those  of  cerebro-spinal  meningitis,  there  being  vomiting,  fever,  head- 
ache, pain  in  the  back  of  the  neck,  convulsions,  and  coma;  the  hemiplcqic 
form  characterized  by  hemiplegia;  and  the  amaurotic  form,  in  which, 
after  the  comatose  symptoms  have  subsided,  complete  blindness  may 
result. 

The  Algid  Form. — In  certain  regions  of  the  Southern  and  INIiddle 
States,  as  well  as  in  other  localities,  there  occur  pernicious  forms  of 
malaria  known  as  algid  forms.  The  symptoms  develoj)  after  one  or  more 
paroxysms,  or  they  may  be  the  primary  symptoms.  The  characteristic 
condition  is  one  of  profound  collapse  attended  by  profuse  perspiration,  the 
temperature  at  the  same  time  being  more  or  less  elevated,  although  in 
many  cases  the  temperature  is  subnormal.  Patients  suifering  from  this 
form  of  malarial  infection  present  a  characteristic  countenance,  the 
cheeks  being  drawn  and  pinched,  the  eyes  sunken,  the  nostrils  dilated  and 
the  skin  bedewed  with  persjiiration.  The  entire  body  is  cold  and  the  skin 
cyanotic  and  bathed  with  cold  sweat.  The  lips  and  finger  nails  are 
intensely  cyanotic.  The  tongue  is  tremulous,  dry,  and  coated  with  a  dirty 
white  fur.  The  pulse  is  rapid,  thready,  and  easily  compressible,  and 
generally  more  or  less  intermittent;  the  heart  somids  are  muffled  and  the 
second  sound  sometimes  inaudible,  and  as  death  approaches  the  pulse 
becomes  imperceptible;  the  respirations  are  irregular,  superficial  in 
character,  and  labored;  the  muscular  weakness  is  extreme,  while  the 
mental  condition  of  the  patient  is  one  of  apathy  to  his  surroundings  and 
indifference  as  to  his  condition.  These  symptoins  rarely  last  over  a  few 
hours,  death  generally  resulting.  This  is  one  of  the  most  pernicious 
types  of  malarial  infection  and  one  which  is  most  resistent  to  treatment. 
Such  cases  have  been  described  by  Laveran,  Thayer,  Marchiafava, 
Bignami,  Osier  and  Sternberg.  In  one  case  observed  by  the  writer  in  the 
person  of  a  volunteer  soldier  who  contracted  a?stivo-autumnal  fever  in 
Cuba,  algid  symptoms  developed  and  death  occurred  after  six  hours, 
despite  all  therapeutic  aid.  He  had  suffered  previously  from  several 
paroxysms  and  his  blood  showed  large  numbers  of  sestivo-autumnal 
parasites. 

The  Choleraic  Form. — In  certain  cases  of  pernicious  .Tstivo-autumna  1 
malaria,  the  patient  presents  symptoms  which  very  closely  simulate 
those  of  cholera.  As  has  been  mentioned,  diarrhoea  is  by  no  means  an 
infrequent  s}Tnptom  in  attacks  of  pestivo-autumnal  fever,  but  in  these 
eases  choleraic  symptoms  develop,  the  stools  suddenly  becoming  watery, 
very  profuse  and  numerous.  The  diarrhoea  leads  to  profound  collapse 
accompanied  by  the  usual  symptoms.  Death  is  a  common  result  in  un- 
treated cases,  but  where  therapeutic  measures  are  applied  promptly, 
recovery  occurs  in  the  majority  of  cases.    The  temperature  is  generally 


THE  MALARIAL  FEVERS  425 

elevated  in  this  form.  The  great  importance  of  this  variety  of  sestivo- 
autumnal  fever  consists  in  the  HabiUty  with  which  it  may  be  mistaken 
for  cholera  in  countries  in  which  epidemics  of  cholera  are  common. 
Microscopic  examination  of  the  blood  is  the  only  absolutely  correct 
method  of  arriving  at  a  diagnosis  in  such  cases. 

Closely  allied  to  the  choleraic  form,  so  far  as  sym]jtoms  pointing  to 
the  abdomen  are  concerned,  is  the  gastralgic  form  which  has  been  de- 
scribed by  Laveran,  Colin,  and  Hasj^el.  Prominent  symptoms  are  agon- 
izing pain  in  the  epigastrium,  the  vomiting  of  matter  tinged  with  blood, 
while  a  diarrhoea  severe  in  character  may  also  occur  at  the  same  time. 
This  form  is  interesting  from  a  surgical  standpoint,  as  a  diagnosis  of 
appendicitis  may  be  made. 

The  Dysenteric  Form. — A  considerable  proportion  of  patients  suffering 
from  ajstivo-autumnal  infection  present  symptoms  of  dysentery,  consisting 
in  frequent  mucoid  and  bloody  stools,  tenesmus,  colicky  pain  in  the  ab- 
domen, progressive  emaciation,  etc.  At  the  Army  General  Hospital, 
Presidio  of  San  Francisco,  California,  a  very  large  proportion  of  ajstivo- 
autumnal  patients  coming  from  the  Philippine  Islands  presented 
dysenteric  symptoms.  In  fact,  sixty-five  per  cent,  of  the  cases  of  unrec- 
ognized malarial  fever  observed  there  were  diagnosed  either  as 
chronic  diarrhoea  or  dysentery.  This  proves  how  commonly  dysenteric 
symptoms  in  the  tropics  are  due  to  malarial  infection,  and  probably  a  cer- 
tain proportion  of  cases  diagnosed  as  dysentery  in  tropical  regions  are  in 
reality  the  dysenteric  form  of  malarial  infection.  The  proper  administra- 
tion of  quinine  in  these  cases  has  always  resulted  in  the  disappearance  of 
the  symptoms,  thus  proving  their  malarial  nature. 

The  Bilious  Form. — Certain  cases  of  malarial  infection  present  a 
symptom  complex  in  which  jaundice  and  the  vomiting  of  bile-stained 
fluid  are  most  prominent.  These  cases  have  long  been  known  under  the 
term  of  bilious  remittent  fever.  The  attack  is  generally  characterized 
in  the  beginning  by  well-marked  malarial  paroxysms,  but  the  temperature 
becomes  more  or  less  remittent  or  continuous.  Marked  jaundice 
appears  and  severe  vomiting  is  present,  the  matter  vomited  being 
greatly  bile-stained.  Epistaxis  is  rather  common,  and  haematemesis  often 
occurs.  Delirium  may  be  present  or  there  may  be  a  condition  of  semi- 
coma, or  even  coma.  The  patient  often  complains  of  severe  pain  in  the 
epigastrium  and  hiccough  is  one  of  the  most  common  symptoms.  The 
temperature  curve  in  well-marked  cases  is  generally  remittent  or  almost 
continuous,  somewhat  resembling  that  of  typhoid  fever.  If  untreated, 
this  form  of  the  disease  is  almost  invariably  fatal,  but  if  the  proper  thera- 
peutic measures  are  applied  recovery  is  generally  the  result. 

The  Irregular  and  Remittent  Forms. — As  has  been  stated,  any  of  the 
malarial  infections  may  become  irregular  or  remittent  in  character  as 
regards  the  temperature,  but  the  sestivo-autumnal  infections  are  especially 
prone  to  present  peculiar  irregularities  in  the  fever,  which  in  many 
cases  are  very  confusing.  A  malarial  fever  may  become  continuous, 
irregular  or  remittent  in  various  ways,  the  principal  of  which  are  the  an- 
ticipation or  retardation  of  the  paroxysm,  infection  with  one  or  more  groups 
of  parasites,  and  insufficient  treatment  by  quinine.  In  these  infections  it 
is  very  seldom  possible  to  demonstrate  the  complete  life-cycle  of  the  para- 
site in  the  blood,  but  in  those  cases  which  are  caused  by  mixed  infection 


426 


DISEASES  CAUSED  BY  PROTOZOA 


with  more  than  one  variety  of  parasite  the  forms  may  be  easily  differen- 
tiated. It  is  these  forms,  especially  the  remittent  or  continuous  types, 
which  are  so  often  confused  with  typhoid  fever  and  septic-emia,  especially 
where  {i?stivo-autinnnal  infections  are  infrecjuent. 

The  remittent  type  is  the  one  which  is  of  the  most  importance,  as  cases 
of  this  kind  are  not  .infrequently  supposed  to  be  typhoidal  in  character. 
The  symptoms  are  very  variable  and  inconstant.  The  prodromal  symp- 
toms are  generally  weakness,  malaise,  more  or  less  headache,  loss   of 

Fig.  30. 


Sub-coutinued  ffistivo-autiminal  malarial  fever. 


appetite,  etc.  The  attack  may  or  may  not  begin  with  chills,  but  there  are 
always  slight  chilly  sensations.  The  patient's  appearance  is  very  sug- 
gestive of  typhoid,  the  face  being  flushed,  the  eyes  brilliant,  the  mucous 
membranes  congested,  and  the  skin  hot  and  dry.  There  is  severe  head- 
ache and  muscular  pain,  especially  marked  in  the  back  and  limbs.  There 
is  often  marked  nervousness,  sleep  being  poor,  and  there  may  be  slight 
delirium.  The  tongue  is  dry  and  coated  and  resembles  markedly  the 
tongue  of  typhoid,  while  nausea  and  vomiting  are  present  and  diarrhoea 
is  common.  The  pulse  is  rapid  and  dicrotic  in  character,  while  the  res- 
pirations are  hurried  and  often  very  superficial.  There  is  often  tender- 
ness of  the  abdomen,  and  the  spleen  is  generally  more  or  less  enlarged. 
In  some  cases  the  resemblance  to  typhoid  is  very  remarkable,  epistaxis, 
an  eruption  resembling  the  roseola  of  that  disease,  and  tenderness  and 
gurgling  in  the  right  iliac  region  being  present.  In  fact,  in  many  of 
these  cases  it  is  impossible  to  make  a  diagnosis  between  malaria  and 
typhoid  fever  without  the  aid  of  the  microscope. 

The  temperature  curve  in  these  infections  is  very  variable,  but  usually 
there  are  present  more  or  less  marked  intermissions,  thus  serving  to  differ- 
entiate it  from  the  fever  of  typhoid.  In  rare  cases,  how^ever,  the  curve 
cannot  be  distinguished  from  that  of  a  mild  typhoid  fever,  there  being 
slight  daily  remissions  but  no  marked  intermissions. 

An  examination  of  the  blood,  if  carefully  made  and  repeated  if  neces- 
sary, will  invariably  demonstrate  the  type  of  malarial  parasite  concerned, 
which  is  generally  one  of  the  sestivo-autumnal  organisms.  The  duration 
of  the  remittent  or  sub-continued  fevers  may  be  several  weeks,  but  as 
a  rule  spontaneous  cure  or  death  occurs  within  tlii-ee  weeks.  If  properly 
treated,  the  symptoms  are  easily  controlled  within  a  week,  although  in 


THE  MALARIAL  FEVERS  427 

very  rare  instances  the  parasites  may  be  very  resistant  to  quinine  and  per- 
sist for  eight  or  ten  days. 

Spontaneous  recovery,  which  has  been  mentioned,  is  often  oVjserved 
in  the  mild  tertian  and  quartan  infections  and  rarely  in  the  tcstivo-autum- 
nal  infections.  The  chief  causes  leading  to  spontaneous  recovery  in 
malaria  are: 

1.  Production  and  excretion  of  certain  substances  bactericidal  and 
antitoxic  in  nature,  by  certain  leukocytes,  especially  the  eosinophiles, 
v^rhich  lead  to  the  death  of  the  malarial  plasmodia. 

2.  Disintegration  of  the  leukocytes  and  the  liberation  of  certain  anti- 
toxic and  bactericidal  substances  having  a  similar  action. 

3.  Phagocytosis;  i.  e.,  the  engulfing  and  digestion  of  the  plasmodia. 

It  is  probable  that  all  of  these  processes  occur  simultaneously  and  aid 
in  the  destruction  of  the  infection. 

Combined  Infections. — ^Any  of  the  varieties  of  malarial  plasmodia  may 
occur  together,  thus  causing  what  is  known  as  a  combined  infection.  In 
such  infections  the  temperature  chart  is  apt  to  be  irregular  or  remittent, 
but  very  often  one  type  of  parasite  may  so  predominate  in  numbers  that  it 
will  give  to  the  infection  the  characteristic  symptoms  caused  by  the  par- 
ticular organism  concerned;  thus  we  may  have  a  combined  infection 
with  sestivo-autumnal  and  tertian  parasites  in  which  the  sestivo-autumnai 
parasites  are  so  much  more  numerous  than  the  tertian  that  the  case  will 
present  the  symptoms  of  an  sestivo-autumnal  infection.  As  would  be 
expected,  some  very  peculiar  temperature  charts  are  presented  in  these 
combined  infections,  and  the  symptoms  are  often  so  anomalous  that  a 
diagnosis  of  malaria  cannot  be  made  without  the  aid  of  the  microscope. 

Latent  and  Masked  Infections. — In  previous  communications^  the 
writer  has  called  attention  to  the  importance  of  the  occurrence  of  latent  and 
masked  malarial  infections,  especially  in  individuals  who  have  resided  in 
malarious  localities.  A  latent  malarial  infection  may  be  defined  as  one  in 
which  parasites  can  be  demonstrated  in  the  blood  but  in  which  there  are 
no  symptoms  which  would  lead  a  clinician  to  suspect  malaria,  while  a 
masked  infection  is  one  in  which  the  symptoms  are  obscured  by  those  of 
some  accompanying  disease,  or  in  which  they  are  atypical  in  character. 
At  the  U.  S.  Army  General  Hospital  in  San  Francisco,  California,  out  of 
1,267  cases  of  malaria  in  which  the  parasites  were  demonstrated  in  the 
blood,  395,  or  25  per  cent.,  have  shown  either  latent  or  masked  infections. 
The  sestivo-autumnal  infections  comprised  275  of  the  cases,  thus  showing 
that  the  sestivo-autumnal  parasite  is  concerned  most  often  in  latent  and 
masked  malaria.  Examinations  of  the  blood  in  such  cases  have  shown 
the  parasites  in  all  stages  of  development,  but  always  in  small  numbers. 
Of  the  395  cases,  277  were  latent  infections,  or  infections  in  which  the 
malarial  parasites  could  be  demonstrated  in  the  blood  but  which  presented 
no  clinical  symptoms,  while  118  were  masked  infections,  most  of  them 
being  in  patients  suffering  from  other  diseases  which  masked  the  malarial 
symptoms.  Of  the  masked  infections,  chronic  dysentery,  chronic  diar- 
rhoea, pulmonary  tuberculosis,  and  amoebic  dysentery  were  the  diseases 
which  most  often  masked  the  malarial  infection.  Lobar  pneumonia  was 
simulated  very  closely  in  three  cases  by  the  malarial  infection,  and  a 

^Medical  Record,  Feb.  15,  1902,  also  American  Medicine,  Oct.  21,  1904. 


428  DISEASES  CAUSED  BY  PROTOZOA 

diagnosis  of  this  ilisease  was  made  ])i'cvi()us  to  an  examination  of  tlie 
blood. 

The  pathology  of  eertain  fatal  eases  of  latent  and  masked  malarial  in- 
fection demonstrates  that  the  malarial  j)arasitc  may  undergo  its  complete 
life-cycle  in  the  s])leen  without  producing  any  symptoms  of  the  disease. 

The  remarkable  ])ercentage  of  latent  and  masked  infections,  as  shown 
in  the  cases  studied  at  this  hospital,  proves  the  great  importance  of  a 
routine  examination  of  the  blood  in  all  patients  coming  from  malarious 
localities.  It  is  obvious  that  recognition  of  such  infection  is  of  the  greatest 
importance,  as  in  the  latent  infections  we  are  thus  able  to  cure  the  disease 
before  any  annoying  symptoms  are  present,  and  in  the  masked  cases  we 
are  able  to  remove  the  malarial  element  which  may  be  of  the  greatest 
importance  as  regards  the  recovery  of  the  patient.  Not  only  is  this  so, 
but  an  examination  of  the  blood  in  these  cases  will  often  prove  of  service, 
not  only  to  the  physician,  but  also  to  the  surgeon,  as  certain  malarial 
infections  simulate  very  closely  surgical  conditions.  The  following  case  is 
of  especial  interest,  as  it  demonstrates  how  closely  malarial  infection  may 
simulate  appendicitis. 

The  patient  was  an  officer  of  the  U.  S.  Army  who  was  transferred  to 
the  Army  General  Hospital  with  a  diagnosis  of  suspected  appendicitis, 
transfer  being  made  with  a  view  to  operation  if  the  diagnosis  was  verified. 
He  gave  a  history  of  having  intermittent  attacks  of  malaria  in  the  Philip- 
pines which  did  not  necessitate  admission  to  sick  report.  He  had  not  been 
feeling  well  for  some  time,  but  on  the  day  before  admission  to  the  hospital 
he  had  an  attack  of  pain  in  the  region  of  the  ascending  colon.  Upon 
admission  he  complained  of  pain  in  this  region,  at  times  very  severe;  his 
tongue  was  coated;  bowels  regular;  and  his  pulse  and  temperature  about 
normal.  A  blood  count  was  made  and  a  slight  leukocytosis  was  foimd. 
Physical  examination  showed  no  rigidity  of  the  muscular  wall,  but  he 
complained  of  pain  in  the  right  iliac  region  on  pressure,  and  after  careful 
examination,  operation  the  next  morning  was  determined  upon.  That 
evening  he  had  a  slight  chill  and  his  temperature  rose  to  104°  F.  An 
examination  of  the  blood  was  made  and  numerous  hyaline  forms  of  the 
tertian  pestivo-autumnal  parasite  were  found.  Quinine  was  promptly 
administered,  which  resulted  in  a  prompt  fall  of  temperature,  and  con- 
tinued administrations  of  it  in  a  complete  cure.  In  this  case  an  operation 
would  undoubtedly  have  been  performed  in  the  morning  for  a  condition 
which  was  essentially  malarial  in  character.  Microscopic  examination 
of  the  blood  in  these  cases  is  our  only  means  of  diagnosing  the 
disease. 

Complications  and  Sequelae. — The  malarial  fevers,  like  other  disease 
processes,  are  apt  to  be  complicated  by,  or  associated  with,  other  diseases, 
and  are  also  apt  to  be  followed  by  certain  grave  sequelae.  While  this 
is  so,  the  conditions  complicating  malarial  infection  should  not  be  con- 
fused with  the  infection  itself;  in  other  words,  a  typhoid  fever  compli- 
cating malaria  should  not  be  considered  as  being  due  to  malarial  infection; 
nor  is  a  pneumonia  which  may  complicate  such  infections,  due  to  the 
malarial  parasites.  Boudin  advocated  the  theory  that  the  complications 
were  due  to  malarial  poison,  but  in  the  light  of  our  present  knowledge 
this  theory  is  entirely  untenable.  Of  the  many  diseases  which  may  com- 
plicate the  various  forms  of  malaria,  and  especially  the  sestivo-autumnal 


THE  MALARIAL   FEVERS  429 

infections  (for  these  infections,  being  more  severe  in  cliaracter  than  the 
tertian  or  quartan,  are  more  apt  to  be  accompanied  by  complications), 
the  following  may  be  mentioned: 

Of  the  diseases  of  the  nervous  system  acute  mania,  severe  hysteria,  par- 
aplegia, hemiplegia  and  meningitis  may  be  noted. 

The  most  serious  disease  of  the  respiratory  system  complicating  malarial 
infections  is  lobar  and  lobular  pneumonia.  For  a  long  time  pneumonia 
complicating  these  fevers  was  held  to  be  due  to  the  malarial  plasmodia, 
and  while  this  is  true  in  a  very  small  number  of  cases,  it  should  be  remem- 
bered that  true  lobar  or  lobular  pneumonia  may  occur  coincidently  with 
any  of  the  malarial  fevers.'  Pneumonia  may  complicate  the  malarial 
infection  at  any  time,  and  may  develop  suddenly  or  insidiously.  The 
course  of  the  disease  is  similar  to  that  in  a  patient  in  whom  no  malarial 
infection  is  present,  but  the  prognosis  in  pneumonias  complicating  the 
sestivo-autumnal  infections  is  very  grave,  Ascoli  placing  the  mortality 
as  high  as  60  to  78  per  cent.  The  pneumonic  symptoms  may  mask 
the  malaria,  or  vice  versa.  Among  the  other  respiratory  complications 
may  be  mentioned  pneumonic  septicaemia  and  empyema.  Acute 
bronchitis  is  very  common  in  all  varieties  of  malarial  infection  and  in 
the  sestivo-autumnal  infections  is  observed  in  about  40  per  cent,  of 
the  cases.  Tuberculosis  very  often  occurs  in  conjunction  with  malarial 
infections,  and  often  the  symptoms  of  the  disease  mask  those  of  malaria. 
Pleurisy  is  somewhat  rare. 

Diseases  of  the  circulatory  system  not  infrequently  complicate  malarial 
fevers.  As  would  be  expected,  many  cases  of  malaria  present  organic 
disease  of  the  heart  and  in  such  cases  the  prognosis  is  often  grave.  Acute 
endocarditis  is  a  rare  complication,  while  functional  disorders  of  the  heart 
are  very  common. 

The  most  common  disease  of  the  genito-urinary  system  complicating 
malaria  is  nephritis.  Some  form  of  nephritis  occurred  in  at  least  4  per 
cent,  of  sestivo-autumnal  infections  and  in  about  |  per  cent,  of  tertian 
infections  personally  observed.  It  is  more  frequently  a  sequel  of  malaria 
than  a  complication.  Orchitis  and  epididymitis  very  commonly  occur 
as  complications,  but  a  history  of  gonorrhoea  can  usually  be  obtained. 
It  is  doubtful  if  true  malarial  orchitis  ever  occurs. 

The  most  frequent  and  important  disease  of  the  g astro-intestinal  tract 
complicating  the  malarial  fevers  is  dysentery  or  some  form  of  enteritis. 
Dysentery  is  especially  frequent  in  patients  returning  from  regions  where 
both  malaria  and  dysentery  are  endemic.  Sixty-five  per  cent,  of  the 
patients  with  malarial  parasites  in  the  blood  observed  at  the  Army 
General  Hospital,  Presidio  of  San  Francisco,  suffered  at  some  time  from 
acute  or  chronic  dysentery.  Of  these  over  25  per  cent,  were  suffering 
from  amoebic  dysentery.  Dysentery  complicating  malaria  is  very  apt 
to  run  an  aggravated  course,  and  the  prognosis  is  much  worse  than 
where  it  occurs  alone.  Frequently  the  malarial  forms  are  masked  by 
the  symptoms  of  dysentery. 

The  administration  of  quinine  in  cases  complicated  by  dysentery  has 
always  resulted  in  the  removal  of  the  malarial  infection  and  the  improve- 
ment of  the  dysenteric  condition.  In  a  certain  proportion  of  patients 
suffering  from  dysentery,  the  disease  is  probably  due  to  the  localization 
of  the  malarial  parasites  within  the  capillaries  of  the  intestines,  for  in  no 


430  DISEASES  CAUSED  BY  PROTOZOA 

other  way  can  vre  explain  the  rapid  recovery  of  many  such  patients  after 
the  administration  of  quinine. 

Typhoid  fever  occasionally  occurs  in  conjunction  with  the  malarial 
fevers.  In  nearly  5,000  cases  of  malaria  personally  observed  the  com- 
plication of  the  disease  with  typhoid  has  only  occurred  8  times.  Of  these 
8  cases,  5  were  combined  infections  of  typhoid  and  lestivo-autumnal 
malaria,  1  a  combined  infection  with  tertian  malaria,  and  1  with 
quartan.  The  latter  case,  which  has  been  reported,'  is  rare,  in  that  the 
quartan  parasite  was  demonstrated  in  the  blood  in  conijjination  with 
typhoid.  As  a  rule,  the  malarial  attacks  occur  during  convalescence  from 
typhoid  but  may  occur  tluring  any  stage  of  the  disease.  ^Vhere  malaria  is 
complicated  by  tyj^hoid,  or  even  vice  versa,  the  symptoms  do  not  vary 
markedly  from  those  occurring  in  a  single  infection.  The  subject  of 
combined  infections  of  t}']5hoid  and  malaria  has  been  very  fully  inves- 
tigated by  Lyon,^  who  has  collected  all  the  published  cases,  which, 
at  the  time  the  classification  was  completed,  numbered  29  in  all. 
Undoubtedly,  this  is  far  from  being  the  actual  number  of  such  combined 
infections,  as  Lyon  considered  only  as  such  infections  cases  in  which  the 
parasites  of  malaria  were  demonstrated  in  the  blood  at  the  same  time 
that  the  Widal  test  was  present. 

The  discovery  of  such  combined  infections  is  of  the  greatest  importance, 
as  the  malarial  element  in  the  case  can  be  easily  removed  by  the  proper 
administration  of  quinine,  and  thus  a  source  of  injury  to  the  patient 
eliminated. 

Among  other  complications  may  be  mentioned  erysipelas,  acute  rheu- 
matism, sciatica,  various  skin  eruptions  and  variola. 

Sequelae. — The  toxins  elaborated  during  the  development  of  the 
malarial  plasmodia  may  give  rise  to  certain  conditions  which  develop 
coincident  with  or  after  the  malarial  infection  itself  has  ceased,  and  these 
must  be  regarded  as  sequels  of  the  disease.  Among  the  most  common 
are  those  occurring  in  the  nervous  system,  the  genito-winary  system, 
the  glandular  system,  and  the  blood. 

The  most  numerous  complications  occur  in  the  nervous  system,  due  to 
the  blocking  of  the  capillaries  of  the  cortex  of  the  brain  by  the  malarial 
parasites  and  their  products,  or  to  the  effect  of  certain  toxins  liberated  by 
them.  Local  paralysis  frequently  occurs,  due  undoubtedly  to  the  blocking 
of  the  capillaries  of  certain  cortical  regions,  but  these  are  generally 
evanescent  in  character.  Various  psychical  disturbances  are  common  and 
the  memory  is  often  defective  after  repeated  malarial  attacks.  Melan- 
cholia, delusional  insanity  and  mania  may  follow  severe  attacks  of 
sestivo-autumnal  malaria,  and  especially  common  is  a  condition  of 
melancholia.  Mania,  melancholia  and  delusional  insanity  have  been 
observed  in  soldiers  returning  from  the  tropics  which  were  undoubtedly 
sequelfe  of  severe  and  repeated  attacks  of  sestivo-autumnal  malaria. 
INIultiple  neuritis  rarely  occurs.  One  of  the  most  common  sequelse  is 
neuralgia,  but  it  should  be  remembered  that  many  so-called  malarial 
neuralgias  have  in  reality  no  connection  whatever  with  malarial  in- 
fection. 

*  Philadelphia  Medical  Journal,  June  17,  1899 

^  The  Johns  Hopkins  Hospital  Reports,  Vol.  VIII,    1900. 


THE  MALARIAL  FEVERS  431 

Among  diseases  of  the  genito-urinary  system,  albuminuria  is  of  frequent 
occurrence  during  acute  attacks  of  malaria  and  oftentimes  persists  for 
some  time  after  the  cessation  of  such  attacks.  Thayer  and  Hewetson 
found  albuminuria  in  over  50  per  cent,  of  their  cases.  Thayer  found 
that  it  was  most  frequent  in  sestivo-autumnal  infections,  occurring  in 
58.3  per  cent,  of  these  infections,  in  contrast  to  38.6  per  cent,  of  tertian  and 
quartan  infections.  Rem-Pici  has  contributed  most  extensively  to  our 
knowledge  of  the  albuminurias  occurring  during  and  after  malarial 
infections.  From  personal  experience,  albuminuria  apparently  occurs 
in  about  50  per  cent,  of  cases  of  sestivo-autumnal  and  in  about  30  to  35 
per  cent,  of  cases  of  tertian  and  quartan  malaria. 

Both  acute  and  chronic  nephritis  may  occur  as  sequelae  of  the  malarial 
fevers.  Kelsch  and  Keiner  have  contributed  valuable  data  regarding  the 
symptomatology  and  pathology  of  nephritis  occurring  after  malarial 
infections.  It  may  be  stated  that  all  forms  may  occur,  the  most  common 
being  acute  glomerular  and  chronic  parenchymatous  and  interstitial 
nephritis.  Personal  observations  suggest  that  nephritis  occurs  in  at  least 
3  per  cent,  of  all  cases  of  sestivo-autumnal  infections,  the  most  common 
form  being  chronic  parenchymatous.  It  is  rare  in  tertian  and  quartan 
infections,  but  is  always  found  in  fatal  cases. 

Polyuria  is  a  frequent  sequela  of  the  malarial  fevers,  especially  the 
sestivo-autumnal  variety,  but  as  a  rule  the  condition  is  transient,  although 
it  may  be  persistent.  Glycosuria  is  a  rare  sequela  of  the  malarial  infec- 
tions. 

Among  the  sequelse  occurring  in  the  glandular  system  may  be  mentioned 
hypertrophy  of  the  liver  and  rupture  of  the  spleen.  After  repeated 
attacks  of  malaria,  a  condition  which  may  be  termed  hypertrophic, 
malarial  hepatitis  may  develop,  the  liver  becoming  greatly  enlarged, 
while  the  perilobular  tissue  is  increased  in  amount  and  the  capillaries 
greatly  dilated  and  congested.  The  condition  does  not,  as  a  rule,  cause 
any  clinical  symptoms.  Many  authorities  have  endeavored  to  prove  that 
continued  malarial  infection  will  give  rise  to  cirrhosis  of  the  liver,  but 
when  present  it  is  undoubtedly  due  to  some  other  cause,  as  cirrhosis  of 
the  liver  is  no  more  common  in  malarial  than  in  non-malarial  districts. 

Rupture  of  the  spleen  is  a  rare  sequela  of  malaria  and  is  generally  due 
to  falls  or  blows,  in  which  the  greatly  enlarged  organ,  rendered  soft  and 
pliable  by  the  malarial  infection,  is  ruptured.  The  writer  has  reported 
two  cases  of  this  character.  The  symptoms  are  sharp,  lancinating  pain  in 
the  left  side  and  the  usual  symptoms  of  collapse  due  to  hemorrhage. 
Death  may  occur  in  a  few  moments  or  after  a  day  or  more. 

The  Blood. — In  repeated  and  severe  attacks  of  sestivo-autumnal 
malaria  there  is  produced  a  post-malarial  ansemia  which  may  be  very 
severe  and  persistent.  In  tertian  and  quartan  infections,  after  complete 
recovery  the  regeneration  of  the  red  blood  corpuscles  is  generally  rapid, 
but  in  the  sestivo-autumnal  infections  the  anaemia  may  persist.  Along 
with  the  ansemia  there  is  a  marked  reduction  in  the  haemoglobin,  always 
in  about  the  same  ratio  as  the  red  blood  corpuscles,  while  the  leukocytes 
are  reduced  in  number  as  a  whole,  but  the  large  mononuclear  forms 
increased. 

A  pernicious  type  of  ansemia,  occurring  as  a  sequela  of  the  sestivo- 
autumnal  infections,  have  been  observed  by  the  writer  in  6  cases,  all  of 


432  DISEASES  CAUSED  BY  PROTOZOA 

which  provotl  fatal.  The  bUxJtl  showed  no  nucleated  red  cells,  the  red 
cells  numbering  from  490,000  to  590,000  per  cubic  millimeter.  The 
leukocytes  were  about  normal  in  number,  relatively,  but  the  polymor- 
phonuclear leukocytes  were  increased.  Poikilocytosis  was  not  marked, 
but  there  were  great  differences  in  the  size  of  the  red  cells.  This  form  of 
severe  ana^nia  has  been  described  by  Bignami  and  Bastianelli,  and  is 
remarkable  in  that  no  nucleated  red  cells  can  be  demonstrated,  due, 
according  to  these  authors,  to  the  almost  complete  absence  of  regenerative 
power  in  the  blood-forming  organs.  In  certain  instances  the  classical 
type  of  pernicious  anaemia  may  occur  as  a  sequela  of  the  malarial  in- 
fections, esi)ecially  the  a^stivo-autumnal  variety. 

Malarial  Cachexia. — In  patients  who  have  suffered  from  repeated 
attacks  of  malarial  fever  which  have  not  been  properly  treated,  there 
develops  a  peculiar  condition,  the  most  characteristic  symptoms  of  which 
are  a  more  or  less  severe  aniemia  and  a  greatly  enlarged  spleen.  This 
so-called  malarial  cacliexia  is  most  frequent  in  troi)ical  regions  in  which 
the  tiestivo-autumnal  infections  are  endemic,  and  least  frequent  in  locali- 
ties in  which  tertian  infections  are  present.  It  is  especially  apt  to  develop 
after  latent  and  masked  infections  which  have  gone  untreated  because  un- 
recognized The  ansemia  which  is  present  partakes  of  the  character  of  a 
secondary  anaemia,  the  red  cells  being  reduced  to  2,000,000  or  less  per 
cubic  millimeter,  while  there  is  a  marked  increase  in  the  large  mono- 
nuclear leukocytes  and  a  corresponding  decrease  in  the  haemoglobin.  The 
spleen  may  be  enormously  enlarged,  reaching  as  low  as  the  crest  of  the 
ilium,  but  as  a  rule  it  does  not  extend  more  than  four  to  eight  cm.  below 
the  border  of  the  ribs.     It  is  firm  and  not  painful  on  palpation. 

Patients  suffering  from  malarial  cachexia  present  a  peculiar  yellowish 
or  grayish  hue  of  the  skin,  while  the  mucous  membranes  are  very  pale,  due 
to  the  antemia.  There  is  a  loss  of  appetite,  diarrha^a,  dyspnoea,  emacia- 
tion, and  a  general  condition  of  nervous  exhaustion.  The  temperature 
may  be  normal,  but  generally  shows  a  slight  rise  toward  evening;  it 
seldom  reaches  102°  F.  The  condition  is  especially  freciuent  in  children 
living  in  tropical  localities. 

The  long-continued  malarial  infection  renders  these  patients  especially 
liable  to  acute  infectious  diseases  and  slight  injuries  are  often  attended 
by  serious  results,  such  as  phlegmonous  inflammation  or  hemorrhage. 
Marchiafava  and  ]3ignami  state  that  it  has  never  been  their  experience  to 
observe  in  patients  suffering  from  malarial  cachexia,  grave  infections  with 
many  parasites  in  the  blood,  but  that  there  are  always  a  few  parasites  and 
very  little  melansemia.  Thus  it  will  be  seen  that  malarial  cachexia  cannot 
always  be  determined  by  microscopic  examination  of  the  blood,  as  the 
parasites  will  not  be  present  in  any  number  except  when  there  are  acute 
symptoms,  and  even  melanaemia  may  be  almost  absent. 

Diagnosis.— The  diagnosis  of  the  malarial  fevers  from  clinical  symp- 
toms alone  is  often  difficult  and  sometimes  impossible,  especially  in  the 
sestivo-autumnal  infections,  but  there  are  two  methods  of  diagnosis  which 
are  all-sufficient  and  deserving  of  confidence;  i.  e.,  examination  of  the 
blood  and  the  therapeutic  test  by  quinine.  Of  these  two  methods  the 
examination  of  the  blood  is  the  more  valuable,  for  the  therapeutic  test  by 
quinine  may  be  misleading,  as  other  fevers  may  decline  under  the  ad- 
ministration of  this  drug.     The  mild  tertian  and  quartan  infections,  if 


THE  MALARIAL  FEVERS  433 

uncomplicated,  can  usually  be  easily  diagnosed  by  the  clinical  symptoms 
alone,  but  where  double  infections  occur,  a  diagnosis  of  malaria  is 
often  impossible  from  a  clinical  study  of  the  symptoms,  and  in  a^stivo- 
autumnal  infections  a  diagnosis  of  malaria  is  generally  impossible  with- 
out an  examination  of  the  blood,  as  the  symptoms  are  often  so  con- 
fusing and  atypical  that  they  are  of  little  value. 

Examination  of  the  Blood. — In  most  instances  one  examination  of 
the  blood  will  be  sufficient,  but  if  a  negative  result  is  obtained  repeated 
examinations  should  be  made  at  short  intervals.  If  this  is  done,  almost 
invariably,  even  in  the  most  obscure  sestivo-autumnal  infections,  the 
parasites  will  be  discovered.  Cases  of  malaria  of  this  variety  undoubtedly 
occur  in  which  no  parasites  can  be  demonstrated  in  the  peripheral  blood, 
but  not  when  the  infection  is  severe  enough  to  produce  symptoms.  The 
symptoms  in  sestivo-autumnal  infections  are  often  so  obscure,  or  even 
so  slight,  that  malaria  is  not  suspected,  and  in  many  cases  an  exami- 
nation of  the  blood  will  show  the  presence  of  the  malarial  plasmodia 
before  any  clinical  symptoms  sufficiently  severe  to  excite  a  suspicion 
that  the  infection  existed.  It  follows,  then,  that  an  examination  of  the 
blood  in  all  cases  of  disease  occurring  in  malarious  localities  should  be 
adopted  as  a  routine  measure. 

The  blood  may  be  examined  either  in  the  fresh  state  or  in  stained 
specimens.  The  desirability  of  the  examination  of  the  blood  in  the 
fresh  condition  rather  than  in  permanent  specimens,  which  have  been 
hardened  and  stained,  has  been  advised  but  since  the  development  of 
Wright's  modification  of  Romanowski's  stain,  the  examination  of  speci- 
mens stained  by  this  method  is  preferable,  except  in  the  hands  of  an 
expert,  to  the  examination  of  the  fresh  blood. 

If  fresh  blood  is  to  be  examined,  the  patient's  ear  is  carefully  cleaned 
with  alcohol,  dried  thoroughly,  and  a  slight  puncture  made  with  a  lancet 
or  needle,  and  the  first  drop  or  two  of  blood  allowed  to  flow  away.  A 
small  drop  is  then  taken  on  a  slide  which  has  been  carefully  cleaned  and  a 
coverglass  placed  over  it.  Specimens  should  be  examined  as  soon  as 
possible,  but  if  carefully  wrapped  in  paper  can  be  carried  for  several 
hours  without  much  danger  of  changes  occurring  which  would  obscure 
the  Plasmodia.  The  ear  is  preferable  to  the  finger,  especially  in  the 
case  of  children,  as  there  is  less  pain,  and  the  patient  cannot  watch 
the  operator  during  the  procedure.  The  blood  should  be  examined 
with  a  one-twelfth  oil-immersion  objective  and  a  one  inch  eye-piece.  At 
least  half  an  hour  should  be  spent  on  the  specimen  before  it  is  pro- 
nounced negative.  For  the  examination  of  certain  stages  in  the  life-cycle 
of  the  malarial  plasmodia,  the  examination  of  fresh  blood  is  essential,  but 
with  our  improved  methods  of  staining,  better  results  in  diagnosis  will  be 
arrived  at  by  the  majority  of  physicians  if  stained  specimens  are  used. 

Examination  of  Stained  Specimens.— -There  have  been  numerous 
methods  proposed  for  the  staining  of  the  malarial  plasmodia,  the  most 
valuable  of  which  have  been  Romanowski's  and  its  many  modifications, 
such  as  Jenner's  and  Wright's.  In  1902,^  the  writer  described  a 
method  of  staining  which  is  simple  and  can  be  easily  applied  by  the 
practicing  physician.    It  is  not  as  satisfactory  in  showing  the  finer  struc- 

^New  York  Medical  Journal,  September  13,  1902. 
28 


434  DISEASES  CAUSED  BY  PROTOZOA 

ture  of  the  organisms  as  is  Wright's  method,  but  from  a  diagnostic  stand- 
point it  is  easier  of  appheation  in  that  the  solution  can  be  much  more 
easily  made,  and  the  process  is  not  so  involved.  In  consists  in  the  em- 
ployment of  t\yo  solutions:  Solution  A,  a  saturated  aqueous  solution  of 
methyl  violet  B  (Griiblcr's).  This  solution  should  be  prepared  with 
distilled  water  and  sliould  be  at  least  three  weeks  old.  Solution  B,  a  five 
per  cent,  solution  of  aqueous  eosin  (Griiblcr's). 

The  method  is  as  follows:  Very  thin  blood  smears  are  made  upon 
perfectly  clean  coverglasses.  These  smears  are  hardened  in  absolute 
alcohol  for  five  minutes,  and  are  then  carefully  dried  and  stained  with 
solution  A  for  ten  seconds;  they  are  then  thoroughly  washed  in  water  and 
stained  with  solution  B  for  from  three  to  five  seconds.  Specimens  are 
then  dried  and  mounted  in  Canada  balsam.  If  the  method  is  used  as 
described  the  results  are  very  satisfactory.  The  red  blood  corpuscles 
stain  a  beautiful  dark  blue  while  the  parasites  take  a  much  lighter  stain, 
the  chromatin  staining  a  deep  red.  The  stain  is  especially  useful  in  de- 
monstrating the  crescentic  forms.  These  stain  a  very  dark  violet,  the 
chromatin  being  reddish  in  color.  The  protoplasm  of  the  polymor- 
phonuclear leukocytes  stains  a  dull  pinkish  violet,  and  the  nucleus  stains 
much  less  intensely.  The  granules  of  the  eosinophiles  stain  dark  red  and 
the  nucleus  bright  blue,  while  the  protoplasm  of  the  lymphoc}i;es,  both 
large  and  small,  stain  crimson  violet  and  the  nucleus  pale  blue. 

Probably  the  most  satisfactory  of  all  staining  methods  for  the  malarial 
Plasmodia  is  the  modification  of  Romanowski's  stain  described  by  Wright. 
While  the  method  of  preparing  the  staining  solution  is  somewhat  com- 
plicated, a  careful  following  of  the  directions  will  result  satisfactorily. 
Numerous  commercial  houses  have  Wright's  stain  for  sale,  but  as  a  rule 
the  stains  purchased  in  this  way  are  unsatisfactory  and  cannot  be  relied 
upon.  It  is  much  better  for  the  physician  to  make  his  own  stain.  Dr. 
H.  R.  Oliver  has  recently  modified  Wright's  method  slightly,  and  the 
staining  solution  as  prepared  by  him  gives  very  excellent  results.  The 
following  is  the  method  of  preparation: 

Add  .5  gni.  of  soda  bicarbonate  to  100  Cc.  of  distilled  water,  dissolv- 
ing thoroughly,  and  then  add  one  gram  of  methylene  blue  (Griibler's) 
and  heat  for  one  hoiu"  in  a  sterilizer  after  the  steam  is  up.  After  heating 
allow  the  mixture  to  cool.  Make  a  1  to  1000  solution  of  yellow  eosin 
(Griiblcr's)  and  add  this,  stirring  constantly,  to  the  cooled  methylene 
blue  solution  in  the  proportion  of  500  Cc.  of  the  eosin  solution  to  75  Cc.  of 
the  blue  solution.  This  should  be  done,  preferably,  in  a  large  porcelain 
dish.  Let  the  mixture  stand  for  a  few  minutes,  and  then  filter  through 
one  small  filter  paper  and  save  the  residue.  The  residue,  which  is  a 
crystalline,  greenish-black  powder,  should  be  dried  in  a  hot  air  oven  and 
preserved.  To  make  the  staining  solution,  take  .3  gm.  of  the  residue 
and  add  100  Cc.  of  pure  methylic  alcohol  (Merck's)  reagent.  This 
should  then  be  filtered,  and  to  80  Cc.  of  the  filtrate  add  20  Cc.  of  methylic 
alcohol.  This  is  the  stock  solution  ready  for  use.  To  stain,  add  a  few 
drops  of  this  solution  to  the  preparation  and  let  stand  for  two  minutes, 
and  then  add  enough  distilled  water  to  cause  a  slight  metallic  scum  to 
form  on  the  surface  of  the  preparation.  Specimens  should  then  stand 
for  two  to  ten  minutes,  be  finally  washed  in  running  distilled  water  and 
mounted. 


THE  MALARIAL  FEVERS  435 

By  this  method  all  varieties  of  malarial  parasites  stain  as  follows:  The 
protoplasm  stains  a  robin's-egg  blue,  the  vesicular  portion  of  the  nucleus 
remains  unstained,  while  the  chromatin  stains  a  dark  cherry  red.  The 
very  young  forms  of  the  plasmodia — that  is,  the  ring  forms — are  very 
distinctive,  appearing  as  a  bright  blue  ring  at  some  portion  of  which  is 
situated  a  dark  cherry  red  dot  marking  the  chromatin  of  the  nucleus,  the 
red  blood  cell  being  stained  a  very  light  red  or  brownish-yellow. 

The  only  objection  to  the  use  of  staining  methods  in  the  diagnosis  of  the 
malarial  plasmodia  is  that  certain  other  material,  especially  broken-down 
leukocytes  or  extraneous  matter,  may  take  the  stain  and  be  so  situated 
within  the  red  cell  as  to  be  mistaken  for  the  organism.  But  to  one  who 
has  once  seen  preparations  stained  by  the  methods  described  no  mistake 
is  possible  in  this  direction.  Particular  care  should  be  taken  to  make  the 
blood  smears  very  thin,  and  this  is  best  done  by  the  use  of  the  method 
advocated  by  Cabot,  which  consists  in  using  the  ordinary  ribbed  rice 
cigarette  paper,  small  pieces  the  width  of  the  coverglass  being  cut  parallel 
with  the  rib.  The  edge  of  the  paper  should  then  be  passed  quickly  across 
the  drop  of  the  blood  as  is  exudes  from  the  ear,  placed  on  the  slide  and 
drawn  carefully  along  it.  With  practice,  very  even,  thin  smears  can  be 
obtained  in  this  way. 

The  Therapeutic  Test. — As  Osier  has  well  said,  any  fever  which  resists 
the  action  of  quinine  properly  administered  for  more  than  four  to  five 
days,  is  not  malarial  in  character.  This  fact  is  used  as  a  means  of  diag- 
nosis w^here  for  any  reason  an  examination  of  the  blood  is  impossible,  but 
it  must  not  be  forgotten  that  quinine  is  capable  of  reducing  the  temperature 
in  diseases  other  than  malaria.  In  many  instances,  also,  much  harm  may 
be  done,  especially  in  typhoid  fever,  which  often  resembles  the  continued 
sestivo-autumnal  infections,  and  in  which  quinine  is  not  only  contra-in- 
dicated, but  may  be  harmful. 

Differential  Diagnosis  of  the  Various  Forms  of  Malarial  Fever. 
— A  differential  diagnosis  of  the  various  types  of  malaria  is  most  quickly 
and  scientifically  made  by  an  examination  of  the  blood.  In  this  w^ay  the 
entire  life-cycle  of  the  tertian  and  quartan  plasmodia  may  be  studied,  and 
the  various  types  of  plasmodia  easily  differentiated.  Where,  however,  an 
examination  of  the  blood  for  any  reason  is  impracticable,  the  clinical 
symptoms  may  be  of  service  in  distinguishing  the  various  types;  thus,  a 
typical  tertian  or  quartan  infection  is  easily  differentiated  by  the  time  of 
the  occurrence  of  the  paroxysm  and  the  study  of  the  temperature  chart 
alone,  but  it  is  impossible  to  differentiate  a  double  tertian  infection  from  a 
quotidian  sestivo-autumnal  infection  in  this  way,  and  it  is  obvious  that 
mixed  infections  cannot  be  differentiated  by  the  clinical  symptoms  only. 
The  temperature  chart  occurring  in  uncomplicated  cases  of  tertian  sestivo- 
autumnal  fever  is  so  characteristic  that  a  differentiation  of  this  form  from 
other  malarial  infections  can  be  easily  made,  but  in  all  forms  of  malarial 
infections,  the  diagnosis  should  rest  chiefly  upon  the  result  of  blood 
examinations.  While  it  may  not  appear  to  be  of  great  importance  to  be 
always  able  to  differentiate  the  exact  type  of  malarial  infection  that  is 
present,  it  surely  is  so  from  a  scientific  standpoint,  and  is  often  so  practi- 
cally. Grave  mistakes  have  been  made  in  considering  a  severe  sestivo- 
autumnal  infection  as  a  mild  tertian,  and  many  lives  have  no  doubt  been 
lost  by  such  mistakes  in  diagnosis.     The  sestivo-autumnal  infections  are 


436  DISEASES  CAUSED  BY  PROTOZOA 

apt  at  any  time  to  Ijccoinc  ])crnicious  and  unless  prompt  treatment  is 
instituted  death  is  liable  to  follow.  It  can  be  easily  seen  that  such  an 
infection  mistaken  for  tertian  malaria,  and  treated  by  the  administration 
of  small  doses  of  quinine,  migiit  result  fatally. 

While  in  uncom[)licated  tertian  and  quartan  malaria  the  examination 
of  the  blood  may  not  be  absolutely  essential  in  making-  a  diagnosis,  it  is  in 
the  a\stivo-autumnal  infection,  and  it  is  especially  in  those  presenting 
anomalous  symptoms  that  such  an  examination  is  of  the  greatest  service. 
In  these  cases  the  presence  in  the  blood  of  the  small  intracellular  ring 
forms,  or  of  the  crescents,  demonstrates  tat  once  the  character  of  the 
infection  and  enables  us  promptly  to  apj^ly  the  proper  treatment. 

The  differential  diagnosis  of  the  malarial  fevers  from  other  disease 
processes  which  may  closely  resemble  them  is  only  possible,  in  many 
instances,  by  the  use  of  the  microscope.  This  is  especially  true  of  the 
restivo-autumnal  infections  which  so  often  present  anomalous  sym])toms 
resembling  those  of  some  other  disease,  that  from  a  study  of  the  clinical 
symptoms  alone  a  diagnosis  cannot  be  arrived  at.  There  are  a  number 
of  diseases  with  which  malarial  fevers,  especially  the  irregular  types,  may 
be  confused. 

Typhoid  Fever. — Perhaps  no  other  disease  has  been  so  often  confused 
with  malaria  as  has  ty])hoid  fever.  This  was  well  borne  out  during  our 
war  with  Spain.  Clinically,  the  confusion  regarding  these  two  diseases 
has  much  to  justify  it.  It  is  probable  that  a  typical  tertian  or  cjuartan 
infection  is  never  suspected  to  be  typhoid,  or  vice  versa,  but  in  the  more 
irregular  a?stivo-autumnal  infections  this  mistake  has  often  been  made. 
In  regions  in  which  testivo-autumnal  malaria  is  endemic,  or  supposed  to 
be,  it  is  a  very  common  mistake  to  regard  patients  suffering  from  typhoid 
fever  as  victims  of  this  type  of  malaria.  This  is  because  many  cases  of 
sestivo-autumnal  infection  present  typhoid  symptoms  and  a  clinical 
differentiation  is  impossible.  The  mistake  of  considering  a  typhoid  in- 
fection, however,  as  malarial,  after  quinine  has  been  administered  for 
several  days,  is  inexcusable,  for  experience  has  shown  that  there  is  no 
malarial  fever  which  will  resist  the  action  of  quinine,  when  properly 
administered,  for  a  period  of  over  six  or  eight  days.  Despite  this  fact, 
many  patients  with  typhoid  fever  in  malarious  regions  are  drenched  with 
quinine  under  the  suspicion  that  they  are  cases  of  restivo-autumnal  malaria. 
The  differentiation  of  these  two  diseases  depends  upon  the  microscopic 
examination  of  the  blood  for  the  malarial  plasmodia.  Secondary  to  this 
is  the  therapeutic  test  by  quinine.  If  parasites  are  present  in  the  blood 
and  the  Widal  test  is  negative,  the  diagnosis  is  at  once  established,  and 
cases  of  combined  infection  are  rare.  The  administration  of  quinine  will 
remove  the  malarial  element  and  the  typhoid  will  pursue  its  ordinary 
course.  During  the  decline  of  the  temperature  in  typhoid  cases  a  marked 
intermittent  temperature  may  be  observed  which  resembles  very  closely 
that  of  quotidian  malarial  infection.  Chills  also  may  occur  at  this  time 
and  a  diagnosis  of  malaria  is  made.  Unless  supported  by  the  finding 
of  the  malarial  plasmodia  in  the  blood,  such  a  diagnosis  is  unjustifiable. 

Yellow  Fever. — In  regions  in  which  yellow  fever  is  endemic,  the  differ- 
entiation of  malaria  from  this  disease  is  often  exceedingly  difficult  unless 
a  blood  examination  be  made.  The  so-called  bilious  remittent  type  of 
sestivo-autumnal  malaria  is  especially  apt  to  simulate  yellow  fever,  there 


THE  MALARIAL  FEVERS  437 

being  present  a  yellow  tint  of  the  skin,  severe  vomiting,  sometimes  of  dark 
material  resembling  "black  vomit,"  while  albumin  appears  in  the  urine. 
A  patient  presenting  such  a  clinical  picture  in  a  yellow  fever  region  is 
almost  always  thought  to  have  yellow  fever,  and  it  is  in  these  cases  that 
an  examination  of  the  blood  is  of  the  greatest  importance. 

Tuberculosis. — In  many  cases  tuberculosis  is  complicated  by  a  strep- 
tococcus infection,  and  the  temperature  chart  closely  resembles  that  found 
in  quotidian  malarial  infections.  There  may  also  be  daily  chills  or  chilly 
sensations,  and  the  patient  presents  the  facies  so  often  observed  in  long- 
continued  malarial  infection.  An  examination  of  the  sputum  will  gener- 
ally result  in  the  demonstration  of  the  tubercle  bacillus,  while  physical 
examination  will  shov.  pulmonary  lesions  to  be  present.  An  examination 
of  the  blood,  however,  is  essential,  as  not  infrequently  patients  suffering 
from  tuberculosis  may  contract  malaria. 

Hepatic  Abscess. — In  regions  where  amoebic  dysentery  is  endemic, 
certain  cases  suffering  from  hepatic  abscess  may  present  symptoms  which 
closely  simulate  those  of  malarial  fever;  thus  there  may  be  daily  chills  and 
a  temperature  curve,  which,  while  it  is  that  of  sepsis,  very  closely  simulates 
that  of  some  of  the  forms  of  sestivo-autumnal  infection.  The  chief 
clinical  points  in  favor  of  hepatic  abscess  are  enlargement  of  the  liver  and 
tenderness  over  the  hepatic  region,  while  the  spleen  is  not  enlarged.  In 
malaria,  enlargement  of  the  spleen  is  almost  always  present.  A  history 
of  dysentery  can  generally  be  obtained  in  cases  of  hepatic  abscess. 
Examination  of  the  blood  will  decide  if  malaria  be  present,  while  a  leu- 
kocytosis will  point  toward  a  hepatic  abscess. 

Ulcerative  Endocarditis. — The  temperature  chart  in  ulcerative  endo- 
carditis often  resembles  that  of  quotidian  malaria,  and  Dock  has  published 
a  very  interesting  case  of  this  character.  Examination  of  the  heart  wall 
generally  suffice  to  determine  the  natvire  of  such  cases,  and  if  not,  an 
examination  of  the  blood  will  decide  the  question. 

Cerebral  Apoplexy. — The  differential  diagnosis  between  the  comatose 
pernicious  form  of  malaria  and  cerebral  apoplexy  is  often  extremely  diffi- 
cult unless  a  blood  examination  be  made.  The  main  clinical  points  to  be 
relied  upon  in  arriving  at  a  diagnosis  of  malaria  are  high  fever,  although 
this  is  not  constant,  the  age  of  the  patient,  and  the  splenic  enlargement. 
An  examination  of  the  blood  will  generally  decide  the  question  at  once. 

Sunstroke. — Especially  in  tropical  or  sub-tropical  regions,  certain  forms 
of  pernicious  malaria  very  closely  resemble  sunstroke.  It  should  be 
remembered  that  in  such  regions  the  heat  very  often  aggravates  or  brings 
on  severe  malarial  paroxysms.  It  is  therefore  necessary  to  be  sure  in  such 
cases  whether  or  not  a  malarial  infection  be  present  and  a  microscopic 
examination  of  the  blood  is  often  our  only  means  of  arriving  at  a  differ- 
ential diagnosis. 

Dysentery. — Malarial  infections  may  occur  with  dysentery,  and  the 
removal  of  the  malarial  element  in  a  certain  proportion  of  such  cases 
results  in  a  rapid  improvement  of  the  dysenteric  symptoms  and  their  final 
disappearance.  In  view  of  the  fact  that  malarial  infection  is  capable  of 
producing  the  clinical  symptoms  of  dysentery,  it  is  important  that  a  dif- 
ferential diagnosis  should  be  arrived  at  in  regions  where  dysentery  is 
endemic.  An  examination  of  the  blood  is  therefore  essential  in  every  case 
of  dysentery  occurring  in  such  regions. 


438  DISEASES  CAUSED  BY  PROTOZOA 

Among  other  disease  processes  which  may  be  confused  with  malaria, 
may  be  mentioned:  septicannia,  pyaniiia,  diseases  of  the  gall  bladder  or 
ducts,  acute  suppurative  processes  in  any  of  the  viscera,  pneumonia,  and 
Weil's  disease.  In  all  of  these  a  careful  examination  of  the  blood  is 
sometimes  our  only  method  of  arriving  at  a  differential  diagnosis. 

Prognosis, — The  prognosis  in  cases  of  uncomplicated  tertian  and 
quartan  malaria  is  good,  but  in  the  more  severe  a^stivo-autumnal  infections 
prognosis  should  be  guarded.  Osier  has  called  attention  to  the  fact  that 
while  in  temperate  climates  it  is  well  known  that  the  prognosis  in  malaria 
is  most  favorable,  still  the  vital  statistics  in  some  of  our  large  cities  show 
a  greater  death-rate  for  malaria  than  for  typhoid  fever.  Ke  says^ :  "In  the 
United  States  census  report  of  1890,  which  covers  the  six  preceding  years, 
the  deaths  from  malarial  fever  in  New  York  and  Brooklyn  were  more 
numerous  than  from  typhoid  fever.  In  both  these  cities  it  is  notorious 
that  a  death  from  true  malaria  is  a  great  rarity.  No  more  than  three  or 
four  cases  occur  each  year  in  the  entire  hospital  practice  of  the  city  of  New 
York."  Nothing  could  illustrate  more  forcibly  the  immense  importance 
of  a  scientific  diagnosis  of  malaria  fevers  by  an  examination  of  the  blood 
than  does  this  cjuotation. 

^Yhile  the  prognosis,  as  stated,  in  uncomplicated  cases  of  tertian  and 
quartan  malaria  is  good,  fatal  cases  of  both  these  forms  of  fever  have 
occurred,  especially  the  quartan' variety.  As  regards  the  prognosis  of  the 
sestivo-autumnal  infections,  certain  factors  have  to  be  taken  into  con- 
sideration, such  as  locality,  age,  occupation,  position  in  life,  and  physical 
condition.  These  factors  apply  with  some  force  also  to  the  prognosis  of 
the  simple  intermittent  fevers,  but  are  especially  important  in  the  sestivo- 
autumnal  infections. 

In  the  tropics  the  prognosis  in  sestivo-autumnal  infections  is  much  more 
grave  than  in  temperate  regions,  and  in  certain  local  regions  these  fevers 
are  much  more  fatal  than  in  others.  The  prognosis  is  most  grave  at 
the  extremes  of  life.  It  is  more  grave  in  the  poor  than  in  those  who  are 
well-to-do,  in  the  case  of  individuals  in  ill  health  than  in  those  who  are 
well  nourished  and  healthy.  Complications  which  are  so  frequent  in  sestivo- 
autumnal  infections  also  have  much  to  do  with  the  prognosis,  among  the 
most  serious  being  the  various  forms  of  nephritis,  tuberculosis,  pneumonia, 
dysentery,  and  the  infectious  fevers.  The  prognosis  in  the  pernicious 
varieties  of  sestivo-autumnal  infection  should  always  be  guarded,  espe- 
cially if  the  patient  is  seen  after  having  suffered  from  several  severe  parox- 
ysms, although  even  then  if  treatment  be  vigorously  instituted  the  patient 
may  recover.  However,  the  pernicious  symptoms  may  last  for  several 
days  and  despite  all  treatment,  death  ensue.  The  prognosis  is  very 
grave  in  the  cerebral  forms,  especially  the  comatose  form.  While  a  large 
number  of  such  cases  recover  under  proper  treatment,  a  great  majority 
of  the  fatal  cases  of  malaria  suffer  from  this  form  of  sestivo-autumnal 
infection.  In  the  algid  form  the  prognosis  is  almost  as  grave  as  in  the 
cerebral  forms,  and  not  a  few  go  on  to  a  fatal  termination  despite  all 
treatment.  The  prognosis  is  very  grave  in  the  choleraic  form  and  also 
the  pneumonic.  In  the  dysenteric  form  the  prognosis  is  always  grave, 
depending  upon  the  fact  that  the  dysenteric  symptoms  have  often  masked 

^Article  on  "Malaria"  in  AUhutfs  System  of  Medicine, 


THE  MALARIAL  FEVERS  439 

those  of  malaria  for  a  considerable  time  and  treatment  is  not  instituted 
until  too  late. 

In  soldiers  campaigning  in  tropical  countries  where  pernicious  forms  of 
malaria  are  endemic,  many  deaths  are  often  due  to  this  cause,  and  the 
prognosis  in  such  infections  should  also  be  very  guarded. 

In  malarial  cachexia  where  a  change  of  locality  cannot  be  secured  the 
prognosis  is  always  grave,  death  resulting  not  so  much  from  the  malarial 
infection  as  from  some  complicating  disease.  While  under  proper  treat- 
ment a  great  majority  of  cases  of  sestivo-autumnal  infection  recover, 
unless  quinine  be  administered  for  a  long  period  of  time  relajjses  in- 
variably occur,  and  one  of  these  may  prove  fatal.  It  may  be  stated  as  an 
axiom  that  the  prognosis  in  tertian  and  quartan  malaria  is  good  but  in  the 
sestivo-autumnal  infections  is  always  grave,  as  at  any  time  during  their 
course  pernicious  symptoms  may  develop  and  prove  rapidly  fatal. 

Prophylaxis. — Pi-ophylaxis  in  malarial  disease  is  of  much  greater 
importance  at  this  time  than  ever  before  in  the  history  of  such  infections. 
We  now  know  the  etiological  factor  concerned  in  the  production  of  the 
malarial  fevers  and  their  method  of  transmission,  and  we  also  know  that 
proper  methods  of  prophylaxis  have  already  resulted  in  the  disappear- 
ance of  the  infection  from  numerous  localities. 

The  subject  of  prophylaxis  may  be  divided  mto  general  and  personal 
methods,  all  of  which  are  directed  against  the  mosquito.  If  it  were  possible 
to  destroy  all  mosquitoes  of  the  genus  Anopheles  in  malarious  localities, 
it  is  undoubtedly  true  that  malaria  would  soon  disappear.  All  our 
theories,  regarding  the  transmission  of  the  disease  by  water  or  any  other 
way  than  by  the  aid  of  the  mosquito,  have  been  disproved  and  wx  now  know 
that  the  prophylaxis  of  malaria  consists  in  the  destruction  of  this  insect, 
or,  if  this  is  not  possible,  the  protection  of  the  individual  from  the  bite  of 
the  infected  insect. 

General  Prophylaxis. — General  prophylaxis  may  be  considered 
under  the  following  divisions :  (1)  destruction  of  the  mosquito;  (2)  isola- 
tion of  the  patient;    (3)  use  of  quinine. 

1.  Destruction  of  the  Mosquito. — The  mosquito  is  most  easily  destroyed 
during  the  larval  stage,  and  many  substances  have  been  experimented 
with  in  the  hope  of  obtaining  one  which  would  prove  efficacious,  being 
at  the  same  time  cheap  and  easily  obtained.  Howard,  in  1892,  published 
the  results  of  his  work  upon  the  destruction  of  the  mosquito  larvse  by 
sprinkling  a  thin  layer  of  kerosene  upon  the  surface  of  the  water  in  which 
they  breed.  This  method  is  very  efficacious,  not  only  killing  the  larvse 
in  the  water,  but  the  mosquitoes  when  in  the  act  of  depositing  their  eggs. 
The  method  is  especially  applicable  to  collections  of  water  which  cannot 
be  drained  and  which  are  not  very  large  in  extent.  The  quantity  of 
kerosene  used  is  approximately  one  ounce  to  fifteen  square  feet  of  surface, 
and  as  a  rule  the  application  does  not  need  to  be  renewed  more  than  once 
a  month.  This  method  has  been  used  largely  throughout  the  world  and 
has  proved  of  great  value. 

Of  other  substances  which  are  capable  of  killing  the  larvse,  may  be 
mentioned  sulphurous  oxide,  permanganate  of  potash  with  hydrochloric 
acid,  sulphate  of  iron  or  copper,  carburet  of  lime,  corrosive  sublimate, 
formaline,  cresol,  certain  aniline  dyes,  and  coal-tar.  It  is  obvious  that 
most  of  these  substances  cannot  be  used  in  practice,  the  only  one  really 


440  DISEASES  CAUSED  BY  PROTOZOA 

available  being  kerosene,  but  this  agent  cannot  be  employed  in  water 
which  is  used  for  drinking  purposes  unless  in  the  case  of  large  reservoirs 
where  the  water  is  drawn  from  the  bottom. 

The  introduction  of  certain  fish  into  reservoirs  from  which  water  is 
used  for  tlrinking  purposes,  and  in  which  mosquitoes  breed,  has  been 
suggested  instead  of  the  use  of  petroleum,  and  has  been  tried  in  some 
localities  with  success.  The  fish  principally  used  have  been  carp  and  the 
connnon  stickle])ack. 

The  most  imiM)rtant  of  all  methods  of  destroying  the  mosquito  larvae 
is  that  by  drainage  of  their  breeding  places,  and  this  is  a  method  which  can 
be  employed  over  very  large  areas  of  country  in  which  malaria  is  endemic, 
and  which  ex])erimentally  has  proved  to  be  of  greatest  service.  In  many 
regions  in  which  the  most  virulent  forms  of  malarial  infection  are  endemic, 
drainage  is  feasible  and  can  be  carried  out  with  but  little  trouble,  although 
the  expense  is  often  a  factor  in  the  problem,  and,  as  Celli  says,  "such 
methods  for  the  destruction  of  the  mosciuitoes,  while  experimentally 
soluble,  will  only  be  practically  so  when  economic  interests  desire  it." 
AVhere  drainage  is  impossible  the  breeding  places  of  the  mosquito  may  be 
filled  up  with  loam,  and  it  is  very  important  in  malarious  localities  to  fill 
up  all  areas  of  depression  in  the  surface  of  the  land  that  cannot  be  ade- 
quately drained.  Swampy  areas,  if  not  too  large,  can  thus  be  filled  in, 
and  one  of  the  greatest  sources  of  mosquitoes  removed. 

Besides  drainage  and  the  filling  up  of  areas  which  serve  as  breeding 
places  for  the  mosquitoes,  the  formation  of  mosquito  brigades,  as  sug- 
gested by  Ross,  is  of  the  greatest  service  in  limiting  malarial  infection. 
This  consists  essentially  in  detailing  a  certain  number  of  men  whose  busi- 
ness it  is  to  inspect  the  premises  and  destroy  the  larvae  in  the  small 
breeding  grounds  which  harbor  the  Anojiheles,  such  as  domestic  water 
receptacles,  water  butts,  and  tanks,  the  removal  of  small  puddles  in  streets 
and  yards,  as  well  as  empty  tins,  jars,  broken  bottles,  or  anything  in 
which  water  collects,  and  in  which  the  mosquitoes  may  breed.  In  the 
formation  of  such  brigades  the  region  to  be  covered  is  divided  into 
portions,  each  portion  being  under  the  supervision  of  a  certain  number  of 
men  detailed  for  the  purpose.  Methods  similar  to  this  were  pursued  in 
Havana  by  Gorgas,  resulting  in  the  almost  total  disappearance  of  the 
yellow  fever  mosquito  in  that  city.  Garden  wells,  water  barrels,  and 
tanks,  being  prolific  sources  of  mosquitoes,  should  be  covered,  preferably 
with  wire  moscjuito-netting,  thus  preventing  the  laying  of  eggs  and  the 
development  of  the  larvae.  If  for  any  reason  this  is  not  possible,  and  the 
water  is  not  used  for  drinking  purposes,  the  surface  should  be  sprinkled 
with  kerosene  oil. 

In  the  adult  stage  the  mosquito  can  be  destroyed  by  various  odors, 
fumes  or  gases.  Among  the  odors  may  be  mentioned  turpentine,  menthol 
and  camphor.  Among  the  fumes,  tobacco,  chrysanthemum  powder, 
pyrethrum  powder  and  the  fresh  leaves  of  eucalyptus;  while  among  the 
gases,  sulphuric  oxide  is  very  efficacious.  In  using  any  of  these  agents, 
however,  it  is  very  necessary  that  the  air  of  the  room  should  be  saturated, 
as  otherwise  the  insect  may  be  simply  stunned,  and  revive  when  the  fresh 
air  is  admitted.  The  most  useful  of  these  agents  is  pyrethrum  powder, 
which  can  be  burned  in  rooms  infected  with  mosquitoes,  and  which  is  very 
fatal  to  them. 


THE  MALARIAL  FEVERS  441 

2.  Isolation  of  the  Patient. — We  have  seen  that  the  mosquito  is  neces- 
sary as  an  intermediate  host  in  the  Ufe-cycle  of  the  malarial  plasmodia, 
and  that  the  mosquito  is  infected  by  biting  an  individual  suffering  from 
malarial  disease.  From  this  it  is  obvious  that  if  v^e  can  place  the  infected 
individual  in  a  position  v^here  the  mosquitoes  cannot  obtain  access  to  him 
the  transmission  of  the  infection  will  be  impossible.  Theoretically,  if 
every  patient  suffering  from  malaria  could  be  screened  from  mosquitoes 
the  disease  would  entirely  disappear,  but  practically,  the  disease  is  of  such 
a  character  that  even  when  no  symptoms  are  present  the  parasites  may  be 
present  in  the  blood  and  the  mosquitoes  may  become  infected.  In  fact, 
in  Bestivo-autumnal  infections  the  crescentic  form  of  the  organism,  which 
really  is  the  form  intended  to  undergo  its  life-cycle  in  the  mosquito,  is 
frequently  present  in  the  blood  when  there  are  no  symptoms  of  malaria,  so 
that  it  is  obvious  that  we  cannot  in  this  way  entirely  prevent  malarial 
infection.  Still,  in  the  light  of  our  present  knowledge,  the  malarial  fevers 
should  be  regarded  as  infectious  and  the  patient  should  be  isolated  in  a 
screened  room.  Not  only  is  this  isolation  of  importance  to  those  sur- 
rounding the  patient  but  also  to  himself,  for  if  he  is  not  protected  from 
mosquitoes  he  is  in  constant  danger  of  reinfection  from  the  bites  of  the 
insects.  Isolation  of  the  patient  is,  therefore,  of  the  greatest  importance 
in  the  prophylaxis  of  malaria,  and  should  be  carried  out,  especially  in 
regions  where  the  more  pernicious  forms  of  the  disease  are  endemic. 
Besides  the  isolation  of  the  patient,  Ross  and  Stephens  have  suggested  as 
a  method  of  general  prophylaxis  the  segregation  of  certain  classes  of  the 
population.  This  applies  especially  to  Europeans  living  in  the  tropics. 
They  suggest  that  the  European  quarter  should  not  be  built  in  the  midst  of 
the  native  villages  in  malarious  localities,  but  should  be  situated  at  some 
distance  and  should  be  surrounded  by  the  proper  hygienic  conditions, 
which  it  is  impossible  to  obtain  among  a  native  population. 

3.  Use  of  Quinine. — ^The  use  of  quinine  as  a  general  prophylactic 
measure,  as  suggested  by  Koch,  is  undoubtedly  of  value  in  malarial 
regions.  As  is  well  known,  this  drug  destroys  the  malarial  organisms,  and 
if  it  were  administered  to  all  the  natives  of  a  malarial  region  it  is  probably 
true  that  malarial  fever  would  gradually  disappear.  In  other  words,  the 
malarial  plasmodia  present  would  be  destroyed  and  thus  the  mosquitoes 
would  not  become  infected  upon  biting  the  native  population.  Unfor- 
tunately, the  cost  of  the  drug  precludes  any  general  use  of  it  in  large 
localities,  although  theoretically  the  employment  of  it  in  general  prophy- 
laxis would  be  indicated. 

Summing  up,  then,  the  methods  of  general  prophylaxis  which  are  most 
important  are  drainage  and  filling  in  of  all  depressed  areas  on  the  surface 
of  the  ground,  the  use  of  kerosene  upon  the  surface  of  collections  of  water 
which  cannot  be  drained,  the  formation  of  mosquito  brigades  for  the 
purpose  of  cleaning  or  destroying  the  smaller  breeding  places  of  the 
mosquitoes,  isolation  of  the  patient,  and  the  general  use  of  quinine. 

Personal  Prophylaxis. — By  personal  prophylaxis  we  mean  measures 
which  the  individual  himself  may  take  in  order  to  prevent  infection,  or, 
in  other  words,  to  prevent  being  bitten  by  the  mosquitoes.  The  use  of 
mosquito-netting  is  of  the  greatest  importance  in  malarious  localities  and 
no  one  should  neglect  the  use  of  this  means  of  prevention.  The  screening 
of  the  houses  is  also  indicated,  and  the  screening  should  be  done  most 


442  DISEASES  CAUSED  BY  PROTOZOA 

carefully,  every  door  and  window  being  screened.  If  one  is  obliged  to 
travel  in  malarial  districts,  the  season  of  the  year  in  which  such  fevers  are 
less  prevalent  should  be  selected,  if  possible,  and  traveling  should  be  done 
in  the  day-time.  In  selecting  camp  sites  and  sites  for  buildings,  high, 
well-drained  land  should  be  chosen.  The  drinking-water  should  always 
be  boiled,  for  although  nuilaria  is  not  transmitted  in  this  way,  the  measure 
may  prevent  other  diseases  which  would  so  deplete  the  system  as  to  render 
it  easily  susceptible  to  nudarial  infection.  If  mosquitoes  are  numerous  it 
is  better  to  sleep  above  the  ground  fioor.  In  tropical  regions  the  use  of 
punkas,  or  fans,  as  well  as,  where  obtainable,  electric  fans,  is  serviceable 
in  keeping  away  the  mosquitoes.  For  the  protection  of  the  hands  and  face 
during  the  day,  or  when  travelling  at  night,  odorous  substances  may  be 
employed,  these  being  smeared  on  the  skin  and  renewed  when  needed. 
Among  the  most  useful  are  oil  of  ]iennyroyal,  camphor,  oil  of  eucalyptus, 
oil  of  anise,  and  kerosene.  Pyrethrum  powder  should  be  burned  before 
retiring,  in  rooms  in  which  mosquitoes  are  present.  Individuals  in 
malarial  localities  should  always  sleep  under  a  mosquito  net. 

One  of  the  most  important  aids  in  personal  prophylaxis  is  the  use  of 
quinine.  It  is  borne  out  by  the  experience  of  all  who  have  resided  for 
any  length  of  time  in  regions  where  malaria  is  endemic,  that  quinine 
exhibited  daily  in  small  doses  is  of  the  greatest  value  in  preventing  infec- 
tion. The  drug  should  be  given  in  doses  of  from  5  to  6  grains  (.30-. 35  gm.) 
every  day,  or  in  larger  doses,  8  to  10  grains  (.50-. 60  gm.),  two  or  three 
times  a  week.  In  the  vast  majority  of  instances  the  prophylactic  use  of 
quinine  will  prevent  malarial  infection,  but  a  few  individuals,  despite  its 
use,  succumb  to  the  infection.  Some  indi\dduals  cannot  take  cpiinine 
regularly  without  suffering  from  disturbances  of  digestion  or  of  the  ner- 
vous system,  and  in  such  instances  some  substitute  for  it  may  be  used, 
such  as  thiocol,  or  methylene  blue.  Neither  of  these  agents,  however, 
is  as  useful  as  quinine. 

Treatment. — The  treatment  of  malarial  infection  may  be  divided  into 
hygienic  and  medicinal.  While  the  medicinal  is  altogether  the  most 
important,  hygienic  measures  should  always  be  combined  with  it.  For- 
tunately, in  the  malarial  infections  we  have  a  specific  which  is  invariably 
successful,  when  properly  administered,  in  curing  the  disease.  This 
specific  is  quinine,  an  alkaloid  of  cinchona,  wdiich  was  introduced  into 
Europe  nearly  260  years  ago,  and  had  probably  been  used  by  the  natives 
in  South  America  for  many  years  before  it  was  discovered  by  Europeans. 
Perhaps  no  drug  known  to  the  therapeutist  is  as  true  a  specific  in  any 
disease  as  is  quinine  in  malaria.  When  properly  administered  it  will 
invariably  destroy  the  malarial  plasraodia  and  thus  cure  malarial  in- 
fection. There  are  rare  instances  in  which  quinine  seems  to  be  powerless 
to  limit  the  course  of  malarial  infection,  but  a  careful  examination  will 
prove  that  if  it  is  administered  in  the  proper  manner  it  is  efficient  in  these 
cases  as  in  others.  Thus,  certain  individuals  cannot  absorb  quinine 
through  the  stomach,  but  in  such  persons  the  hypodermic  administration  of 
it  will  result  in  a  cure  of  the  infection,  and  thus  it  is  that  the  successful  treat- 
ment of  malaria  by  quinine  depends  almost  entirely  upon  the  proper 
administration  of  the  drug. 

The  mild  intermittent  malarial  infections,  such  as  the  tertian  and 
quartan,  tend  towards  spontaneous  recovery,  which  has  already  been 


THE  MALARIAL  FEVERS  443 

discussed.  In  many  instances  of  infection  by  the  tertian  and  quartan 
Plasmodia,  recovery  may  occur  without  the  aid  of  medicinal  measures, 
but  it  should  be  remembered  that  even  these  infections  may  become  per- 
nicious, and  even  if  they  do  not,  the  occurrence  of  repeated  paroxysms  of 
the  fever  results  in  a  diminution  of  the  vitality  of  the  patient,  as  evidenced 
by  the  anremia  which  invariably  accompanies  such  repeated  attacks. 
Thus  it  is  important  that  every  malarial  infection  should  be  treated  medic- 
inally and  not  left  for  nature  to  cure. 

Hygienic  Treatment. — It  is  undoubtedly  true  that  in  all  malarial 
infections,  however  mild,  rest  is  most  important,  and  the  patient  should  be 
confined  in  bed  until  the  active  symptoms  have  disappeared.  While  this 
is  not  essential  in  some  of  the  mildest  tertian  and  quartan  infections,  it 
should  always  be  followed  out  in  cases  of  sestivo-autumnal  infection. 
Treatment  by  quinine  is  always  much  more  effective  when  the  patient  is 
confined  to  bed,  recovery  is  always  more  rapid  and  permanent,  and  the 
danger  of  pernicious  symptoms  is  also  much  lessened. 

The  diet  should  be  light,  while  there  are  any  active  symptoms  of  malarial 
infection  present,  consisting  of  milk,  soups,  custards,  soft  boiled  eggs,  etc. 
A  light  diet  should  be  persisted  in  until  the  temperature  has  been  normal 
for  at  least  a  day,  and  then  a  more  liberal  diet  is  indicated.  The  more 
nutritious  such  a  diet  is  the  better,  as  in  many  cases  of  malarial  infection 
the  debility  and  anaemia  following  the  paroxysms  is  remarkable. 

It  is  a  good  plan  in  treating  all  malarial  infections  to  secure  a  complete 
evacuation  of  the  bowels  coincident  with  or  before  the  administration  of 
quinine.  The  administration  of  calomel  until  the  bowels  move  freely, 
not  only  serves  to  better  the  patient's  condition,  but  also  renders  the 
action  of  quinine  much  more  efficient.  It  hastens  and  favors  the  absorp- 
tion of  the  drug. 

In  all  cases  of  malarial  infection  the  sick-room  should  be,  if  possible,  in 
an  upper  story,  well  ventilated  and  thoroughly  screened,  thus  limiting  the 
chances  of  infection  to  others.  Care  should  be  taken  that  the  room  is  not 
subject  to  draughts,  and  the  patient  should  be  guarded  against  any  irrita- 
tion, as  in  the  most  severe  malarial  infections,  such  as  the  sestivo-autumnal, 
the  nervous  irritability  is  apt  to  be  very  great. 

Medicinal  Treatment. — In  the  vast  majority  of  malarial  infections 
but  one  drug  need  be  considered,  that  is,  quinine,  and  by  quinine  any 
derivative  of  cinchona  bark  is  meant.  In  considering  the  therapeu- 
tical uses  of  the  derivatives  of  cinchona  the  following  points  should 
be  discussed:  (1)  the  action  of  quinine  upon  the  malarial  plasmodia; 
(2)  the  choice  of  preparations;  (3)  the  time  of  administration;  (4)  the 
methods  of  administration;  (5)  the  dosage;  and  (6)  contra-indications 
to  its  administration. 

1.  The  Action  of  Quinine  Upon  the  Malarial  Plasmodia. — Quinine 
exerts  its  beneficial  action  upon  malarial  infections  by  directly  destroying 
the  malarial  plasmodia.  Binz,  in  1867,  was  the  first  to  discover  that  the 
drug  had  a  marked  influence  upon  the  parasites  concerned  in  malaria,  and 
his  observations  have  been  confirmed  by  every  investigator  who  has 
studied  the  subject.  Quinine  causes  a  degeneration  of  the  parasites, 
especially  marked  in  the  youngest  organisms  and  most  marked  at  the 
time  of  segmentation.  Marchiafava  and  Bignami,  from  their  careful 
study  of  the  subject,  conclude  as  follows:    "Quinine  acts  upon  the 


444  DISEASES  CAUSED  BY  PROTOZOA 

malarial  parasites  in  that  phase  of  their  life-cyele  in  which  they  are  nour- 
ished and  developed.  Wlien  the  nutritive  activities  cease  by  an  arrest  of 
the  transformation  of  hannoglobin  into  black  j)ignient,  and  the  repro- 
dnetive  phase  begins,  the  quinine  is  inetl'ectnal  in  its  action." 

In  other  words,  the  drug  is  most  etfective  from  the  time  of  segmenta- 
tion until  pigmentation  commences  within  the  red  blood  corpuscles. 
Many  observations  upon  the  blood  of  patients,  showing  malarial 
parasites,  to  whom  quinine  has  been  administered,  have  shown  that 
the  chief  changes  consist  in  loss  of  ama^joid  motion  and  a  granular  degen- 
eration of  the  endoglobular  ])arasites.  The  red  cell  containing  the  para- 
site very  often  appears  to  be  shrunken,  as  Avell  as  the  parasite  within  it. 
The  changes  are  most  marketl  in  the  tertian  and  quartan  organisms,  but 
the  same  changes  occur  in  the  a^stivo-autumnal  varieties.  In  the  latter, 
especially,  the  young  unpigmented  forms  appear  greatly  shrunken,  their 
protoplasm  more  or  less  granular,  while  amoeboid  motion  is  entirely  lost. 
A  study  of  stained  specimens  of  malarial  parasites  after  cjuinine  has  been 
administered,  demonstrates  more  clearly  than  do  fresh  specimens  the 
effect  of  the  drug.  In  all  such  specimens  the  intensity  of  the  stain  is 
greatly  diminished,  and  this  loss  of  intensity  is  confined  almost  entirely  to 
the  chromatin  substance  of  the  nucleus,  while  the  protoplasm  stains  more 
nearly  as  it  does  in  the  healthy  organism.  These  changes  prove  that 
quinine  acts  directly  upon  the  parasites  causing  the  disease  and  that  it  is 
thus  a  true  specific  in  malaria. 

2.  Choice  of  Preparation, — Of  the  ten  or  more  salts  of  quinine  which 
have  been  used  in  the  treatment  of  malarial  fevers,  but  tw^o  are  really 
deserving  of  attention,  in  that  they  are  of  practical  use.  These  are  the 
sulphate  and  the  dihydrochlorate  or  bimuriate  of  cjuinine.  Of  these  two 
preparations,  the  dihydrochlorate  is  the  more  soluble,  being  dissolved  in 
the  proportion  of  1  part  to  .96  parts  of  water,  while  the  sulphate  is  only 
soluble  in  1  to  9  parts  of  water.  Of  the  two  preparations,  however, 
the  sulphate  is  the  more  used,  as  it  is  the  cheaper  and  can  be  procured 
most  easily.  Where  it  is  desired  to  use  the  drug  hypodermically  or  intra- 
venously, the  hydrochlorate  should  always  be  used. 

3.  Time  of  Administration. — The  time  of  administration  of  quinine  in 
malaria  has  been  the  subject  of  much  discussion,  but  it  may  be  said  that 
in  the  tertian  and  quartan  infections  the  drug  should  be  given  during  the 
decline  in  temperature  in  one  large  dose,  while  in  the  festivo-autumnal 
infections  it  should  be  administered  in  broken  doses  at  equal  intervals 
throughotit  the  day.  This  subject  has  been  very  thoroughly  discussed 
by  Dock,^  with  whose  conclusions  the  writer  agrees.  In  tertian  and 
quartan  infections  if  the  qtiinine  is  administered  during  the  decline  of 
the  temperature,  or  at  least,  at  the  end  of  the  apyrexia,  in  the  vast  majority 
the  next  paroxysm  will  be  prevented,  as  the  clrtig  has  thus  been  brought 
in  contact  with  the  youngest  forms  of  the  plasmodia,  upon  which  it  acts 
most  vigorously.  In  all  such  cases  the  sulphate  administered  in  solution 
dissolved  in  dilute  sulphuric  or  hydrochloric  acid  is  the  most  effective 
preparation.  If  given  in  this  way,  one  drop  of  the  acid  should  be  used 
for  each  grain  of  quinine.  If  perchance,  there  should  be  double  tertian 
or  quartan  infection,  quinine  administered  at  this  time  may  not  prevent 

^Journal  of  the  American  Medical  Association,  July  29,  1899, 


THE  MALARIAL  FEVERS  445 

the  succeeding  paroxysm,  and  if  tliis  occurs,  a  second  dose  should  be 
given  at  the  same  time,  when  almost  invariably  the  paroxysms  will  cease. 
Quinine  should  not  be  discontinued,  however,  in  the  mildest  cases,  even 
after  the  paroxysms  have  ceased,  but  should  be  administered  in  doses 
of  from  5  to  10  grains  (.30  to  .00  gm.)  for  at  least  a  week.  Only  in 
this  way  can  the  return  of  the  paroxysms  be  prevented. 

In  tertian  and  quartan  infections  the  time  of  administration  can  be 
accurately  determined  by  a  study  of  the  temperature  chart,  but  this  is 
not  so  in  the  more  irregular  sestivo-autumnal  types.  In  these  forms  the 
period  of  intermission  may  not  be  indicated  clearly  in  the  temperature 
chart,  and  it  is  therefore  necessary  in  order  to  combat  the  infection  to 
give  quinine  in  divided  doses  of  from  5  to  10  grains  (.30  to  .00  gm.)  at 
intervals  of  four  to  six  hours  until  the  temperature  reaches  normal.  When 
this  occurs,  quinine  may  be  administered  in  one  large  dose  at  bed-time  or 
in  smaller  divided  doses  during  the  twenty-four  hours.  In  pernicious  and 
irregular  forms  of  malarial  fever,  especially  if  caused  by  the  sestivo- 
autumnal  plasmodium,  the  administration  of  the  drug  cannot  be  delayed 
and  it  should  be  invariably  given  hypodermically. 

4.  Methods  of  Administration. — Quinine  may  be  administered  by  the 
mouth,  by  the  rectum,  hypodermically  and  intravenously.  If  adminis- 
tered by  the  mouth  it  is  best  given  in  the  form  of  solutions  or  capsules. 
Pills  and  tablets  are  very  apt  to  be  insoluble  and  therefore  should  not  be 
administered.  When  possible,  the  drug  should  always  be  administered 
in  solution,  but  on  account  of  the  bitter  taste,  which  is  very  objectionable 
to  some  patients,  capsules  may  be  substituted  instead  of  the  solution. 

The  rectal  administration  of  quinine,  in  the  form  of  enemata  or  supposi- 
tories, has  been  advocated  by  some  authorities  but  is  most  unsatisfactory. 
Absorption  is  very  slow,  and  rectal  irritability  is  almost  certain  to  occur. 
When  the  drug  is  given  in  this  way  the  dose  should  be  one-half  again  as 
large  as  when  given  by  the  mouth. 

In  the  pernicious  forms  of  malarial  fever  quinine  should  be  adminis- 
tered hypodermically,  and  this  is  also  true  in  cases  in  which  the  drug  can- 
not for  certain  reasons  be  administered  by  the  mouth.  The  solution 
which  is  generally  used  is  the  following: 

Dihydrochlorate  of  quinine gr.  Ixxv 5   gm. 

Distilled  water  add 5iiss 10  gm. 

In  this  solution  1  Cc,  15  m.  contains  grs.  viiss(.5  gm.)  of  quinine. 

In  giving  hypodermic  injections  of  quinine,  the  utmost  care  should  be 
taken  that  the  syringe  be  thoroughly  sterilized  and  also  the  skin  over  the 
area  m  which  the  injection  is  made.  The  solution,  also,  should  be  sterile 
and  freshly  prepared.  The  best  sites  for  the  injection  are  the  muscles  of 
the  back,  gluteal  region  or  the  abdomen,  the  gluteal  region  being  prefer- 
able. The  injections  should  be  made  deeply  into  the  muscles,  and  the 
wound  made  by  the  needle  of  the  syringe  covered  with  a  small  piece  of 
cotton  held  in  place  by  collodion.  Despite  the  greatest  care  in  gi^'ing 
hypodermic  injections  of  this  drug,  much  discomfort  and  pain  is  often 
caused,  while  if  the  operation  has  been  carelessly  done  abscess  forma- 
tion is  apt  to  result.  If  proper  antiseptic  methods  are  followed  this 
generally  may  be  avoided,  although  a  considerable  amount  of  induration 
is  apt  to  occur  around  the  site  of  the  puncture. 


446  DISEASES  CAUSED  BY  PROTOZOA 

Bacelli  was  the  first  to  suggest  the  intravenous  injection  of  quinine. 
Such  a  method  of  administration  is  indicated  wherever  the  symptoms  of 
Inalaria  are  so  severe  as  to  threaten  grave  peril  to  the  patient,  and  should 
never  be  followed  unless  such  symptoms  are  present.  The  solution  used 
by  him  is  made  as  follows: 

Hydroclilorate  of  quinine   grs.  xv 1.       gm. 

Chloride  of  sodium grs.  xii 75  gm. 

Distilled  water  add oiisa 10.       Cc. 

The  entire  amount  is  to  be  injected  into  a  vein,  ])rcfcrably  of  the  fore- 
arm, the  most  careful  antiseptic  measures  being  used  to  prevent  infection. 

5.  The  Dosage. — It  is  probably  true  that  in  the  administration  of  qui- 
nine in  malarial  fevers  too  much  of  the  drug  is  generally  given.  Very 
frequently  quinine  is  administered  in  such  large  doses  that  a  large  pro- 
portion of  it  is  simply  wasted.  In  tertian  and  c^uartan  infections  a  single 
dose  of  15  grains  (1  gm.)  is  amply  sufficient  to  prevent  the  next  paroxysm, 
while  in  the  vast  majority  of  a?stivo-autumnal  infections  30  grains  (2gm.) 
given  in  divided  doses  during  the  twenty-four  hours  will  result  in  cure. 
When  the  drug  is  used  hypodcrmically,  a  dose  of  8  grains  (.5  gm.)  should 
be  administered  and  repeated  until  about  24  grains  (1.50  gm.)  have  been 
injected.  In  very  severe  infections  more  of  the  drug  may  be  needed,  but 
in  my  experience  this  amount  is  amply  sufficient  if  administered  promptly. 
When  given  intravenously,  15  grains  (1  gm.)  is  sufficient. 

Suinniary  of  Treatment. — In  tertian  and  quartan  infections  quinine 
should  be  administered,  preferably  in  solution  and  by  the  mouth  in  single 
doses  of  from  15  to  30  grains  (1  to  2  gm.)  during  the  decline  of  the 
temperature,  and  these  doses  repeated,  if  necessary,  upon  the  following 
day.  For  a  period  of  at  least  a  month  the  drug  should  be  given  in  grad- 
ually decreasing  doses,  thus  preventing  a  recurrence.  In  eestivo-autumnal 
infections,  quinine  should  be  given  in  doses  of  5  grains  (.32  gm.)  every 
four  hours  until  the  active  symptoms  have  disappeared,  and  every  five  or 
six  hours  afterward  for  a  period  of  three  days.  During  the  next  week  the 
drug  should  be  admini'^tered  in  doses  of  15  grains  (1  gm.)  on  every 
other  day  and  for  at  least  two  months  thereafter  upon  every  sixth  day. 
If  the  drug  is  thus  administered  a  definite  cure  of  such  infections  may  be 
predicted.  The  too  rapid  abandonment  of  treatment  is  one  of  the  most 
serious  mistakes  which  is  made  in  the  use  of  quinine.  Relapses  are 
almost  sure  to  occur  unless  the  drug  be  administered  for  a  period  of  sev- 
eral weeks  after  the  disappearance  of  active  symptoms,  and  only  in  this 
way  can  we  be  positive  that  a  recurrence  of  the  disease  will  not  take 
place. 

Contra-indications  to  the  Use  of  Quinine. — It  has  been  the  experience 
of  most  physicians  that  certain  patients  protest  against  the  use  of  quinine, 
claiming  that  they  are  unable  to  take  it.  In  most  instances  it  is  simply 
a  matter  of  personal  opinion,  and  if  the  physician  be  firm  in  insisting  upon 
the  use  of  the  drug  it  will  be  found  that  such  objections  are  generally  the 
effect  of  imagination.  However,  in  rare  instances,  the  administration  of 
quinine  is  contra-indicated,  in  that  the  drug  produces  such  unpleasant 
and  even  dangerous  symptoms  that  it  cannot  be  safely  used.  Idiosyn- 
crasy to  quinine  undoubtedly  exists  in  certain  patients,  and  therefor^ 


THE  MALARIAL  FEVERS  447 

some  substitute  for  the  drug  has  to  be  administered.  Among  these  sub- 
stitutes, none  of  whieh  are  as  eflieient  as  the  drug  itself,  may  be  mentioned 
euchinin,  an  ethyl  carbonate  of  quinine  which  is  tasteless,  and  which  may 
be  given  in  about  twice  the  dose  of  quinine,  and  methylene  blue,  which 
has  been  advocated  by  Ehrlich,  and  which  may  be  useful  in  some  cases, 
but  is  not  nearly  as  effective  as  quinine.  It  is  also  not  devoid  of  dangerous 
properties  as  it  may  produce  severe  diarrhoja,  strangury,  and  albuminuria- 
It  has  been  administered  with  good  results  in  a  few  cases,  in  doses  of 
from  8  to  15  grains  (.5  to  1  gm.),  during  the  twenty-four  hours.  For 
many  years  it  has  been  supposed  that  the  administration  of  quinine  in 
large  doses  may  result  in  hsematuria.  A  careful  investigation  of  the 
literature  bearing  upon  this  subject  should  convince  any  one  that  it  is 
untrustworthy,  and  that  true  cases  of  haematuria  following  the  adminis- 
tration of  quinine  are  so  rare  as  to  be  of  practically  no  importance.  The 
belief  that  haematuria  may  be  produced  in  this  manner  is  one  of  the  medi- 
cal superstitions  which  remain  as  a  legacy  to  the  profession,  despite  all 
scientific  proof. 

Treatment  of  Special  Symptoms. — A  cathartic  dose  of  calomel  should 
be  given  in  all  malarial  fevers  before  the  administration  of  quinine.  Dur- 
ing the  acute  stages  symptomatic  treatment  should  be  adopted;  thus, 
in  the  cold  stage  warm  drinks,  with  the  application  of  external  heat  in 
some  form,  are  indicated;  while  in  the  warm  stage,  if  the  temperature 
reaches  a  dangerous  point,  baths  of  tepid  or  cold  water  should  be  given. 
Antipyretics,  such  as  phenacetin,  acetanilide,  etc.,  should  never  be  admin- 
istered during  the  paroxysm  of  malarial  fever,  as  they  never  do  any  good 
and  may  do  much  harm.  If  the  vomiting  be  exhausting,  or  nervous 
symptoms  be  very  pronounced,  the  hypodermic  injection  of  morphine  is 
indicated.  Should  cardiac  weakness  be  present,  suitable  stimulants 
should  be  administered,  such  as  hypodermic  injections  of  ether,  brandy, 
or  strychnia.  In  the  pernicious  forms  of  eestivo-autumnal  infection, 
symptomatic  treatment  is  of  the  greatest  importance;  thus,  if  algid 
symptoms  develop,  stimulants  should  be  freely  administered,  external 
heat  applied  by  means  of  hot  water  and  warm  blankets,  and  collapse 
should  be  treated  by  hypodermic  injections  of  brandy,  strychnine,  and 
by  transfusion. 

While  the  treatment  of  special  symptoms  during  the  malarial  parox- 
ysms is  important,  it  should  be  remembered  that  unless  quinine  be  given, 
all  other  treatment  is  useless,  and  that  the  prompt  and  proper  adminis- 
tration of  this  drug  will  alone,  in  many  instances,  cause  the  disappearance 
of  all  alarming  symptoms. 

Treatment  of  Complications  and  Sequelae. — The  treatment  of  the  com- 
plications occurring  with  the  malarial  fevers  and  the  sequelae  following 
them  does  not  require  any  discussion,  it  being  the  same  as  that  pursued  in 
all  similar  conditions. 

Treatment  of  Malarial  Cachexia. — The  treatment  of  chronic  malarial 
poisoning  is  most  unsatisfactory  if  the  patient  remains  in  the  locality  in 
which  he  contracted  this  infection.  While  various  remedial  measures 
may  be  pursued,  such  as  the  administration  of  quinine,  arsenic,  and 
tonics  of  various  kinds,  but  little  result  will  follow  unless  a  change 
of  climate  is  secured.  All  these  patients  should,  if  possible,  have 
a  change  of  climate  to  a  high,  dry  altitude,  which  is  non-malarious, 


448  DISEASES  CAUSED  BY  PROTOZOA 

and  this  will  invaribly  do  more  for  the  patient  than  any  therapeutic  meas- 
ure. 

In  conclusion,  the  fact  is  emphasized  that  no  substitute  for  quinine 
can  equal  it  in  treatment  of  malaria,  and  that  in  the  worst  cases  the  proper 
administration  of  this  drug  will  result  in  prompt  recovery,  provided  the 
patient  be  seen  in  time.  There  are  one  or  two  substitutes  for  the  drug 
which  may  be  used- in  very  rare  instances  where  quinine  is  contra-indi- 
cated, but  the  writer  believes  with  Osier,  that,  "the  physician  who  at  this 
day  cannot  treat  malarial  fever  successfully  with  quinine,  should  abandon 
the  practice  of  medicine," 


CHAPTER    XX. 

BLACK-WATER  FEVER. 
By  J.  W.  W.  STEPHENS,  M.D.  (Cantab.),  D.P.H. 

Definition. — Black-water  fever,  or  hsemoglobinuric  fever;  a  disease 
occurring  in  tropical  and  subtropical  countries,  the  chief  symptom  of 
which  is  the  passing  of  haemoglobin  in  the  urine. 

Distribution. — This  is  still  imperfectly  known.  The  number  of  cases 
recorded  from  any  locality  is  unsatisfactory  evidence  as  to  the  frequency 
in  that  locality,[forwe  know  of  instances  where  cases  have  existed  for  years 
in  a  district  and  yet  have  been  recorded  only  quite  recently.  We  shall 
consider  later  the  factors  that  determine  its  occurrence ;  one  may  here  be 
mentioned:  viz.,  that  as  it  is  a  disease  affecting  chiefly  Europeans,  at 
least  in  Africa,  its  occurrence  in  a  particular  region  will  depend,  first,  upon 
the  presence  of  Europeans;  and,  secondly,  whether  such  Europeans  are 
subject  to  the  conditions  which  give  rise  to  it.  Again  we  cannot  say  the 
disease  is  equally  common  in  any  two  particular  places ;  for  in  one  case 
we  may  have  a  single  record  only,  in  others  many.  Bearing  in  mind 
these  limitations  to  our  knowledge  of  its  distribution  we  may,  in  giving 
the  following  list,  note  any  peculiarities. 

In  North  America  it  has  been  recorded  from  Arkansas,  Mississippi,  Lou- 
isiana, Tennessee  (?),  Texas,  Florida,  Georgia,  North  Carolina,  Alabama, 
South  Carolina,  Virginia.  Among  these  records  we  find  that  it  occurs 
mainly  among  white  but  occasionally  also  among  colored  persons.  Al- 
though no  doubt  the  statistical  statements  as  to  the  mortality  from  ma- 
laria in  the  United  States  require  to  be  accepted  with  caution,  yet  from 
the  census  returns  it  appears  that  these  states  are  the  most  malarious  in 
America.  There  are  no  exact  data  on  record  for  judging  of  its  frequency 
iji  any  particular  state. 

In  Central  America  it  is  recorded  from  Nicaragua,  Costa  Rica,  and 
Venezuela. 

West  Indies:  Cuba,  Martinique  and  Guadeloupe,  French,  British,  and 
Dutch  (?)  Guiana,  Trinidad,  and  British  Honduras.  In  Martinique  it 
was  recorded  by  French  naval  surgeons  before  1850;  but  the  only  record 
from  British  Honduras  occurs  in  1905. 

South  America:  The  data  here  are  very  scanty,  but  it  is  recorded  from 
Brazil  and  the  Argentine  Republic.  Lutz  in  a  personal  communication 
says  it  occurs  at  S.  Paolo,  but  it  is  rare  there. 

Europe  and  Asia  Minor:  The  countries  in  which  it  is  best  known  are 
Italy,  Sicily,  Sardinia,  and  Greece.  It  occurs  at  Merv  (Russia),  in  Tur- 
key, and,  according  to  Marchoux,  along  the  banks  of  the  Danube  and  in 
the  Caucasus.  In  Italy  it  is  practically  unknoT\m  in  the  North;  a  few 
cases  occur  in  the  Campagna;  but  it  is  in  the  South  and  especially  in  Sic- 
ily that  it  prevails,  and  here,  too,  malaria  is  most  intense;  thus,whereas  the 

29  449 


450  DISEASES  CAUSED  BY  PROTOZOA 

mortality  from  malaria  in  North  Italy  is  less  than  1  in  10,000,  in  Sicily  it 
is  7  to  S  per  10,000.  It  is  apparently  quite  common  in  Greece,  but  we  have 
no  data  as  to  its  relation  to  malarial  mortality  there.  It  occurs  in  Pales- 
tine and  with  considerable  severity  in  certain  districts.  It  is  not,  however, 
known  in  Cyprus. 

Africa:  Its  distribution  is  fairly  well  known,  as  the  disease  has  here 
been  carefully  studied.  It  is  found  along  the  coast-line  from  the  Senegal  to 
the  Orange  rivers.  It  is  found  in  the  countries  drained  by  the  Congo,  the 
Niger,  and  the  Zambesi,  and  recently  a  few  cases  have  occurred  also  in 
the  upper  reaches  of  the  Blue  and  White  Nile;  in  Senegambia,  Gambia, 
Sierra  Leone,  Gold  Coast,  Lagos,  Nigeria,  Cameroons,  Damara-land  on 
the  west,  and  British,  German  and  Portuguese  East  Africa  on  the  east. 
It  occurs  in  Uganda  and  British  Central  x\frica,  but  probably  does  not 
extend  much  further  south  than  Delagoa  Bay.  In  all  these  regions  we 
may  say  that  intense  malaria  is  found.  In  Algeria  it  is  by  no  means  rare, 
but  is  miknown  in  Egypt,  where  malaria,  at  any  rate  among  Europeans, 
is  very  micommon.  In  INIadagascar  it  has  been  described  since  1851  by 
French  naval  surgeons.  It  is  known  also  in  Mauritius  and  Bourbon,  but 
its  occurrence  in  Zanzibar  is  doubtful. 

India:  Over  the  greater  part  of  India  it  appears  to  be  unknown.  Foci 
occur  in  the  Jeypoi'e  agency  (Madras),  in  the  Canara  district  (Bombay), 
and  in  the  Duars  (Bengal)  the  A\Titer  saw  more  cases  in  a  fortnight 
than  in  the  same  time  in  iVfrica.  It  also  occurs  in  the  Terai  (Bengal) 
and  in  Assam.    According  to  Marchoux  it  exists  in  Burma. 

Other  Countries:  It  is  recorded  from  Cochin  China  and  Tonkin;  also 
from  Java  (Tjilatjap),  New  Guinea  (German),  and  single  cases  from 
British  INIalaya  and  New  Hebrides.  Finally,  it  occurs  in  Formosa,  but 
not  in  Japan. 

We  believe  that  a  consideration  of  these  data,  imperfect  though  they  be, 
will  show  that  the  distribution  of  black-water  fever  and  severe  malaria  is 
co-extensive.  This  holds  good  for  the  United  States  and  for  Italy,  where 
the  figures  are  probably  fairly  trustworthy.  There  is  a  further 
method  of  gauging  malarial  intensity  which  so  far  has  been  applied  only 
in  a  few  cases.  Perhaps  there  is  no  more  sensitive  test  of  the  malarial  en- 
demicity  of  a  district,  or  endemic  index,  as  we  may  term  it,  than  the  number 
of  young  native  children  with  parasites  in  their  blood  (or  with  enlarged 
spleens).  In  many  native  villages  of  Africa  for  instance,  90  to  100  per 
cent,  of  children  (under  ten  years  of  age)  are  infected  with  parasites, 
whereas  if  we  take  a  similar  determination  in  a  large  town  or  its  suburbs 
the  index  will  rapidly  fall  to  20,  or  10,  or  even  0.  It  is  possible  by  this 
means  to  measure  marked  changes  in  the  malarial  endemicity  of  dis- 
tricts which  in  no  other  way  could  make  themselves  evident. 

By  this  means  we  believe  it  would  be  possible  to  compare  the  amount 
of  malaria  for  instance  in  British  Central  Africa  with  that  of  Italy.  W^e 
should  at  least  get  some  definite  numerical  basis  of  comparison,  far  more 
accurate  than  we  now  possess.  That  malaria  (and  we  are  concerned  with 
malaria  here  because  we  believe  black-water  fever  to  be  malarial)  is  a 
deadly  disease  in  the  Congo  and  a  tri\dal  one  in  North  Italy  we  can 
hardly  doubt.  On  what  this  difi'erence  depends  we  cannot  certainly  say. 
It  very  possibly  may  be  due  to  climatic  differences,  whatever  that  im- 
plies.    In  the  contrast  between  malaria    in  North  Italy  and  Sicily  we 


BLACK-WATER  FEVER  451 

have  a  striking  fact;  and  it  is  necessary  to  emphasize  these  differences  in 
considering  the  relationship  of  malaria  to  black-water  fever,  because  one 
of  the  objections  frequently  urged  against  its  malarial  origin  is  the  fact 
that  the  distribution  of  the  two  diseases  is  not  the  same.  But  neither  is 
the  distribution  of  mild  and  severe  malaria  the  same,  a  point  to  be  remem- 
bered in  considering  the  etiology  of  the  disease.  In  considering  the  dis- 
tribution of  black-water,  the  circumstances  under  which  a  susceptible 
European  population  lives  is  important.  For  instance  in  many  in- 
tensely malarious  districts  of  Africa,  segregated  stations  or  cantonments 
have  now  been  provided  for  the  European  residents.  In  other  places 
Europeans  still  live  under  the  evil  conditions  of  infection  which  almost 
universally  prevailed  before  a  knowledge  of  the  mosquito  malaria  cycle 
became  well  known.  In  such  a  segregated  area  malarial  fever  is  reduced 
to  a  minimum,  and  black-water  fever  also  disappears.  If  all  Europeans 
were  segregated  from  native  dwellings,  then  we  could  conceivably  get 
an  intensely  malarious  region,  as  judged  by  the  number  of  young 
children  having  parasites  in  their  blood,  without  any  black-water  fever. 
For  at  least  in  the  African  negro,  black-water  is  exceedingly  rare,  and  if 
Europeans  live  away  from  natives  instead  of  in  their  midst,  as  is  too  often 
still  the  case,  then  they  will  escape  infection  and  consequently  black- 
water  fever.  We  have  dwelt  upon  this  point,  because  unless  Europeans 
live  under  dangerous  conditions  black-water  fever  may  be  absent  even 
in  highly  malarial  districts. 

It  has  rather  been  assumed  so  far  that  black-water  fever  is  malarial  in 
origin.  What  are  the  facts  ?  Many  hypotheses  existwhich  need  not  con- 
cern us.  We  may  refer  to  one  which  if  true  would  be  a  simple  solution 
of  all  difficulties  that  arise  about  this  problem.  Black-water  fever  implies 
haemoglobin  in  the  urine.  Now,  in  cattle  there  is  a  well-known  disease 
with  haemoglobin  in  the  urine  as  one  of  its  chief  symptoms.  This  disease  is 
due  to  a  parasite,  piroplasma;  consequently,  ex  hypothesi,  black- 
water  fever  in  man  is  due  to  piroplasma.  If  all  problems  could  be 
solved  as  simply  as  this,  research  into  the  nature  of  disease  could 
be  conducted  in  a  library.  Unfortunately  there  is  not  a  shred  of 
fact  to  support  this  simple  hypothesis  which  the  weary  investigator  has 
only  too  often  wished  true.  That  black-water  fever  is  not  a  piroplasmosis 
is  proved  by  the  fact  that  piroplasma  does  not  exist  in  the  blood  and 
tissues  of  cases  of  black-water  fever,  though  repeatedly  sought  for  by 
competent  observers;  and  there  is  no  question  of  its  having  been  over- 
looked, for  it  is  a  parasite  recognized  without  any  difficulty.  What,  then, 
leaving  aside  this  hypothesis,  are  the  facts  for  and  against  the  malarial 
origin  of  this  disease? 

First,  there  are  arguments  of  a  general  nature  but  yet  of  much  force. 

1 .  There  is  no  case  on  record  of  any  one  having  contracted  black-water 
fever  who  has  not  previously  suffered  from  malaria  and  generally  much 
malaria.  Now  if  black- water  were  a  disease  sui  generis,  this  would  be  very 
difficult  of  explanation ;  for  were  it,  e.  g.,  piroplasmosis,  then  we  should  ex- 
pect that  an  immigrant  coming  into  a  black-water  district  would  at  least 
occasionally  contract  black-water  before  he  had  contracted  malaria;  but 
this  is  contrary  to  the  facts. 

2.  It  is  well  known  that  in  the  tropics  the  disease  is  commonest  among 
those  who  have  suffered  from  repeated  attacks  of  fever,  even  if  these  are 


452 


DISEASES  CAUSED  BY  PROTOZOA 


only  slight  in  nature;  and  the  frequency  of  attack  according  to  the  length 
of  life  in  the  tropics  confirms  this.  Recent  statistics  on  this  })oint  confirm 
the  old  ones  of  Berenger-Feruud,  according  to  whom,  of  Europeans  there 
are  attacked  5.4  per  cent,  in  their  first  year,  22.5  per  cent,  in  their  second 
year,  42.5  jjer  cent,  in  their  third  year,  20  per  cent,  in  their  fourth  year, 
and  4.8  per  cent,  in  their  fifth  year.  These  figures  conform  with  the  experi- 
ence of  physicians  practicing  in  the  tropics  at  the  present  day,  who  well 
know  that  it  is  among  the  "old"  residents  that  they  see  the  cases. 
This  peculiar  distribution  of  black-water  is  strong  evidence  against  the 
disease  being  due  to  any  specific  parasite,  be  it  protozoon  or  bacterial. 

3.  Tropical  Africa  is  admittedly  one  of  the  most  malarial  regions  on 
the  earth,  and  yet  the  mortality  from  malaria  is  slight  when  com- 
pared with  that  of  black-water,  as  the  following  figures,  compiled  from  the 
statistics  relating  to  (icrmau  troops  in  Africa  over  a  period  of  years,  show: 


Cases  of 
malaria 

Deaths  from 
malaria 

Cases  of 

black-water 

fever 

Deaths  from 

black-water 

fever 

G.  E.  Africa,  April,  1897,  to  March,  1898 
G.  E.  Africa,  April,  1898,  to  March,  1899 
G.  E.  Africa,  April,  1899,  to  March,  1900 

312 
345 
390 
213 
138 
149 
186 
72 

0 

1  (?) 

0 

0 

1 

4 
0 
2 

30 
33 
17 
10 
12 
12 
28 
5 

2 
3 

8  (or  ?  11) 
1 

Cameroon,  July,  1897,  to  June,  1898. . . 
Cameroon,  July,  1899,  to  June,  1900... 
Cameroon,  July,  1900,  to  June,  1901. .  . 
Togo.  1899  to  1900 

2 
7 
8 
5 

Total 

1805 

S  (?7) 

147 

36  (?39) 

Thus  malaria  has  a  mortality  of  about  0.4  per  cent.,  while  that  of  black- 
w^ater  fever  is  about  25  per  cent.,  i.  e.,  60  times  as  great.  We  believe  that 
the  true  explanation  of  these  figures  is  that  malaria  is  not  a  mild  disease, 
but  that  its  intensity  is  displayed  in  the  form  of  black-water  fever. 

4.  If  black-water  fever  is  malarial  in  origin,  then  those  who  protect 
themselves  from  malaria,  either  by  careful  personal  prophylaxis  (mos- 
quito nets,  adequate  clothing,  etc.),  or  by  the  taking  of  quinine,  should  be 
less  attacked  by  black-water  than  those  who  are  unprotected.  The  fol- 
low^ing  data  of  A.  Plehn  support  this  view: 


Attacks  of 
malaria 

Interval  between 

attacks  in 

months 

Black-water 
cases 

Interval  between 

the  cases  in 

months 

Deaths  from 
black-water  fever 

287 
70 

2 
5 

31 
6 

18.5 
74.0 

10%  about 
0. 

The  first  row^  consists  of  those  who  did  not  submit  themselves  to  a  sys- 
tematic quinine  prophylaxis,  the  second  row^  of  those  who  did,  taking 
seven  and  one-half  grains  of  quinine  every  fifth  day. 

5.  Finally  w^e  come  to  the  positive  facts  in  favor  of  the  malarial  origin; 
and  first  as  to  the  occurrence  of  malarial  parasites  in  the  blood  of  patients 
suffering  from  black-water.    Here  we  may  incidentally  consider  one  of  the 


BLACK-WATER  FEVER 


453 


main  arguments  against  the  malarial  origin;  viz.,  that  in  the  majority  of 
cases  of  black-water,  parasites  are  not  found,  or,  if  they  are,  in  so  small  a 
number  as  to  have  no  causative  relationship.  The  first  part  of  this  state- 
ment is  true,  and  the  observer  w^ho  examines  cases  of  black-water  will  be 
disappointed  with  the  negative  results  of  his  examinations.  The  second 
proposition  that  the  number  of  parasites,  when  they  are  found,  bears  no 
relationship  to  the  severity  of  the  symptoms,  may  or  may  not  be  true,  but 
it  is  not  necessarily  so,  for  in  malaria,  at  least  in  the  tropics,  we  may  get 
severe  malaria  with  few  or  no  parasites  in  the  blood,  and  also  the  reverse 
condition:  viz.,  a  considerable  number  of  parasites  and  yet  practically  no 
symptoms.  But  wc  must  consider  the  first  part  of  this  statement  more 
closely,  for  it  is  only  true  as  a  general  statement,  and  when  analyzed  care- 
fully it  is  found  not  to  accord  with  the  facts.  The  following  table  is  com- 
piled from  the  records  of  observers  who  were  well  acquainted  with  the 
malarial  parasite: 


AUTHOR 

DAY    BEFORE 
HEMOGLOBINURIA 

DAY    OP 
HEMOGLOBINURIA 

DAY    AFTER 
ONSET 

No.  of 
cases 

No. 
positive 

No.  of 
cases 

No. 
positive 

No.  Of 
cases 

No. 
positive 

A.  Plehn 

5 
0 
5 
1 
3 
9 

5 
0 
5 

1 
3 
8 

5 
21 
8 
9 
3 
17 

3 

18 
6 
2 

1 
9 

10 
10 

6 
16 

2 
20 

2 

F.  Plehn 

3 

Koch 

1 

Stephens  and  Christophers. .  .  . 

0 
0 

5 

Total 

23 

22 

63 
61.9  p 

39 
Br  cent. 

64 

11 

Thus  when  the  blood  is  examined  before  the  attack,  parasites  are  found  in 
95.6  per  cent,  of  cases,  on  the  day  of  the  hemoglobinuria  in  61.9  per  cent, 
of  cases,  and  on  the  day  after,  when  frequently  the  cases  are  first  seen,  in 
only  17.1  per  cent,  of  cases.  So  that  it  appears  that  not  only  is  black-water 
dependent  on  a  malarial  infection  at  some  previous  time,  but  that  the  rela- 
tionship is  a  very  close  one,  depending  upon  the  actual  presence  of  para- 
sites immediately  prior  to  the  attack.  To  deny  the  significance  of  these 
parasites,  as  has  been  done,  seems  equivalent  to  denying  the  significance 
of  parasites  in  an  equivalent  number  of  malaria  cases,  and  to  be  contrary 
to  common  sense.  One  of  the  most  striking  characters  of  the  blood  ex- 
amination in  these  cases  is  the  rapidity  with  which  parasites  disappear. 

Subsidiary  evidence  of  malaria:  In  cases  of  true  malaria  it  occasion- 
ally happens  that  parasites  cannot  be  found  in  the  blood,  and  perhaps 
this  is  most  frequent  during  the  pyrexial  stages  of  the  attacks.  Again,  in 
other  cases  parasites  are  so  few  in  number  that  the  argument  that  has  been 
applied  to  black- water  fever  might  equally  well  be  apphed  here:  wz.,  that 
the  number  of  parasites  bears  no  relationship  to  the  severity  of  the  dis- 
ease. Another  cause  of  the  absence  of  parasites  in  malaria  is  the  previous 
administration  of  quinine;  though  the  fever  may  still  persist,  yet  no  par- 
asites can  be  found.     In  such  cases  we  have  means  at  our  disposal  by 


454  DISEASES  CAUSED  BY  PROTOZOA 

which  we  can  still  diagnose  malaria  even  though  parasites  are  absent. 
These  arc  two  in  luiniber:  (1)  the  presence  of  pigmented  large  mononu- 
clear leukocytes;  and  (2)  an  increasein  the  percentage  of  large  mononuclear 
leukocytes.  The  yalue  of  these  is  usually  about  5  to  8  per  cent.,  but  in  ma- 
laria the  percentage  is  often  markedly  increased  eyen  up  to  40  per  cent., 
so  that  a  value  of  20  per  cent.,  which  is  not  uncommon,  may  be  considered 
as  fairly  good  evidence  of  malaria,  especially  as  in  such  cases  diligent 
search  is  almost  always  certain  to  detect  pigmented  leukocytes  also. 
Christophers  and  the  writer,  in  Africa,  found  that  parasites  were  present 
only  in  12.5  per  cent.,  while  by  applying  these  two  subsidiary  tests 
evidence  of  malaria  was  found  in  93.8  per  cent,  of  cases;  and  it  may  be 
stated  that  care  was  taken  to  make  adequate  control  observations  among 
a  number  of  persons  selected  as  being  liable  to  infection,  but  in  these  no 
such  evidence  of  a  malarial  infection  existed. 

If  we  sum  up  now  the  actual  evidence  on  which  a  malarial  origin  of 
black-water  is  based,  we  find  that,  apart  from  general  considerations,  (1) 
parasites  are  found  in  (nearly)  all  cases,  provided  the  examination  is  made 
early  enough;  (2)  that  when  parasites  are  absent,  as  is  generally  the  case 
when  the  patients  are  seen  late,  still  we  have  subsidiary  evidence  of 
malaria  in  (a)  the  presence  of  pigmented  leukocytes  and  (b)  the  increased 
percentage  of  large  mononuclear  leukocytes.  That  parasites  when  found 
rapidly  disappear  is  a  well-known  fact,  but  we  must  first  consider  another 
factor  in  the  etiology  of  black-water  fever.  Black-water  is  common  in 
Sicily,  and  it  was  here  that  Tomaselli  first  put  forward  the  view  that 
hsemoglobinuria  in  malaria  is  a  quinine  intoxication.  This  view  has 
been  vehemently  controverted,  but  its  adherents  have  steadily  increased 
and  at  the  present  day  it  is  impossible  to  deny  that  quinine  can  at  least 
occasionally  produce  hsemoglobinuria.  Patients  who  have  themselves 
known  that  quinine  certainly  did  induce  an  attack  of  hsemoglobinuria, 
have  volunteered  to  undergo  the  experiment  in  hospital,  and  the  result  has 
been  precisely  as  they  stated.  Thus  it  may  now  be  taken  as  conclusively 
proved  that  quinine  can  induce  black-water  fever.  It  does  not  follow 
that  all  cases  of  black-water  are  due  to  quinine,  sometimes  in  small  and 
sometimes  in  large  doses;  but  although  absolute  proof  is  wanting,  yet  any 
one  who  has  carefully  investigated  the  histories  of  cases  of  black- water 
and  has  observed  patients  in  a  hospital,  can  hardly  doubt  that  quinine 
is  often  and  indeed  most  often  the  exciting  cause.  Thus  one  patient 
had  a  typical  malignant  tertian  malaria  with  a  characteristic  tempera- 
ture chart  and  abundance  of  parasites.  Quinine  was  administered,  and 
after  a  doubtful  interval  hsemoglobinuria  came  on;  then  the  parasites 
completely  disappeared  and  were  not  found  again  till  after  death,  in  the 
spleen.  Secondly,  we  have  seen  a  patient  admitted  with  black- water  fever 
about  midnight;  the  next  day  at  noon  the  urine  was  clear;  then  quinine  was 
given  and  the  same  afternoon  black-water  returned.  Such  cases  are, 
when  seen,  very  convincing;  but  it  must  be  admitted  that  they  are  not  as 
conclusive  evidence  of  the  quinine  etiology  as  the  experimental  cases 
just  mentioned.  This  quinine  factor  is  probably  one  of  the  reasons  why 
parasites  disappear  so  rapidly;  another  probably  is  the  actual  destruction 
of  red  cells,  which  may  affect  especially  those  cells  infected  with  parasites. 

Whatever  be  the  cause,  it  is  very  necessary  to  examine  for  parasites  as 
early  as  possible.    If  they  are  to  be  found,  a  few  hours'  delay  may  mean  a 


BLACK-WATER  FEVER  455 

negative  examination.  With  regard  to  this  quinine  factor,  two  recent  ob- 
servations are  worthy  of  note:  {!)  According  to  Marchoux,  quinine  is  not 
excreted  in  the  urine  during  the  actual  hsemoglobinuria,  but  reappears 
after  this  has  ceased.  This  may  imply  that  the  retention  of  quinine  is  as- 
sociated with  the  hsemoglobinuria,  but  though  probable  we  have  no  actual 
chemical  evidence  of  the  truth  of  this  hypothesis.  (2)  Poch  records  a  case 
where,  as  the  result  of  quinine  administration,  no  actual  hsemoglobinuria 
occurred,  but  only  a  diminution  in  red  cells  of  340,000.  There  are  also 
other  observations  on  record  where  quinine  repeatedly  induced  black- 
water,  yet  on  other  occasions  only  gave  rise  to  albuminuria.  There  are  of 
course  many  objections  to  the  quinine  view;  viz.:  (1)  The  multitudes  of 
people  who  take  quinine  and  yet  do  not  suffer  from  black-water.  (2) 
Quinine  will,  we  assume,  produce  an  attack  one  day,  but  if  administered 
on  a  subsequent  day  no  such  result  occurs.  We  consider,  however,  that 
against  the  positive  experimental  evidence  such  objections  cannot  count, 
and  the  discrepancy  means  that  we  are  in  the  dark  as  to  the  conditions  of 
blood  which  allow  of  this  hsemolytic  action  of  quinine.  We  indeed  should 
expect  that  if  quinine  has  destroyed  the  less-resistant  cells,  then  a  second 
administration  would  not  have  the  same  result,  as  the  residual  cells  are 
more  resistant;  but  these  are  speculations  about  the  resistance  of  red  cells 
of  which  but  little  is  known.  We  may  sum  up  the  etiology  of  black- water 
somewhat  in  this  way :  it  is  not  a  disease  per  se,  but  rather  a  condition  of 
blood  in  which  quinine,  other  drugs,  cold,  or  even  exertion,  may  produce 
a  sudden  destruction  of  red  cells.  The  condition  is  produced  only  by 
malaria  and  generally  by  repeated  small  attacks  insufficiently  combated 
by  quinine.  In  such  cases  of  chronic  malaria  {i.  e.,  in  those  suffering 
from  anaemia  with  repeated  attacks  of  fever  and  repeated  doses  of  qui- 
nine) black-water  fever  sooner  or  later  almost  certainly  supervenes,  at 
least  in  tropical  climates.  The  two  main  factors  in  hsemoglobinuria 
are,  then,  malaria  and  quinine.  While  then  we  believe  that  the  cause 
of  black- water  is  known,  yet  it'  must  be  admitted  that  much  work 
remains  to  be  done  in  analyzing  more  minutely  the  exact  blood  condition 
which  predisposes  to  an  attack,  and  why  especially  quinine  at  one  time 
will  produce  haemolysis,  and  at  another  time  will  not. 

Morbid  Anatomy.— Spleen.— Melanin  may  be  found  in  cells  of  the 
splenic  reticulum  in  macrophages  and  in  large  mononuclear  leukocytes. 
Hsemosiderin  (yellow  ocherous  pigment)  also  is  present.  As  already 
stated,  pigmented  leukocytes  may  be  found  here  while  absent  in  the  blood 
during  life;  the  same  also  holds  good  for  parasites. 

Liver. — Melanin  occurs  in  endothelial  cells  and  pigmented  leukocytes 
in  the  capillaries :  areas  of  necrotic  liver-tissue  are  found  laterally  to  the 
intralobular  vein,  and  thrombi  occur  in  the  sublobular  veins,  and  in 
these,  pigmented  leukocytes  can  be  found. 

Kidneys. — The  epithelium  of  the  convoluted  tubes  shows  degen- 
eration, and  the  lumen  is  filled  with  a  granular  mass;  similar  changes 
are  found  in  the  straight  and  collecting  tubules.  Melanin  is  not  usually 
present. 

Red  Marrow» — Melanin  is  found  in  the  capillary  endothelium  and  in 
large  branch  cells,  and  also  in  leukocytes. 

Brain. — Occasionally  parasites  occur  here  when  absent  elsewhere, 
but  frequently  no  pigment  can  be  found. 


45G  DISEASES  CAUSED  7?r  PROTOZOA 

Symptoms. — As  a  rule  tlie  attack  begins  witli  a  violent  rigor;  at  the 
same  time  tlie  temperature  rapidly  rises  to  103°  to  105°  F.  This  is  accom- 
panied or  preceded  by  general  pain  in  the  limbs,  lassitude,  and  loss  of 
appetite  and  not  uncommonly  there  is  great  depression  of  spirits.  On  the 
other  hand,  sometimes  the  first  indication  the  patient  has  that  he  is  really 
unwell,  is  the  passing  of  black  water.  There  may  be  practically  no  other 
objective  sign.  It  has  been  attempted  to  separate  these  cases  from  the 
previous  ones  and  to  regartl  them  as  true  cases  of  cpiinine  hicmoglobin- 
uria,  but  no  sharp  line  can  be  drawn  between  such  cases  and  the  severe 
ones  with  intense  initial  rigor.  When  the  attack  has  set  in — which  the 
patient  may  have  regarded  as  only  a  more  than  usually  severe  attack 
of  fever — the  urine  next  passed  is  found  to  be  more  or  less  black.  The 
attack  is  accompanied  by  severe  vomiting,  which  increases  in  severity 
and  duration;  the  vomited  matter  is  eventually  almost  entirely  dark-green 
bile,  and  the  persistence  of  this  symptom  exhausts  the  patient  and  is 
frequently  of  l)ad  significance.  Jaimdice  appears  more  or  less  early  and 
eventually  the  body  becomes  of  a  light  lemon-yellow  color,  though  this 
may  not  be  well  marked  in  slight  cases.  The  spleen  and  liver  are  usually 
enlarged  and  there  may  be  considerable  pain  in  these  regions  and  over  the 
kidneys.  Tympanites  is  often  a  distressing  symptom,  and  the  epigastrium 
is  painful  on  pressure.  In  severe  cases  hiccough  troubles  the  patient  much, 
and  if  there  is  a  deficiency  in  the  excretion  of  urine  the  prognosis  is  grave. 
Somnolence  adds  to  the  gravity  and  may  progress  into  a  fatal  coma. 
The  quantity  of  urine  passed  in  mild  cases  is  greater  than  normal, 
but  a  deficiency  of  urine  is  always  unfavorable,  for  such  cases  may 
result  in  complete  suppression.  The  passage  of  the  urine  is  not  uncom- 
monly slightly  painful.  In  a  case  of  medium  severity,  however,  after  the 
initial  symptoms,  the  temperature  may  quickly  fall  and  the  urine  become 
free  from  haemoglobin  on  the  next  day,  still  for  some  time  retaining  its 
"high"  color.  The  fall  of  temperature  is  accompanied  by  sweating,  and 
with  an  abatement  of  the  other  symptoms  convalescence  has  already  be- 
gun. In  other  cases,  however,  a  relapse  may  occur  with  a  rigor  and  a 
return  of  the  hfemoglobinuria.  Unusual  complications  are  bloody  diar- 
rhoea or  effusions  of  blood  through  the  ear  or  nose.  Occasionally 
parotitis  is  seen.  Thrombosis  of  the  heart  is,  according  to  Plehn,  the  com- 
monest cause  of  death. 

The  Blood. — The  drop  of  blood  is  often  evidently  yellow  and  "thin"  in 
character;  it  has  lost  its  viscosity,  so  that  often,  excej)t  by  taking  a  large 
drop,  it  is  difficult  to  procure  satisfactory  smears.  If  a  drop  of  blood 
is  allowed  to  clot  in  a  small  capillary  tube,  either  hfemoglobinjemia 
or  cholaemia  may  be  found.  Hfemoglobinsemia,  ma}^,  however,  be 
absent  even  when  the  haemoglobinuria  is  increasing — a  fact  which  possibly 
supports  the  view  that  the  haemolysis  really  takes  place  for  the  most  part  in 
the  kidneys.  Microscopically,  the  blood  does  not  show  any  appreciable 
evidence  of  the  great  destruction  that  may  l)e  going  on  ;  at  most  the  red 
cells  may  look  ana-mic  and  have  their  central  depressions  enlarged ;  but 
there  is  no  deformity  of  the  red  cells,  as  has  been  stated  by  some,  such  an 
appearance  being  due  simply  to  badly  made  films.  A  stained  specimen, 
e.g.,  with  the  Romanowsky  stain,  may  show  two  conditions — (l)poly- 
chromasia  and  (2)  basophilia.  These  should  be  carefully  looked  for,  as 
by  some  observers  such  a  condition  is  supposed  to  indicate  a  further 


BLACK-WATER  FEVER  457 

tendency  toward  hfemolysis  and  to  make  administrtiion  of  quinine 
dangerous.  Further,  normoblasts  occur.  The  red  cells  may  fall  as  low 
as  a  million  in  severe  cases,  and  there  is  a  corresponding  deficiency  in 
haemoglobin. 

Parasites. — ^We  have  said  that  as  a  rule  parasites  will  not  be  found,  as 
cases  of  black-water  fever  are  not  uncommonly  first  seen  some  time  after 
the  onset  of  the  symptoms  ;  but  if  examination  is  made  early,  parasites 
occur.  In  the  absence  of  parasites  careful  search  should  be  made  through 
well-made  films  (most  conveniently  on  the  slide)  for  pigmented  large  mon- 
onuclear leukocytes.  Occasionally  they  are  plentiful,  but  as  a  rule  careful 
search  is  required  before  they  are  found ;  and  yet  when  absent  from  the 
blood  during  life,  they  may  be  found  in  the  spleen  postmortem. 

Leukocytic  Changes. — In  malaria  itself  two  conditions  occur :  first, 
there  is  a  transient  leukocytosis  during  the  pyretic  attack;  and,  secondly, 
a  leukopenia,  most  marked  during  the  apyrexia.  In  black-water,  the  leu- 
kocytosis appears  to  be  more  marked,  possibly  associated  with  the  toxic 
condition,  whatever  be  its  cause.  At  this  stage  the  poly  nuclear  leuko- 
cytes may  reach  90  per  cent.,  and  it  is  not  until  the  leukocytosis  ceases 
that  the  increase  in  the  percentage  of  mononuclear  leukocytes  can  be 
appreciated.  This,  which  is  most  marked  when  there  is  leukopenia, 
may  exceed  20  per  cent.,  and,  taken  with  the  finding  of  pigmented  leuko- 
cytes, is  good  evidence  of  a  malarial  infection  when  parasites  are  absent. 
The  hsemoglobinuria  generally  supervenes  some  hours,  one  to  five 
or  more,  after  the  taking  of  quinine,  so  that  it  is  necessary  to  examine 
the  blood  early,  as  quinine  itself  frequently  produces  a  rapid  disappear- 
ance of  parasites. 

The  Urine. — The  urine  is  generally  faintly  alkaline  in  reaction,  and  the 
specific  gravity  less  than  normal.  The  color  may  vary  from  a  very 
dark  red  to  a  brownish  yellow,  in  which  the  spectroscope  may  be  neces- 
sary to  detect  the  haemoglobin.  A  character  of  the  urine  in  severe  cases 
is  the  large  amount  of  sediment,  which  consists  of  a  yellowish  granular 
material,  the  granules  varying  in  size  from  1  to  7^  and  appearing  to 
consist  of  broken-down  blood-cells.  In  the  sediment  a  few  reddish  crys- 
tals of  haematoidin  occur.  The  darkness  of  the  urine  is  not  always  a 
safe  guide  to  the  amount  of  haemoglobin  present,  and  often  a  centrifugal- 
ized  urine  will,  on  examination  with  the  spectroscope,  prove  to  be  free 
from  blood-pigment.  Blood  corpuscles  are  rare;  the  condition  is  one 
of  haemoglobinuria  and  not  hsematuria.  A  spectroscopic  examination 
of  the  urine,  diluted  if  necessary,  shows  the  .double  band  of  oxyhaemo- 
globin  or  the  bands  of  methaemoglobin.  Urobilin  is  commonly  present; 
it  is  best  detected  in  the  form  of  zinc-urobilin.  Further  research  is  re- 
quired both  on  the  pigments  and  on  the  proteid  constituents  of  the  urine. 
The  amount  of  albumin  is  often  so  great  that,  after  boiling,  the  contents 
of  the  test-tube  set  solid  and  may  be  inverted  without  spilling.  Bile-pig- 
ments are  generally  absent,  but  may  appear  with  the  onset  of  the  fever, 
to  be  replaced  later  by  oxyhsemoglobin. 

Diagnosis. — The  disease,  which  may  present  the  greatest  difficulty  in 
diagnosis,  is  perhaps  yellow  fever.  But  the  points  of  distinction  are  many. 
The  history  of  many  previous  attacks  of  malaria  and  of  the  administration 
of  quinine,  point  to  black-water.  In  mild  cases  of  yellow  fever  we  do  not 
get  a  definite  haemoglobinuria,  but  at  most  a  slight  albuminuria.     Fre- 


458  DISEASES  CAUSED  BY  PROTOZOA 

quently  from  past  attacks  of  malaria  the  spleen  is  enlarged;  in  yellow  fever 
it  is  not.  In  yellow  fever  of  greater  severity  there  is  the  pronounced  suf- 
fusion of  the  face,  the  dry  tongue  with  red  tip,  and  later  the  pronounced 
icterus  and  black  vomit.  In  black-water  fever  also  there  is  icterus,  but  the 
other  features  are  wanting,  and  the  black  vomit  of  severe  cases  is  lacking. 
In  black-water,  on  the  contrary,  we  get  almost  pure  dark-green  bile.  Finally 
we  have  in  yellow  fever  the  characteristic  relationship  of  the  pulse  to  the 
temperature,  ri3.,  that  the  pulse  does  not  increase,  but  decreases  in  fre- 
quency with  the  increase  in  temperature.  The  presence  of  parasites  does 
not  exclude  yellow  fever,  but  in  practice  there  should  be  but  little  difficulty 
in  distinguishing  between  the  two  diseases.  Postmortem  the  distinction 
is  equally  well  marketl.  In  black-water  fever  the  spleen  and  liver  are 
usually  enlarged,  may  be  pigmented,  and  parasites  may  be  found  micro- 
scopically. In  yellow  fever  the  liver  is  only  slightly  if  at  all  enlarged,  and 
presents  on  section  a  characteristic  box-wood  color.  In  black-water  fever 
the  liver  is  commonly  enlarged,  and  is  also  icteric,  though  the  tint  is  not 
the  same  as  that  in  yellow  fever.  Ecchymoses  occur  in  the  gall-bladder  in 
yellow  fever ;  they  have  not  been  noted  in  black-water.  The  body  presents 
flecks  and  true  hemorrhages  in  yellow  fever,  the  stomach  and  intestines 
show  a  considerable  amount  of  hypersemia  or  hemorrhages,  and  the 
stomach  often  contains  dark,  slimy  masses. 

Prognosis. — Mild  attacks  are  generally  recovered  from  rapidly.  The 
mortality  may  be  set  down  roughly  as  from  10  to  20  per  cent.  It  is  advis- 
able that  the  patient  who  has  once  suffered  from  black-water  should  not 
return  to  the  tropics  unless  he  makes  up  his  mind  that  he  will  undertake 
strict  prophylaxis  against  malaria,  either  by  protecting  himself  scrupu- 
lously against  mosquitoes,  or  by  a  strict  quinine  prophylaxis  such  as  5 
grains  every  morning  or  10  to  15  grains  every  tenth  day. 

Treatment. — If  the  quinine  view  of  black-water  be  correct  the  question 
arises  as  to  how  black-water  fever  is  to  be  treated.  Whether  or  not  we  be- 
lieve this  view,  the  result  of  experience  is  undoubtedly  against  the  admin- 
istration of  quinine.  As  parasites  rapidly  disappear,  it  is  not  generally 
necessary  in  these  cases  to  administer  quinine.  In  all  cases  a  careful 
blood  examination  should  be  made,  and  if  parasites  still  persist  with  a  con- 
tinuance of  the  fever,  then  the  question  must  be  carefully  weighed  as  to 
whether  quinine  is  to  be  given  or  not.  If  it  can  be  avoided  we  should  say 
it  is  better  to  abstain  ;  but  if  it  is  judged  advisable  from  the  continuance  of 
the  fever,  then  it  should  be  commenced  in  quite  small  doses — one  or  two 
grains  at  a  time.  According  to  some  there  is  less  risk  if  it  is  administered 
subcutaneously,  and  if  this  dose  is  well  borne,  then  it  should  be  in- 
creased to  five  grains  and  from  this  upward.  In  some  cases  methylene 
blue  may  be  tried,  but  this  lacks  the  efficiency  of  quinine.  Should  the 
black-water  return  after  quinine,  a  second  attempt  may  be  made,  but  it 
is  dangerous,  for  in  one  of  Koch's  cases  the  result  was  always  the  same, 
and  finally  the  symptoms  became  so  aggravated  that  quinine  had  to  be 
withheld.  This,  however,  does  not  ahvays  occur,  and  a  second  attempt 
may  be  successful :  if  not,  there  is  no  course  open  but  to  trust  to  the 
fever  subsiding . 

The  general  treatment  is,  however,  the  most  important  matter.  The 
bowels  should  be  kept  open  by  calomel,  jalap,  or  enemata.  Champagne 
is  frequently  necessary  and  is  often  retained  when  all  food  is  rejected. 


BLACK-WATER  FEVER  459 

The  thirst  should  be  allayed  with  ice,  if  procurable,  and  nutrient  enemata 
given  if  necessary.  The  vomiting  is  often  very  troublesome,  and  for  this 
Hearsey  uses  morphia  (gr.  i,  gm.  0.03)  hypodermically.  Hearsey  treats 
his  cases  with  a  mixture  containing  bicarbonate  of  soda  (grs.  10,  gm.  0.6) 
and  perchloride  of  mercury  (gr.  gJ^,  gm.  0.002)  in  each  dose,  given  every 
two  hours.  Acid  drinks  are  at  the  same  time  prohibited.  We  do  not  con- 
sider that  this  treatment  has  the  specific  value  that  the  author  claims  for 
it,  but  it  may  well  be  tried.  Doering  alleviates  vomiting  by  the  use  of 
Carlsbad  salts,  a  teaspoonful  in  water,  repeating  the  dose  if  vomited. 
Injections,  intravenous  or  subcutaneous,  of  normal  saline  solution,  have 
been  used  with  good  effect  by  some.  Vincent  recommends  calcium  chlo- 
ride to  prevent  the  susceptibility  to  black-water  and  also  during  the  attack 
(4-6  gm.  daily  or  1-2  gm.  injected  subcutaneously  in  saline  solution). 
Dannermann  uses  a  decoction  of  a  native  African  fever  remedy,  the 
leaves  of  Combretus  Raimbanthius.  (Decoct,  fol.  combreti  24  parts, 
water  1,500  parts,  used  as  a  tea  during  the  day.)  To  promote  diuresis 
potassium  acetate  is  used. 

The  symptoms  arising  from  the  kidney,  heart,  and  nervous  system,  are 
those  which  require  especial  attention.  General  treatment  and  good  nurs- 
ing especially  are  of  the  greatest  importance,  and  to  these  must  be  at- 
tributed the  successful  treatment,  and  not  to  any  specific  value  of  the 
various  remedies  advocated. 


.    CHAPTER  XXL 

TRYPANOSOMIASIS. 
By  COL.  DAVID  BRUCE,  C.  B.,  F.  R.  S.,  R.  A.  M.C. 

Introduction. — The  group  of  diseases  which  comes  under  the  term 
Trypanosomiasis  attracted  Uttle  attention  until  a  few  years  ago;  now,  it 
seems  to  be  usurping  the  position  of  interest  held  during  the  last  quarter  of 
a  century  by  the  bacteria.^  Diseases  caused  by  trypanosomes  are  found 
over  a  large  area  of  the  earth's  surface,  from  South  America,  through 
Africa,  Southern  Europe,  Persia  to  India,  Burma,  China,  and  the  Philip  • 
pines,^  and  affect  many  kinds  of  animals,  including  man.  These  diseases 
are  all  caused  by  the  presence  in  the  blood  and  body-fluids  of  species  of 
flagellated  protozoa  belonging  to  the  genus  Trypanosoma.  A  trypano- 
some  consists  of  a  single  cell,  and  in  its  best  known  form  is  a  sinuous 
worm-like  creature,  provided  with  a  macronucleus  and  a  micronucleus 
or  blepharoplast,  a  long  terminal  fiagellum,  and  a  narrow  fin-like  mem- 
brane, continuous  with  the  fiagellum  and  running  the  whole  length  of 
the  body.  The  end  from  which  the  fiagellum  protrudes  is  usually  called 
the  anterior;  the  other  end,  near  which  as  a  rule  is  situated  the  micro- 
nucleus,  the  posterior.  When  alive  this  hsematozoon  is  extremely  rapid 
in  its  movements,  constantly  dashing  about  and  lashing  the  red  blood 
corpuscles  into  motion  with  its  fiagellum,  and  it  swims  equally  well  with 
either  extremity  in  front.  These  parasites  give  rise  to  an  extreme  variety 
of  diseases,  sometimes  so  acute  as  to  cause  death  in  a  few  days,  at  other 
times  so  chronic  as  to  take  several  years  to  kill.  Some  of  the  species,  again, 
appear  to  live  in  the  blood  of  their  hosts  without  causing  any  perceptible 
disease,  and  especially  is  this  so  in  those  species  which  livj  in  fish,  frogs, 
and  other  cold-blooded  animals.  As  to  how  the  trypanosome  damages  its 
host  is  not  very  clearly  known  at  present,  but  the  probability  is  that  it  gives 
rise  to  the  presence  of  small  quantities  of  toxins  in  the  blood  and  so  causes, 
in  some  animals,  chronic  inflammatory  processes,  or  in  others  extensive 
and  rapid  destruction  of  the  blood  corpuscles.  However  the  damage  is 
done,  trypanosomiasis  is  extremely  fatal  in  man  and  the  domestic  animals, 
such  as  the  horse,  dog,  and  ox.  Large  native  populations  in  Central 
Africa  are  being  swept  away  at  this  moment  by  this  plague,  and  great 
tracts  of  country  are  rendered  uninhabitable  for  man  and  the  domestic 
animals.  In  this  paper  a  brief  historical  sketch  and  description  of  the 
more  important  try]5anosomes  and  the  diseases  they  give  rise  to,  with 
special  reference  to  that  species  which  affects  man,  are  given. 

*  Trypanosomes  et  Trypanosomiasis  par  A.  Laveran  et  F.  Mesnil,  Masson  et  Cie, 
Paris,  1904,  p.  419. 

2  "Report  on  Trypanosomiasis,"  etc.,  by  W.  E.  Musgrave  and  M.  T.  Clegg, 
Report  of  the  Superintendent  of  Government  Laboratories  in  the  Philippine  Islands, 
1903,  Bureau  of  Insular  Affairs,  War  Department,  United  States. 

460 


TRYPANOSOMIASIS  461 

TRYPANOSOMA  LEWISI. 

The  Rat  Trypanosome. — The  earlier  discoveries  of  trypanosomes 
in  the  blood  of  fish  and  frogs,  dating  from  the  year  1841,  may  be  passed 
over.  They  Mrere  interesting  to  the  zoologist,  but  having  at  that  time  no 
obvious  bearing  on  the  causation  of  disease,  did  not  attract  the  attention 
of  medical  men.  For  about  forty  years  little  or  no  progress  was  made 
in  the  subject  until  Surgeon-Major  T.  R.  Lewis,^  F.  R.S.,  Royal  Army 
Medical  Corps,  made  an  important  observation  by  finding  flagellated 
organisms  in  the  blood  of  rats.  This  interesting  discovery  may  be  de- 
scribed in  his  own  words.  He  says  that  having  been  directed  to  make 
certain  enquiries  regarding  the  nature  of  the  sometimes  designated 
"spirillum  fever,"  which  prevailed  in  Bombay  during  the  early  part  of 
1877,  he  had  occasion  to  examine  the  blood  of  a  considerable  number  of 
animals,  and,  in  July  of  that  year,  detected  spirillum-like  organisms  in 
the  blood  of  healthy  rats.  In  some  instances  these  were  so  numerous 
that  the  blood,  when  examined  under  a  high  power,  seemed  to  quiver 
with  life.  On  careful  focussing,  it  was  ascertained  that  each  organism 
consisted  of  a  body  portion,  and  of  an  extension  of  it  in  the  form  of  a 
gradually  tapering,  long  flagellum.  They  were  found  in  two  species  of 
rats — Mus.  decumanus  and  Mus.  rujescens — and  in  29  per  cent,  of  the 
animals  examined.  Lewis  naturally  fell  into  the  error,  when  Dr.  Grif- 
fith Evans,^  the  Chief  of  the  Veterinary  Department  in  Madras,  discov- 
ered similar  organisms  in  the  blood  of  horses  suffering  from  surra,  of 
considering  that  the  two  parasites  were  identical.  With  better  micro- 
scopes than  Lewis  possessed,  it  can  now  be  seen  that  the  morphology  of 
the  rat  trypanosome  differs  much  from  that  of  surra.  The  only  animal  in 
the  blood  of  which  the  former  will  live  is  the  rat.  This  rat  trypanosome 
is  distributed,  broadly  speaking,  all  over  the  world ;  and  even  in  Uganda, 
in  Central  Africa,  we  found  numbers  of  the  common  field  rat  harboring  it. 
The  rat  trypanosome  does  not  appear  to  give  rise  to  any  symptoms  of  dis- 
ease, although  their  numbers  in  the  blood  may  be  exceedingly  numerous. 

TRYPANOSOMA  EVANSI.^ 

Surra. — This  trypanosome  was  discovered  in  1880,  as  mentioned  above, 
by  Evans.*  Surra  is  mainly  an  Indian  disease,  occurring  in  the  Punjab 
and  in  Burma.  The  disease  usually  appears  during  the  rainy  season,  and 
disappears  gradually  with  the  advent  of  the  cold,  dry  weather.  Places  in 
which  surra  is  reported  to  occur  naturally,  are  mostly  situated  close  to 
swamps  or  alongside  rivers,  and  liable  to  inundation  during  the  rains. 
The  horse  and  mule  are  most  susceptible  to  surra,  the  dog  coming  next, 
and  these  three  always  succumb  to  the  disease.   The  camel  is  supposed 

^  Lewis,  "Flagellated  Organisms  in  the  Blood  of  Healthy  Rats,"  Qwari.Journ. 
Micr.  Sc,  Vol.  XIX,  January,  1879,  109. 

^  Evans,  "On  a  Horse  Disease  in  India  Known  as  'Surra,' Probably  Due  to  a 
Hsematozoon,"  Vet.  Journ.,  Vols.  XIII  and  XIV,  1881-1882. 

^ Steel,  J.  H.,  Report  on  his  Investigation  into  an  Obscure  and  Fatal  Disease 
among  Transport  Mules  in  British  Burma,  1885. 

*EvanSj  G.,  Report  on  Surra,  Published  by  the  Punjab  Government,  1880. 


462  DISEASES  CAUSED  BY  PROTOZOA 

to  live  for  three  years  after  becoming  infected,  while  the  ox  generally 
recovers  after  some  five  or  six  months.  Rogers^  states  that  surra  is 
carried  from  sick  to  healthy  animals  by  species  of  tabanus,  and  other 
■writers  have  stated  that  stomoxys  also  acts  as  an  infecting  agent.  Surra 
is  very  closely  related  to  the  next  disease — nagana — and,  in  fact,  is  con- 
sidered by  many  to  be  identical. 


TRYPANOSOMA  BRUCEI.^ 

Nagana  or  Tsetse-fly  Disease. — As  the  writer  of  this  article  had  the 
good  fortune  to  discover  this  species  of  trypanosome  in  1894,  perhaps 
a  few  words  of  personal  experience  will  not  come  amiss.  In  October, 
1894,  when  serving  in  Natal,  South  Africa,  the  governor  of  that  colony, 
the  Hon.  Sir  Waiter  Hely-Hutchinson,  G.C.  M.G.,  asked  me  to  go 
to  Zululand  to  report  on  a  disease  which  was  causing  severe  loss 
among  the  native  cattle.  The  native  name  of  the  disease  was  nagana. 
At  this  time  no  suspicion  that  nagana  and  the  tsetse-fly  disease  were 
identical  was  entertained.  The  writer  at  once  proceeded  to  Zululand 
and  after  a  month's  travelling  by  ox- wagon  from  Eshowe,  the  capital  of 
that  country,  arrived  in  the  infected  area.  A  small  laboratory  having 
been  set  up  and  some  of  the  aft'ected  cattle  obtained  from  the  surround- 
ing natives,  examination  by  the  ordinary  bacteriological  methods  was 
begun.  The  animals  were  emaciated,  with  staring  hair,  some  fever, 
and  sometimes  oedema  of  the  subcutaneous  tissues  of  the  neck.  Exam- 
ination of  the  blood  and  organs  for  bacteria  by  microscopic  and  cultural 
methods  produced  no  result.  At  this  time  it  was  my  custom,  when  start- 
ing on  the  study  of  a  new  disease,  to  make  a  careful  daily  examination 
of  the  blood  of  the  living  animal,  enumerating  the  number  of  the  red  and 
white  blood  corpuscles  and  estimating  the  percentage  of  the  various  varie- 
ties of  leukocytes.  After  a  few  days  of  this  blood  examination  it  was 
noted  that  there  was  sometimes  to  be  seen  a  peculiar  stained  body,  having 
something  of  the  appearance  of  an  artistic  dolphin,  lying  among  the  red 
blood  corpuscles.  It  must  be  remembered  that  the  trypanosomes  are 
usually  found  in  very  small  numbers  in  cattle,  so  that  it  is  only  after  a 
long  search  that  a  single  one  can  be  found.  It  was  thought  at  first  that 
this  small,  peculiarly  shaped  object  was  an  accidental  appearance  due 
to  the  stain,  but  thinking  that  if  the  body  was  a  parasite,  it  might  show 
motion,  several  specimens  of  fresh  blood  were  examined.  A  long  search 
was  rewarded  by  finding  a  very  active  body,  wriggling  and  twisting  about 
with  great  energy  and  dashing  in  and  out  among  the  red  blood  corpuscles. 
It  was  the  first  time  the  writer  had  seen  a  trypanosome,  and,  as  then  there 
was  little  or  no  literature  on  the  subject  of  these  parasites,  it  was  difiicult 
to  know  how  to  place  it.     It  seemed  that  it  must  be  a  filaria,  but  having 

'Rogers.  "The  transmission  of  the  Trypanosoma  evansi  by  horse-flies, 
and  other  experiments  pointing  to  the  probable  identity  of  Surra  of  India 
and  Nagana  or  Tsetse-fly  Disease  of  Africa."  Proc.  Roy.  Soc,  Vol.  LXVIII, 
March  14,  1901. 

^Bradford  and  Plimmer,  "The  Trypanosoma  Brucei,  the  Organism  found  in 
Nagana  or  Tsetse-fly  Disease,"  Quarterly  Journal  of  Microscopical  Science,  Vol. 
XLV,  1902. 


TRYPANOSOMIASIS  463 

compared  the  description  and  drawing  of  the  rat  trypanosome  in  Lewis's 
book/  with  my  parasite,  it  was  concluded  that  it  was  a  trypanosome. 
But  there  was  no  proof  that  the  parasite  was  the  cause  of  nagana;  it 
occurred  only  in  small  numbers  in  the  blood  of  the  cattle,  and  the  rat 
trypanosome  lives  as  a  harmless  guest  in  healthy  animals.  Therefore, 
the  blood  of  the  infected  cattle  was  inoculated  into  horses  and  dogs.^ 
The  disease  in  the  horse  and  dog  is  much  more  acute  than  in  the  ox. 
In  a  few  days  the  blood,  especially  of  the  dog,  was  found  to  be  teeming 
with  thousands  of  trypanosomes.  It,  therefore,  began  to  appear  probable 
that  this  parasite  might  be  the  cause  of  nagana.  At  that  time  there  was 
no  suspicion  that  this  disease  among  the  native  cattle,  occurring  in  kraals 
situated  many  miles  from  the  "Fly  country,"  was  the  same  disease  as 
that  known  to  travellers  as  the  tsetse-fly  disease.  The  work  at  this  time 
was  being  done  on  the  summit  of  a  mountain  called  Ubombo,  some 
2,000  feet  above  the  surrounding  low  country.  The  low  country  to  the 
east  of  the  mountain  was  known  to  be  infected  with  the  tsetse-fly,  and 
having  often  read,  in  Livingstone's  and  other  books  of  travel  and  hunting, 
about  this  disease,  it  was  determined  to  take  a  few  animals  into  this 
"Fly  country"  and  see  what  the  disease  was  like.  Two  young  oxen,  a 
horse,  and  several  dogs,  were  taken  into  the  heart  of  the  "  Fly  country." 
After  being  there  a  fortnight  the  animals  were  brought  back  to  the  top 
of  the  mountain  and  examined  in  the  usual  way;  their  temperature  taken, 
their  blood  examined,  and  any  symptoms  that  might  occur  noted.  It 
was  found  that  the  blood  of  these  animals  affected  with  the  tsetse-fly  dis- 
ease contained  the  same  parasite  as  that  found  in  nagana.  In  this  way, 
after  many  experiments  and  many  observations,  it  was  forced  upon  me 
that  the  two  diseases,  nagana  and  tsetse-fly,  were  one  and  the  same.  It 
is  a  characteristic  of  this  species  of  tsetse-fly,  Glossina  morsitans,  that  at 
rare  intervals,  probably  due  to  long  continued  drought,  it  overspreads  its 
usual  bounds  to  a  distance  sometimes  fifty  or  sixty  miles,  [and  so  sets 
up  an  epidemic  among  the  native  cattle  in  a  previously  healthy  district. 
This  was  the  case  in  1894;  the  disease  had  overspread  its  natural  bounds 
and  given  rise  to  a  wide  spreading  epidemic  among  the  cattle  to  a  distance 
of  sixty  miles. 

When  it  was  once  established  that  the  two  diseases  were  the  same,  experi- 
ments were  made  to  find  out  how  the  animals  became  infected,  whether 
the  fly  was  the  carrier  or  a  mere  concomitant  of  the  low  lying  unhealthy 
district,  and,  if  a  carrier,  if  it  was  the  only  carrier  of  the  disease  from  sick 
to  healthy  animals.  Horses  taken  down  into  the  "Fly  country,"  and  not 
allowed  to  feed  or  drink  there,  took  the  disease.  Bundles  of  grass  and 
supplies  of  water,  brought  from  the  most  deadly  parts  of  the  "Fly  coun- 
try" to  the  top  of  Ubombo  and  there  used  as  fodder  for  healthy  horses, 
failed  to  convey  the  disease.  Tsetse-flies,  caught  in  the  low  country 
and  kept  in  cages  on  the  top  of  the  mountain,  when  fed  on  affected  animals 
were  capable  of  giving  rise  to  the  disease  in  healthy  animals  up  to  forty- 

^  Lewis,  T.  B.,  Physiological  and  Pathological  Researches,  Published  by  Lewis 
Memorial  Committee,  1888. 

''Bruce,  D.,  Preliminary  Report  on  the  Tsetse-fly  Disease  or  Xagana  in  Zulu- 
land,  Durban,  Natal,  1895,  Further  Report,  Printed  for  the  Royal  Society 
by  Harrison  &  Sons,  London,  1896;  Appendix  to  Further  Report,  Harrison  & 
Sons,  1903. 


464  DISEASES  CAUSED  BY  PROTOZOA 

eight  hours  after  feeding.  Tsetse-fUes,  brought  up  from  the  low  country 
and  placed  straightway  upon  healthy  animals,  were  also  found  to  give  rise 
to  the  disease  The  flies  were  never  found  to  retain  the  power  of  infection 
for  more  than  forty-eight  hours  after  they  had  fed  upon  a  sick  animal,  so 
that  if  wild  tsetse-flies  were  brought  up  from  the  low  country,  kept  with- 
out food  for  three  days  and  then  fed  on  a  healthy  dog,  they  never  gave 
rise  to  the  disease.  ■  In  this  way  it  was  proved  that  the  tsetse-fly,  and  it 
alone,  was  the  carrier  of  nagana  Then  the  (juestion  arose  as  to  where  the 
tsetse-Hies  obtained  the  trypanosomes.  The  Hies  lived  among  the  wild 
animals,  such  as  buffaloes,  koodoos,  and  other  species  of  antelopes,  and, 
naturally,  fed  on  them.  It  seemed  that,  in  all  ])robability,  the  reservoir 
of  the  disease  Avas  to  be  found  in  the  wild  animals.  Therefore  all  the 
different  species  of  wild  animals  obtainable  were  examined  both  by  the 
injection  of  their  blood  into  healthy  susceptible  animals,  and  also  by 
direct  microscopic  examination  of  the  blood  itself.  In  this  way  it  was 
discoveretl  that  many  of  the  wild  animals  harbored  this  trypanosome  in 
their  blood.  The  ])arasites  were  never  numerous,  so  that  it  was  only  after 
a  long  search  that  they  could  be  discovered  by  the  microscope  alone.  The 
wild  animals  did  not  seem  to  be  affected  by  the  trypanosome  in  any  way; 
they  showed  no  signs  or  symptoms  of  the  disease,  and  it  therefore  ap- 
peared probable  that  the  trypanosomes  lived  in  their  blood  as  harmless 
guests,  just  as  the  trypanosome  of  the  rat  lives  in  the  blood  of  that  animal. 
The  flies  were  examined  at  various  times  after  feeding,  to  see  if  there  was 
any  kind  of  metamorphosis  taking  place  within  the  body  cavity.  But  no 
such  evidence  could  at  any  time  be  discovered.  The  trypanosomes  can 
be  found  alive  and  wriggling  vigorously  in  the  oesophagus  and  stomach  for 
about  five  days  after  feeding;  as  long,  in  fact,  as  the  smallest  quantity  of 
blood  remains  imdigested.  No  living  trypanosomes  are  ever  found  in  the 
intestines  or  dro})pings,  and  the  latter,  on  many  occasions  injected  into 
healthy  animals,  failed  in  every  instance  to  give  rise  to  the  disease.  The 
fly  then  can  only  be  regarded  as  a  mechanical  carrier  of  the  trypanosome 
and  not  as  the  specific  intermediate  host.  If  this  is  so  it  seems  strange  that 
the  tsetse-fly  should  be  the  only  carrier  of  the  disease.  That  this  is  so  is 
evident  from  the  fact  that  a  huge  experiment  to  prove  this  has  been  going 
on  in  nature  in  South  Africa  from  time  immemorial.  Here  and  there  are 
tracts  of  country  called  'Tly  belts."  They  are  called  "Fly  belts"  on  ac- 
count of  the  presence  of  the  tsetse-fly.  Outside  the  fly  zone  there  may 
be  a  tract  of  country  differing  little  in  physical  characters  from  "Fly 
country,"  where  many  species  of  biting  flies  abound,  but  no  tsetse. 
Here  the  wild  animals  carrying  the  trypanosome  in  their  blood  are  also 
found.  Horses  and  cattle  remain  quite  healthy  in  such  a  country,  consort- 
ing with  wildebeeste  and  other  antelope,  and  constantly  exposed  to  the  bites 
of  tabanidiie,  stomoxys,  and  other  biting  flies.  During  a  stay  of  two  years 
on  the  top  of  the  Ubombo,  within  an  hour's  march  of  the  "Fly  coimtry," 
although  healthy  animals  lived  side  by  side  with  those  affected  with 
nagana,  not  a  single  case  of  natural  infection  took  place,  albeit  there  were 
many  ordinary  biting  flies  about.  On  the  other  hand,  if  a  horse  or  dog 
was  taken  into  a  "Fly  belt,"  even  for  a  few  hours,  it  almost  certainly  be- 
came infected.  It  seems  then  to  be  a  fact  almost  beyond  suspicion  that 
the  disease  known  as  nagana  or  the  tsetse-fly  disease  is  carried  by  Glossina 
and  by  no  other  genus  of  biting  flies  in  Africa,    It  is  strange  that  some 


TRYPANOSOMIASIS  465 

phenomenon  similar  to  this  should  not  have  been  brought  out  in  regard 
to  the  Indian  trypanosome  disease.  It  is  evident  that  surra  has  a  peculiar 
distribution,  and  it  seems  probable  that  this  will  be  found  to  depend 
upon  the  distribution  of  some  species  or  genus  of  biting  insect. 

Nagana  affects  a  large  variety  of  species  of  animals.  With  the  excep- 
tion of  the  baboon,  it  is  fatal  to  monkeys,  horses,  i  lulco,  donkeys,  cattle, 
dogs,  cats,  rabbits,  guinea-pigs,  rats,  mice,  and  other  animals.  It  is  a 
peculiar  circumstance  that  man  is  one  of  the  few  animals  immune  to  this 
disease.  No  case  has  yet  been  recorded  of  the  occurrence  of  nagana  in 
man,  either  among  the  natives  living  in  the  "Fly  country,"  or  in  Euro- 
peans who  live  or  go  into  the  "Fly  country"  in  search  of  game.  Nagana 
has  probably  been  studied  more  than  any  other  trypanosome  disease,  due 
to  the  writer  having  sent  to  England,  in  1898,  dogs  with  the  trypanosomes 
in  their  blood.  Descendants  of  these  trypanosomes  have  found  their  way 
to  many  laboratories,  even  in  America. 


TRYPANOSOMA  GAMBIENSE.    HUMAN  TRYPANOSOMIASIS. 
SLEEPING  SICKNESS. 

Historical. — ^The  Trypanosoma  Gamhiense  was  first  described  by  the 
late  Dr.  J.  E.  Dutton.  The  parasites  occurred  in  the  blood  of  an  English- 
man who  had  been  employed  for  six  years  as  master  of  a  government  boat 
plying  on  the  Gambia  River,  West  Africa.  He  was  admitted  into  the  hos- 
pital, at  Bathurst,  on  the  10th  of  May,  1901,  under  the  care  of  Dr.  R.  M. 
Forde,  Colonial  Surgeon/  Dr.  Forde  examined  his  blood  and  saw 
actively  moving  worm -like  bodies,  which  he  was  unable  to  identify;  he, 
therefore,  asked  Dr.  Dutton  to  assist  him  in  the  diagnosis.  In  the  mean- 
time, the  patient  had  been  invalided  to  England,  where  he  was  for  some 
time  under  treatment  in  a  hospital  in  Liverpool.  He  returned  to  Bathurst 
in  December,  1901,  and  on  the  15th,  Dr.  Dutton  examined  his  blood  and 
saw  the  trypanosome,  which  he  described  and  named. ^  At  this  time  no 
suspicion  existed  that  the  so-called  trypanosoma  fever  or  Gambia  fever 
had  any  relation  to  sleeping  sickness.  This  discovery  of  trypanosomes  in 
the  blood  of  man  awakened  a  great  deal  of  interest,  and  Dr.  Dutton, 
accompanied  by  Dr.  J.  L.  Todd,  was  sent  out  to  Senegambia  to  make 
further  investigations.  They  arrived  at  Bathurst  on  the  2nd  of  September, 
1902,  and  remained  on  the  West  Coast  for  nearly  a  year  They  examined 
1,043  natives  in  the  Gambia,  and  found  the  parasite  in  6  cases  only. 
They  sum  up  their  report  by  saying  that,  taking  all  the  facts  into  con- 
sideration, they  believe  the  disease,  as  it  occurs  in  natives,  to  be  a  pecul- 
iarly mild  one,  and  that  it  is  at  present  impossible  to  recognize  it  clinically, 
and  they  suggest  the  possibility  that  the  natives  in  this  disease  may  bear 
the  same  relation  to  the  Europeans  as  does  the  wild  game  of  Central 
Africa  to  domestic  animals  in  the  tsetse-fly  disease.^ 

^  Forde,  R.  M.,  The  Journal  of  Tropical  Medicine,  September  1,  1902. 

^Dutton,  J.  E.,  "Trypanosome  Occurring  in  the  Blood  of  Man,"  Thompson- 
Yates  Laboratory  Reports,  Vol.  IV,  pt.  II,    1902. 

^Button  and  Todd,  First  Report  of  the  Expedition  to  Senegambia,  JjiwerTpool 
School  of  Tropical  Medicine,  Memoir  XI,  1902. 
30 


466  DISEASES  CAUSED  BY  PROTOZOA 

In  the  beginning  of  1903,  Dr.  C.  J.  Baker^  noted  the  presence  of  try- 
panosomes  in  throe  cases  in  the  blood  of  man  in  Entebbe,  Uganda. 
Shortly  before  this  Dr.  Castellani,^  a  member  of  the  Commission  sent 
out  to  Uganda  by  the  Royal  Society,  London,  for  the  purjiose  of  investi- 
gating sleeping  sickness,  had  observed  these  ha^niatozoa  in  the  cerebro- 
spinal fluid  of  5  cases  of  sleeping  sickness,  and  in  1  of  these  he  had 
also  seen  them  in  the  blood.  This  was  the  first  time  try{>anosomes  had 
been  seen  in  the  blood  of  recognized  cases  of  sleeping  sickness.  When 
the  writer  arrived  in  Uganda,  on  March  16,  1903,  for  the  purpose  of  con- 
tinuing the  investigation  of  this  disease,  Castellani  described  his  findings, 
and,  as  was  to  be  ex])ected  after  the  work  on  nagana,  the  observation 
was  very  strildng,  Castellani,  who  intended  to  leave  immediately  for 
England,  consented  to  stay  a  week  or  two  longer,  in  order  that  we  might, 
pursue  this  particular  point.  He  remained  in  Entebbe  for  three  weeks, 
and  during  this  time  we  examined  22  cases  of  sleeping  sickness  and  found 
the  trypanosomcs  in  15,  about  70  per  cent. 

From  this  time  the  history  of  the  Tri/panosoma  Gamhiense  is  merged  in 
that  of  sleeping  sickness  and  most  writers  are  now  agreed  that  in  all  pro- 
bability the  so-called  trypanosoma  fever  or  Gambia  fever  is  merely  the 
first,  and  sleeping  sickness  the  last  stage  of  human  trypanosomiasis. 
This,  however,  being  still  a  matter  of  dispute,  will  be  discussed  more  fully 
later  on. 

This  then  is  a  short  account  of  the  Trypanosoma  Gamhiense  from  its 
discovery  as  a  supposed  harmless  parasite  in  the  blood  of  natives  on  the 
Gambia,  to  its  aj^otheosis  as  the  cause  of  the  terribly  fatal  sleeping  sickness. 

Human  Trypanosomiasis  or  Sleeping  Sickness. — The  history  of 
■  the  disease  itself  may  be  given  in  a  few  words.  Human  trypanosomiasis  or 
sleeping  sickness  has  been  known  for  more  than  a  hundred  years  on  the 
West  Coast  of  Africa,  and  has  attracted  a  good  deal  of  interest  and 
curiosity  on  account  of  the  peculiar  symptoms  of  lethargy  which  developed 
and  which  gave  rise  to  the  name  of  sleeping  sickness.  The  disease,  al- 
though of  an  apparently  infectious  nature  in  its  native  haunts,  was  found 
to  lose  its  power  of  spreading  from  man  to  man  upon  removal  to  a  non- 
endemic  area.  Thus  much  interest  was  raised  by  the  fact  that  slaves 
introduced  to  other  countries  from  the  West  Coast  often  died  of  sleeping 
sickness,  but  the  disease  never  spread  to  their  neighbors — never  became 
endemic.  Different  theories  w^ere  held  as  to  its  causation,  some  holding  it 
to  be  a  food  intoxication,  others  blaming  various  kinds  of  bacteria.  As  an 
upholder  of  the  former  Ziemann^  may  be  cited ;  of  the  latter,  Battencourt* 
and  Castellani.^  Another  theory  w^iich  seemed  plausible  was  that  the 
disease  Avas  caused  by  Filaria  perstans  and  found  its  advocate  in  Sir 
Patrick  Manson.®  All  these  speculations  have  been  proved  to  be  un- 
founded, by  the  discovery  that  the  causal  agent  in  this  disease  is  really 
the  Trypanosoma  Gamhiense. 

*  Baker,  C.  J.,  "Three  cases  of  Trypanosoma  in  Man  in  Entebbe,  Uganda." 
British  Medical  Journal,  May  30,  1903,  p.  1245. 

^Castellani,  "Presence  of  Trypanosoma  in  Sleeping  Sickness,"  Royal  Society, 
Reports  of  the  Sleeping  Sickness  Commission,  1903.  Harrison  &  Sons,  London. 

^Ziemann,  H.,  Centralblatt  j.  Balder,  Orig.  Vol.  XXXII,  1903. 

*Battencourt,  A.,  Doenca  do  Somno,  Lisbonne,  1901. 

^Castellani,  A.,  British  Medical  Journal,  March  14,  1903, 

^Manson,  P.,  Tropical  Diseases,  3d  Edition,  1903- 


TRYPANOSOMIASIS  467 

Etiology, — Geographical  Distribution, — Human  trypanosomiasis  has 
been  known  foi  the  last  hundred  years  on  the  West  Coast  of  Africa,  and 
the  disease  may  be  said  to  extend  from  the  River  Gambia  to  the  River 
Congo.  At  the  present  time  it  does  not  seem  to  be  a  common  disease  on 
the  Gambia.  Dr.  Forde,  the  Principal  Medical  Officer  at  Bathurst, 
reports  that,  on  an  average,  he  only  sees  about  one  case  a  year,  and  only 
6  out  of  1,043  natives  showed  trypanosonies  in  their  blood  at  Leopold- 
ville.  On  the  Congo,  of  1,172  natives,  103  were  afi'ected.  These  included 
healthy  laborers,  prisoners,  out-patients  and  patients  in  hospital.  Out  of 
the  103  cases,  57  were  recognized  as  sleeping  sickness.  These  natives  were 
examined  for  trypanosonies  by  microscopic  examination  of  a  drop  of 
blood  from  the  finger-tip.  If  we  had  examined  the  apparently  healthy 
natives  in  this  way  in  Uganda  probably  not  more  than  1  or  2  would  have 
been  detected.  It  is  therefore  probable  that  if  a  more  thorough  examina- 
tion of  the  blood  had  been  made  on  the  Congo  a  larger  percentage  of 
cases  would  have  been  found. 

If  a  map  of  Africa  be  examined  it  will  be  seen  that  the  basin  of  the 
Congo  extends  more  than  half  across  the  continent,  and  that  one  of  the 
tributary  rivers,  the  Aruwimi,  rises  near  Lake  Albert  in  the  northwest  of 
the  Uganda  Protectorate.  At  present,  the  distribution  of  the  disease  has 
not  been  mapped  out  completely  in  the  Congo  State,  but  when  it  is, 
undoubtedly  it  will  be  found  to  extend  far  inland.  It  is  therefore  not  to  be 
wondered  at  that  the  disease  has  crept  still  further  eastward  and  invaded 
Uganda  It  first  broke  out  in  that  part  of  the  country  lying  to  the  north- 
east of  the  great  lake,  Victoria  Nyanza,  called  Usoga.  Dr.  Moffat,  the 
Principal  Medical  Officer  in  Uganda,  is  of  opinion  that  the  disease  was 
introduced  when  Emin  Pasha's  Soudanese,  with  their  wives  and  fol- 
lowers, numbering  some  ten  thousand,  were  brought  into  and  settled  in 
Usoga.  These  natives  were  brought  from  the  edge  of  the  Congo  territory, 
where  in  all  probability  sleeping  sickness  was  endemic.  It  seems,  then, 
quite  probable  that  some  of  these  natives  introduced  the  disease  into 
Usoga.  Be  that  as  it  may,  the  sleeping  sickness  broke  out  in  that  part  of 
the  country,  according  to  Dr.  Hodges,  about  the  year  1896.  It  was  not  re- 
cognized, however,  till  1901,  when  the  cases  became  numerous.-  That 
this  introduction  of  sleeping  sickness  from  the  Congo  to  Uganda  should 
have  taken  place  in  recent  years  should  be  no  matter  for  surprise.  As 
Moffat  remarks,  the  recent  opening  up  of  Equatorial  Africa  has  led  to 
inter-communication  between  countries  and  districts,  which,  in  earlier 
days,  were  absolutely  cut  off  from  each  other.  Civilization  gives  the 
natives  of  Uganda  peace,  and  at  the  same  time  introduces  a  disease^ 
which,  during  the  last  three  years,  has  killed  off  a  hundred  thousand  of 
the  population. 

Race. — ^For  a  long  time  it  was  considered  that  this  disease  was  confined 
to  negroes.  Unhappily,  this  is  not  so;  several  Europeans  have  now 
succumbed  to  the  disease,  as  well  as  the  natives  of  Persia  and  India. 
Christy  states  that  the  Nubian  police  in  Uganda  are  practically  immune, 
but  this  is  obviously  an  error  as  several  of  these  men  were  affected  and 
under  our  observation  in  Entebbe. 

Occupation. — ^Whatever  occupation  leads  a  native  to  spend  much  time 
on  the  wooded  shores  of  Victoria  Nyanza  or  any  river  or  lake  -R^tliin  the 
sleeping  sickness  area,  is  dangerous.    Hence,  fishermen,  canoe-men  and 


468  DISEASES  CAUSED  BY  PROTOZOA 

the  inhal)itant.s  generally  of  the  lake  shore  are  prone  to  suffer.  These 
people  are  half  naked  and  spenil  nuieh  of  their  time  trading  and  gossiping 
on  the  shore,  30  to  SO  per  cent,  of  them  harboring  the  trypanosomes  in 
their  blood,  and  being  constantly  bitten  by  nnmerous  tsetse-flies.  Sex, 
age,  food,  health  or  ill-health,  have  naturally  no  effect;  if  the  trypanosome 
is  introduced  under  the  skin  of  the  youngest  or  the  healthiest  there  is  no 
reason  to  believe  that  it  does  not  take  root  and  multiply. 

Monthfi  and  Seasons. — As  the  climate  in  Central  Africa  is  much  the 
same  all  the  year  round  it  does  not  appear  that  the  disease  is  more  prev- 
alent at  one  season  than  at  another 

Dcscripiion  of  the  Causal  Agent — tJte  Trypanosoma  Gamhiense. — ^When 
the  blooil  of  a  man  suffering  from  human  trypanosomiasis  or  slec])ing 
sickness  is  examined  microscopically,  a  minute,  wriggling,  worm-like 
parasite  may  sometimes  be  seen  among  the  red  blood  corpuscles.  It 
must  not  be  supposed  that  a  casual  examination  of  the  blood  is  all  that  is 
required  to  demonstrate  this  body  An  ordinary  blood  preparation, 
taken  from  the  ear  or  finger,  would,  in  all  probability,  not  show  this  para- 
site once  in  fifty  times.  As  a  rule  the  trypanosomes  are  so  scanty  in  the 
peripheral  blood  that,  in  order  to  demonstrate  them  in  every  case,  a 
quantity  of  blood  must  be  examined.  In  Uganda  we  examined  many 
cases  of  sleeping  sickness  and  found  the  trypanosomes  in  the  peripheral 
blood  of  all  but  one.  At  that  time  we  had  five  workers  and  five  micro- 
scopes. Ten  cubic  centimeters  of  blood  were  drawn  off  from  a  vein  of  the 
arm;  this  was  run  into  test-tubes  containing  a  small  quantity  of  citrate  of 
soda  solution  in  order  to  prevent  coagulation;  the  blood  was  then 
centrifugalized  for  a  quarter  of  an  hour,  to  throw  out  the  red  blood  cor- 
puscles; the  clear  liquid  was  pipetted  off  and  again  centrifugalized  for  a 
quarter  of  an  hour.  Specimens  were  taken  from  the  surface  of  the  red 
blood  corpuscles  and  examined  by  the  five  workers.  As  soon  as  the 
moderately  clear  fluid  had  been  subjected  to  the  fifteen  minutes'  centri- 
fuging,  it  was  poured  off,  leaving  a  small  quantity  of  sediment  behind. 
This  sediment  was  again  made  into  five  specimens  and  examined  micro- 
scopically. The  clear,  supernatant  fluid  was  for  the  third  time  centrifu- 
galized and  the  resulting  small  quantity  of  sediment  again  examined.  As 
a  rule,  it  was  in  the  sediment  obtained  from  the  third  process  that  we 
found  the  trypanosomes  most  frecjuently.  It  will  be  seen  then  that  five 
microscopes  were  employed  and  frequently  fifteen  preparations  would  be 
examined  before  a  parasite  was  discovered.  In  the  specimens  made 
from  the  first  two  preparations  there  are  too  many  red  blood  corpuscles 
to  give  a  good  view ;  it  is  only  in  the  third,  or  perhaps  not  till  the  fourth, 
that  the  red  blood  corpuscles  have  been  so  completely  removed  as  to 
leave  a  clear  fluid  only  containing  a  few  white  blood  corpuscles;  in 
this  fluid  the  active,  living  trypanosome  is  readily  picked  out  under  a  low 
power. 

The  best  method  of  bringing  out  the  various  details  in  the  trypanosome 
is  by  the  use  of  one  of  the  many  Romanowsky  staining  methods.  The 
method  we  used  in  Uganda  was  that  known  by  the  name  of  Leishman's 
stain.  This  is  an  exceedingly  simple  stain  to  use  and  good  results  are 
invariably  obtained  with  little  trouble.  The  following  is  a  description  of 
the  method,  in  Leishman's  own  words,  "I  need  not  recapitulate  the  some- 
what complicated  method  by  which  the  solid  stain  is  prepared,  as  those 


TRYPANOSOMIASIS  469 

who  wish  may  refer  to  my  original  communication;^  but  there  are 
several  points  in  the  preparation  of  the  solution  which  are  of  importance 
to  those  who  have  to  make  this  up  for  thcjuselves.  The  solvent  for  the 
powdered  stain  is  methyl  alcohol  and  it  is  of  the  first  importance  that  the 
right  quality  of  methyl  alcohol  should  be  used  for  the  purpose;  namely, 
Merck's  methyl  alcohol  ('pro  analysi,  acetone  free').  Good  results  are 
not  to  be  expected  if  less  pure  varieties  are  employed.  The  powdered 
stain  is  dissolved  in  this  alcohol  in  the  proportion  of  0.15  per  cent.,  and 
the  following  details  must  be  observed  in  preparing  the  solution  in  order 
to  obtain  its  maximum  staining  power.  The  powder  should  be  ground  in 
a  clean  mortar  as  finely  as  possible  and  the  proper  proportion  of  methyl 
alcohol  measured  into  a  convenient  vessel;  a  little  of  the  alcohol  is  then 
poured  into  the  mortar,  and  the  grinding  continued  for  some  time.  After 
a  few  minutes'  rest,  to  allow  the  undissolved  particles  to  sink  to  the  bot- 
tom, the  upper  part  of  the  fluid  is  poured  into  a  clean  bottle,  a  fresh  supply 
of  the  alcohol  is  added  and  again  rubbed  up  with  the  remains  of  the 
powder.  This  process  is  repeated  until  the  whole  of  the  finely  divided 
powder  is  in  this  way  dissolved  in  the  proper  quantity  of  solvent.  This 
procedure  is  rendered  necessary  by  the  slight  solubility  of  the  powder — 
.15  per  cent  being  nearly  a  saturated  solution — and,  if  not  carried  out, 
or  if  filtration  through  filter  paper  is  employed,  the  resulting  solution  will 
be  unduly  weak  and  the  results  obtained  with  it  inferior." 

"Thin,  even  films  of  blood  are  made  upon  perfectly  clean  coverglasses 
or  slides  and  are  allowed  to  dry  in  the  air  or  by  gentle  heat.  A  few  drops 
of  the  stain  are  poured  upon  the  unfixed  film  and  allowed  to  act  for  fifteen 
to  thirty  seconds,  by  which  time  the  film  will  be  fixed  by  the  methyl 
alcohol — previous  fixation  by  most  of  the  methods  in  general  use  will 
prevent  chromatin  staining.  Only  enough  stain  should  be  used  to  cover 
the  film  with  a  shallow  layer,  and  care  must  be  taken  by  moving  the  slide 
or  coverglass  to  prevent  the  stain  drying  upon  any  part  of  the  film.  At 
the  end  of  this  time  double  the  quantity  of  distilled  water — not  more — is 
added  to  the  stain,  and  the  water  and  the  alcoholic  stain  are  at  once 
thoroughly  mixed  by  shaking,  or  with  the  help  of  a  needle  held  parallel  to 
the  surface  of  the  glass  and  passed  backward  and  forward  through  the 
fluid.  When  the  stain  is  thoroughly  mixed  with  the  water  the  mixture  is 
left  on  the  film  for  five  minutes,  by  which  time  an  iridescent  scum  will 
have  formed  on  the  surface  and  a  fine  flocculent  precipitate  will  be  seen  to 
have  formed.  This  period  of  five  minutes  is  ample  for  all  ordinary  blood 
work,  such  as  leukocytic  counts  and  the  demonstration  of  malaria  para- 
sites, and  the  stain  must  now  be  gently  washed  off  by  pouring  on  the 
film  a  little  distilled  water.  When  ail  the  precipitate  and  stain  is  washed 
away  a  little  of  the  water  is  allowed  to  rest  on  the  film  for  half  a  minute,  as 
this  intensifies  the  brightness  of  the  color-contrasts  of  the  various  cells, 
and  advantage  may  be  taken  of  this  moment  to  glance  at  the  film  with  the 
one-sixth  inch  lens  to  make  sure  that  the  Romanowsky  staining  is  deep 
enough.  The  dense  nuclei  of  the  polynuclears  or  lymphocytes  form  the 
best  index  of  the  depth  of  staining,  and  should  appear  of  a  deep  purplish- 
red  or  ruby  color.    If  these  are  seen  to  be  too  light  in  tint,  as  may  happen 

^Leishman,  Major  W.B.,R.  A.M. C,  British  Medical  Journal,  September  21. 
1902. 


470  DISEASES  CAUSED  BY  PROTOZOA 

with  old  or  bad  films,  the  stain  may  be  rc-applicd  as  before  until  the 
proper  density  of  nuclear  staining  is  attained." 

"Stain  trypanosomes  for  ten  to  fifteen  minutes,  controlling  the  depth  of 
staining  by  examination  under  a  low  power  while  the  film  is  soaking  in 
water.  To  bring  out  all  tiie  details  of  their  structure  rather  deep  staining 
is  necessary,  and  the  film  may  be  allowed  to  soak  in  water  for  a  little 
longer  than  usual.  When  treated  thus,  the  macronucleus  appears  red, 
the  micronucleus  black,  the  fiagellum  red,  and  the  basophile  granules 
black,  while  the  protoplasm  of  the  parasite  is  colored  blue." 

Fia,  31. 


Fig.  31  represents  the  trypanosomes  in  the  blood  of  sleeping  sickness 
cases,  magnified  2,000  diameters,  and  shows  the  macronucleus  in  the 
centre  of  the  body,  the  micronucleus  at  the  posterior  end;  the  flagellum 
taking  its  origin  from  the  micronucleus  and,  running  along  the  margin  of 
the  undulating  membrane,  becomes  free  at  the  anterior  extremity.  A 
large  vacuole  is  seen  near  the  micronucleus  and  dots  of  chromatin  are 
scattered  through  the  protoplasm.  Some  writers  profess  to  be  able  to 
recognize  the  various  species  of  trypanosomes  by  their  shape  and  general 
appearance.  In  this  way  Plimmer  makes  out  that  the  trypanosome 
found  in  Gambia  fever,  or  human  trypanosomiasis,  is  different  from  that 
found  in  sleeping  sickness.  Without  being  too  dogmatic  on  this  point, 
the  writer's  opinion  is  that  it  must  be  very  difficult  to  distinguish  between 
such  trypanosomes  as  T.  evansi,  T.  brucei,  and  T.  gambiense  by  micro- 
scopic examination  alone.  Koch,  on  the  other  hand,  refuses  to  recog- 
nize more  than  one  or  two  species  and  would  group  most  of  the 
trypanosomes  under  one  specific  name. 


TRYPANOSOMIASIS  471 

To  Find  the  Trypanosomes  in  the  Cerebrospinal  Fluid. — In  the  earlier 
stages  of  human  trypanosomiasis,  the  trypanosomes  are  seldom,  if  ever, 
found  in  the  cerebrospinal  fluid.  It  is  only  when  the  symptoms  of 
sleeping  sickness  have  appeared  that  they  are  found  with  any  frequency. 
In  Uganda  we  examined  40  cases  of  sleeping  sickness  by  drawing  off  a 
small  quantity  of  cerebrospinal  fluid  and  found  the  trypanosomes  in 
every  case.  In  all  the  cases  the  patient  v/as  chloroformed  as  the  operation 
done  without  an  anaesthetic  gives  rise,  evidently,  to  a  good  deal  of  pain,  and 
the  native  of  Uganda  was  extremely  nervous  and  easily  frightened.  They 
take  chloroform  very  easily.  Ten  to  fifteen  cubic  centimeters  of  the  cerebro- 
spinal fluid  are  allowed  to  flow  into  a  test-tube.  It  is  needless  to  say  that 
if  any  blood  escapes  with  the  cerebrospinal  fluid  the  specimen  ought  to 
be  rejected.  The  clear,  transparent,  water-like  fluid  is  then  centrifuged 
for  twenty  minutes  to  half  an  hour,  and  the  sediment  examined  in  the 
usual  way  under  a  low  power.  As  might  be  expected,  the  trypanosomes 
are  seen  very  readily  in  the  fields  of  the  microscope,  there  being  no  red 
blood  corpuscles  and  few  cells  of  any  kind. 

The  Trypanosomes  Found  in  Enlarged  Lymphatic  Glands. — One  of 
the  earliest  manifestations  of  this  disease  is  an  enlargement  of  the  lymph- 
atic glands.  It  is  quite  true  that  among  natives  going  about  constantly 
with  bare  feet,  and  their  naked  limbs  exposed  to  scratches  and  wounds  of 
every  description,  it  is  the  rule  and  not  the  exception  for  them  to  have  en- 
larged femoral  glands.  But  in  human  trypanosomiasis  all  the  glands  are 
enlarged — the  cervical,  axillary,  inguinal,  femoral,  etc.  Captain  Greig, 
Indian  Medical  Service,  and  Lieutenant  Gray,  Royal  Army  Medical 
Corps,  made  the  important  observation  that  the  trypanosomes  can  be 
demonstrated  with  great  ease  in  the  swollen  lymphatic  glands,  where 
they  seem  to  be  in  much  greater  numbers  than  in  the  blood  or  the  cerebro- 
spinal fluid.  Greig  found  that  it  was  only  necessary  to  draw  off  a  drop  of 
fluid  by  means  of  a  small  hypodermic  syringe  from  one  of  the  swollen 
cervical  glands  and  to  place  this  fluid  under  the  microscope  to  find  the 
trypanosomes  at  once  or  in  a  comparatively  short  time.  This  is  a  great 
advance  on  the  older  methods  of  examining  the  blood  and  cerebrospinal 
fluid.  It  is  no  exaggeration  to  say  that  it  took  on  an  average  an  hour  to 
find  the  trypanosomes  in  the  blood  of  a  patient,  even  when  there  were  five 
microscopes  employed.  Now,  it  appears  from  Greig's  report  that  the 
cervical  lymphatic  glands  can  be  examined  and  the  trypanosomes  found 
with  great  ease  in  a  few  minutes. 

In  What  Tissues  of  the  Body  can  the  Trypanosoma  Gambiense  he 
Found? — It  seems  that  when  the  trypanosome  is  injected  under  the  skin 
it  makes  its  way  by  the  lymphatic  channels  and  is  evidently  at  first 
blocked  in  the  lymphatic  glands;  this  causes  the  swelling  of  the  glands, 
and,  as  mentioned  above,  the  trypanosomes  are  found  in  much  greater 
numbers  in  the  juice  of  these  glands  than  in  any  other  of  the  fluids  of 
the  body.  From  the  glands  they  evidently  pass  in  small  numbers  into 
the  general  circulation,  and  with  it  to  every  part  of  the  body.  The  liv- 
ing trypanosomes  are  never  found  in  any  of  the  cells  of  the  tissues  but 
are  restricted  to  the  fluids.  There  can  be  no  doubt  that  in  the  first  stages 
of  the  disease  the  trypanosomes  are  not  found  in  the  cerebrospinal  fluid. 
In  an  examination  of  many  apparently  healthy  natives  who  had  trypano- 
somes in  their  blood,  trypanosomes  were  not  found  in  a  single  case  by 


472  DISEASES  CAUSED  BY  PROTOZOA 

lumbar  puncture.  In  the  later  stage,  however,  when  the  symptoms  of 
sleeping  sickness  su})ervene,  the  trypanosomes  can  as  a  rule  be  readily 
fountl  in  every  case  of  the  disease  in  the  cerebros{)inal  fluid. 

Mode  of  Re  product  ion  of  the  Trypanosoma  Gamhiense. — As  far  as  is 
known  up  to  the  present  this  trypauosome  only  reproduces  itself  within 
the  human  organism  by  longitudinal  division.  Other  modes  of  repro- 
duction have  been  describetl  jjy  various  authors,  but  these  at  the  present 
time  are  not  sufficiently  definite  to  warrant  acceptance.  There  can  be 
no  doubt  that  the  number  of  trypanosomes  varies  greatly  from  time  to 
time  in  the  blood  and  fluids.  Huge  numbers  of  them  must  perish  at  times 
and  their  dead  bodies  become  dissolved  in  the  blood  plasma.  It  is  sup- 
posed by  some  that  these  dead  trypanosomes  contain  a  snuxll  quantity  of 
toxin  which  is  thus  set  free  in  the  blood  and  gives  rise  to  the  proliferation 
of  the  lymphatic  elements,  and  to  the  chronic  conditions  afterwards  found 
in  the  brain  and  tissues. 

Life  History  of  Trypanosoma  Gamhiense  outside  the  Body. — It  is 
evident  that  as  the  Trypanosoma  Gamhiense  is  only  found  in  the  blood  and 
lymphatic  fluids  of  the  body,  it  can  only  leave  the  body  on  the  escape  of 
these  fluids.  There  is  no  evidence  that  the  trypauosome  escapes  from 
the  body  by  the  intestinal  or  urinary  tracts,  or  by  the  sweat,  salivary  or 
other  secretions.  When  an  animal  dies  of  the  disease  all  the  parasites 
disappear  rapidly  from  the  tissues  on  account  of  commencing  putrefaction. 
If  blood  is  drawn  off  during  life  and  kept  aseptic  it  only  retains  its  viru- 
lence for  four  days.  Blood  dried  on  threads  sometimes  retains  its  infec- 
tivity  for  twenty-four  hours;  at  the  end  of  forty-eight  hours  it  is  inert. 
If  exposed  to  a  temperature  of  40°  to  44°  C.  it  is  slowly  killed;  45°  C.  is 
rapidly  fatal.  The  curious  observation  has  been  made  that  trypanosomes, 
like  some  bacteria,  can  be  frozen  at  the  temperature  of  liquid  air  (-191°  C.) 
for  a  quarter  of  an  hour  and  still  retain  th-ir  vitality.  There  is,  therefore, 
no  evidence  that  the  trypauosome  is  capable  of  retaining  its  vitality  in 
external  nature  under  natural  conditions  for  more  than  a  few  h  urs.  Under 
artificial  conditions,  however,  Novy  and  IMacNeaP  did  a  remarkable 
feat  in  growing  various  trypanosomes  on  artificial  media.  The  culture 
medium  they  used  was  rdinary  nutrient  agar  t  which  had  been  added 
defibrinated  rabbit's  blood.  They  first  succeeded  in  growing  the  rat 
trypauosome  in  1903.  Later  in  the  same  year  they  also  succeeded  in  cul- 
tivating Trypanosoma  Brucei  outside  the  body.  These  cultures  are,  how- 
ever, by  no  means  so  readily  obtained  as  in  the  case  of  the  rat  trypauosome. 
In  this  way  Trypanosoma  Brucei  has  been  grown  artificially  through 
twenty-three  generations,  and,  so  far  as  the  writer  knows,  is  still  being 
grown.  Up  to  the  present  no  one  has  succeeded  in  the  artificial  cultivation 
of  Trypanosoma  Gamhiense,  but  this  will  probably  be  a  question  of  time. 
It  is  to  be  ho]:)cd  that  the  cultivation  of  the  various  trypanosomes  will  assist 
in  the  identification  of  species  as  at  present  their  classification  is  rapidly 

'  MacNeal,  "  The  life  history  of  Trypanosoma  Lewisi  and  Trypanosoma  Brucei," 
Journal  of  Infectious  Diseases,  Vol.  I,  No.  4,  November  5,  1904,  pp.  517-543, 
Novy  and  MacNeal,  "The  cultivation  of  Trypanosoma  Brucei,"  Journal  of  the 
American  Medical  Association,  November  21,  1903.  Journal  of  Infectious  Dis- 
eases, Vol.  I,  No.  1,  .January,  1904,  p.  1;  MacNeal,  "An  improved  medium  for 
cultivating  Trypanosoma  Brucei,"  Sixth  Annual  Report  of  The  Michigan  Academy 
of  Science. 


TRYPANOSOMIASIS  473 

becoming  chaotic.  But  to  return  to  the  question  of  how  the  trypanosomes 
can  leave  the  body  of  the  host.  The  common  way  in  nature  is  by  the 
agency  of  biting  flies.  It  will  be  interesting  then  to  trace  the  history  of  the 
trypanosome  in  the  interior  of  one  of  these  flies — the  tsetse-fly.  A  priori 
one  would  think  that  the  trypanosomes  on  being  taken  into  the  stomach 
of  the  tsetse-fly  would  soon  perish^  on  account  of  the  processes  of  digestion 
going  on.  The  result  of  observation,  however,  shows  that  the  follow- 
ing are  the  facts  as  far  as  have  been  ascertained:  Immediately  after  feed- 
ing, the  tube  of  the  proboscis  can  be  seen  to  be  crammed  full  of  red  blood 
corpuscles,  among  which  the  trypanosomes  can  be  seen  actively  wriggling. 
Up  to  forty-six  hours  one  can  see  living  trypanosomes  and  red  blood  cor- 
puscles in  the  proboscis.  After  one  hundred  and  eighteen  hours  the  para- 
sites are  still  numerous  and  actively  moving  about  in  what  remains  of  the 
blood  in  the  stomach.  After  one  hundred  and  forty  hours  the  stomach  is 
empty  and  no  appearance  of  trypanosomes  can  be  seen.  Motionless, 
apparently  dead,  trypanosomes  are  sometimes  seen  in  the  contents  of  the 
lower  intestine,  but  the  result  of  the  injection  of  the  droppings  into  sus- 
ceptible animals  always  remained  negative.  There  was  never  any  sign 
that  the  trypanosomes  undergo  any  metamorphosis  in  the  stomach  of  the 
fly,  such  as  occur  in  malaria.  In  regard  to  this  life  of  the  trypanosome  in 
the  stomach  of  the  tsetse-fly,  there  is  some  evidence  that  multiplication 
may  take  place,  as  division  forms  are  seen.  In  the  opinion  of  the  writer, 
if  this  takes  place,  it  can  only  be  to  a  slight  extent,  and  it  seems  more  reason- 
able to  believe  that  no  such  multiplication  takes  place.  It  seems  strange 
that  although  the  trypanosome  remains  actively  alive  for  some  five 
days  in  the  fly,  we  have  never  been  able  to  infect  an  animal  by  means  of 
the  bite  of  the  fly  for  a  longer  period  than  two  days  after  feeding.  This 
may  be  due  to  the  fact  that  the  trypanosome  rapidly  loses  its  virulence 
in  vitro,  and  it  is  probable  that  this  also  takes  place  in  the  interior  of 
the  fly. 

How  does  the  Trypanosoma  Gambiense  Gain  Entrance  to  the  Human 
Organism? — It  is  difficult  to  imagine  that  a  deUcate  blood  parasite,  in^ 
capable  of  living  for  any  length  of  time  outside  the  body,  can  pass  from 
man  to  man  in  food,  water,  or  dust,  as  so  many  other  infectious  agents 
do.  When  the  question  came  to  be  asked  in  Uganda,  the  old  work  on 
nagana  in  Zululand  came  to  the  writer's  aid,  and  a  tsetse-fly  was  at  once 
suspected  of  being  the  carrier.  At  this  time  it  was  hardly  known  that  tsetse- 
flies  were  found  in  Uganda,  but  a  short  walk  along  the  lake  shore  soon  dis- 
posed of  that  objection.  A  species  of  tsetse-fly,  afterward  identified  by 
Austen  as  the  Glossina  palpalis,  was  found  to  be  exceedingly  abundant. 
For  months,  a  few  native  lads  employed  to  catch  these  flies,  brought 
three  or  four  hundred  daily  to  the  laboratory.  This  Glossina  palpalis  is 
very  similar  to  the  Zululand  species,  except  that  the  markings  on  the  upper 
surface  of  the  abdominal  segment  are  less  distinct.  Full  descriptions  of 
these  flies  are  given  in  Austen's  "Monograph,"^  from  which  the  two 
accompanying  figures  are  taken,  the  first  showing  Glossina  palpalis  with 
artificially  outspread  wings,  the  other,  Glossina  longipennis,  s\lO^\\ng  the 

1  Bruce,  D.,  Tsetse-fly  Disease  or  Nagana  in  Zululand,  Further  Report,  1896, 
Harrison  &  Sons,  St.  Martin's  Lane,  London. 

^Austen,  Monograph  of  the  Tsetse-Flies,  Sold  by  Longmans  &  Co.,  37,  Soho 
Square,  London,  B.  Quaritch,  15,  Piccadilly,  London,  W. 


474 


DISEASES  CAUSED  BY  PROTOZOA 


wings  crossed  like  the  blade  of  a  pair  of  scissors,  tlie  usual  attitude  as- 
sumed by  this  genus. 

In  Uganda,  experiments  were  made  to  find  out  if  this  fly  (Glossina  pal- 
falis)  was  capable  of  carrying  infection  from  the  affected  to  the  healthy. 
Tsetse-flies  contained  in  small  muslin-sided  cages  were  fed  on  slee))ing 
sickness  patients  and  then,  after  a  certain  time  had  elapsed,  on  healthy 
monkeys.     We  secured  the  same  results  as  were  previously  obtained  in 

Fig.  32. 


Giussina  palpatis,  Rob.     (  XSJ). 

nagana.  Flies  fed  on  healthy  monkeys,  eight,  twelve,  twenty-four,  and 
forty-eight  hours,  after  having  fed  on  a  native  suffering  from  trypano- 
somiasis, invariably  transmitted  the  disease.  After  three  days  the  flies 
failed  to  transmit  it.  But  this  is  not  the  only  proof  that  these  flies  can 
carry  the  infective  agent.  On  the  lake  shore  there  was  a  large  native 
population  among  whom  we  had  found  about  one-third  to  be  harboring 
trypanosomes  in  their  blood.  The  tsetse-flies  caught  on  this  lake  shore, 
brought  to  the  laboratory  in  cages,-  and  placed  straightway  on  healthy 
monkeys,  gave  them  the  disease  in  every  instance,  and  furnished  a  start- 
ling proof  of  the  danger  of  loitering  along  the  lake  shore  among  these  in- 
fected flies.  It  is  true  that  the  white  man  runs  much  less  danger  than  the 
half-naked  native.  He  is  clothed  as  a  rule  from  head  to  foot,  and  resents 
the  presence  of  a  biting  fly,  whereas  the  natives  lie  almost  naked  in  the 
shade  of  the  dense  woods  which  line  the  shore  of  the  lake  and  are  little 
affected  by  the  presence  of  the  tsetse-flies.  After  these  experiments  it  was 
held  to  be  proved  that  the  Glossina  palpalis  could  convey  the  trypano- 
some  from  the  sick  to  the  healthy. 

Are  other  Species  of  Tseise-Flies  besides  Glossina  palpalis  Capable  of 
Carryinrj  the  Infection? — Probably  this  question  must  be  answered  in  the 


TRYPANOSOMIASIS  475 

affirmative,  as  Wiggins,  experimenting  in  British  East  Africa  with  Try- 
panosoma Gambiense  and  species  of  tsetse-flies  other  than  palpalis-, 
succeeded  in  infecting  healthy  from  affected  animals,  and  Greig  and  Gray 
in  Uganda  found  that  Glossina  palpalis  could  convey  the  trypanosoma 
of  a  disease,  probably  nagana,  which  occurred  among  cattle,  as  well  as 
that  of  sleeping  sickness. 

Do  Flies  other  than  the  Glossina  also  Carry  the  Injection? — The  an- 
swer to  this  is,  in  the  writer's  opinion,  in  the  negative.  Nuttall  states 
that  he  tried  for  a  long  time  in  England  to  convey  the  Trypanosoma 
Brucei  by  means  of  the  genus  of  biting  flies  called  stomoxys.  In  no  case 
did  he  succeed.  Greig  in  Uganda  also  tried  the  same  experiment  and 
failed.  In  regard  to  the  Trypanosoma  Brucei  and  nagana,  there  can  be 
little  doubt  that  it  is  carried  by  Glossina  and  Glossina  alone,  and  the 
distribution  of  nagana  corresponds  with  the  distribution  of  the  tsetse-fly. 
So  in  regard  to  human  trypanosomiasis  in  Uganda,  if  the  Trypanosoma 

Fia.  33. 


A  Tsetse  fly  {Glossina  longipennis,  Corti,  from  Somaliland)  in  resting  attitude,  stowing 
position  of  wings.      (  X  34.) 

Gambiense  is  only  carried  by  the  Glossina  then  the  distribution  of  the  fly 
and  the  disease  should  correspond.  We  set  ours?lves  to  work  out  this 
problem.  Collections  of  all  sorts  of  biting  flies  were  made  from  all  parts 
of  Uganda,  and  at  the  same  time  the  distribution  of  sleeping  sickness 
was  carefully  enquired  into.  In  the  course  of  a  few  months  several  hun- 
dred collections  of  biting  flies  were  examined.  These  were  divided  into 
two  categories,  those  containing  tsetse-flies,  and  ihoz^  containing  other 
kinds  of  biting  flies  but  no  tsetse.  Two  maps  were  taken,  one  to  represent 
the  distribution  of  Glossina  palpalis,  the  other  sleeping  s'ckness.  On  one, 
over  every  locality  where  a  tsetse-fly  was  Cound,  a  red  dot  was  placed,  and 
over  every  spot  where  other  biting  flies  but  no  tsetse  were  found,  a  black 
dot  was  placed.  In  the  same  way  on  ':he  other  map  red  dots  represented 
where  sleeping  sickness  cases  were  found,  black  dots  where  no  sleeping 
sickness  cases  were  found.  When  these  maps  were  completed  it  could  be 
seen  at  a  glance  that  the  distribution  of  Glossina  palpalis  and  sleeping 


476  DISEASES  CAUSED  BY  PROTOZOA 

sickness  coincided,  and  therefore  we  came  to  the  conchision  that  human 
trypanosomiasis  is  conveyed  from  the  sick  to  the  heahhy  by  the  Glossina 
palpali.s  and  by  it  alone.  Austen  wrote  an  account  of  the  biting  flies  sent 
to  him  by  us  from  Uganda,  and  it  can  be  seen  from  it  that  there  is  no 
scarcity  of  genera  and  si)ccics  in  that  country. 

Di.'iirihution  of  ilic  Glo.s.sina  Pal  palls  in  Uganda. — When  it  became 
evident  that  the  Glossina  palpal  is  was  the  only  carrier  of  this  infection 
from  the  sick  to  the  healthy,  it  was  necessary  to  enquire  somewhat  closely 
into  its  habitat  and  habits.  The  results  of  this  showed  that  this  tsetse-fly 
palpalis  is  only  found  on  the  shore  of  the  lake  where  there  is  forest. 
This  forest  is  thick  jungle  ^xith  high  trees  and  dense  undergrowth.  The 
fly  is  never  found  on  open  sandy  beaches  backed  by  grass  plains,  even 
although  there  may  be  some  scrub  near  the  water's  edge.  It  was  never 
found  in  the  grass  of  the  grassy  plains,  even  although  the  grass  was  long 
and  tangled.  It  was  not  found  by  us  in  banana  plantations,  and  not  at 
any  time  far  from  the  lake  shore.  ]\Iost  of  the  rivers  in  Uganda  are  mere 
swamps,  and  up  these  valleys  the  fly  does  not  penetrate.  The  fly  is  found 
along  the  Nile,  almost  as  far  north  as  Gondokoro  on  the  border  of  the 
Soudan.  It  also  occurs  round  Albert  Nyanza.  In  Usoga  the  fly  is  seen 
to  occur  inland,  but  what  the  physical  characters  of  this  province  are  which 
would  account  for  this  have  not  been  learned.  Probably,  rivers  with 
open  water-ways  run  into  this  country.  It  is  evidently  of  the  highest 
importance  that  the  exact  distribution  of  this  genus  should  be  made  out, 
as  the  spread  of  sleeping  sickness  to  the  Albert  Nyanza  and  down  the  Nile 
may  interfere  seriously  with  the  opening  up  of  Upper  Egypt. 

Animals  to  which  Trypanosoma  Gambiense  is  Pathogenic. — Trypano- 
soma Gamhiense,  like  Trypanosoma  Brucei,  is  pathogenic  to  many  species 
of  animals.  It  is  on  the  whole  much  more  chronic  in  its  action  than  the 
latter,  the  duration  of  the  illness  it  gives  rise  to  being  counted  usually  by 
months  or  even  by  years.  It  is  curious  that  Trypanosoma  Gamhiense 
should  include  man  in  its  attack,  as  well  as  the  other  animals,  whereas 
Trypanosoma  Brucei,  although  as  a  rule  much  more  rapidly  fatal  and 
acute  in  the  lower  animals,  has  never  been  recorded  as  having  attacked 
man.  Within  the  limits  of  this  paper  it  is  impossible  to  enter  fully  into  the 
course  of  this  disease  in  the  lower  animals,  but  a  list  of  the  principle 
species  affected  and  a  short  account  may  be  useful: — 

Monkeys. — The  monkeys  we  used  for  inoculation  in  Uganda  were 
Macacus  rhesus  and  a  Cercopithecus,  (sp  ?).  In  both  species  Trypanosoma 
Gamhiense  gives  rise  to  a  chronic  and  fatal  disease  resembling  human 
trypanosomiasis.  The  trypanosomes  first  appeared  in  the  blood  from 
about  the  tenth  to  the  twentieth  clay,  were  found  in  smaller  or  larger 
numbers  every  time  the  blood  was  examined,  and  the  animals  died  after 
an  illness  lasting  from  four  to  twelve  months.  From  our  experience  the 
disease  is  always  fatal  in  monkeys.  On  postmortem  examination,  the 
same  appearances  are  found  as  in  man,  except  that  in  the  fairly  rapid 
cases  there  is  not  the  characteristic  small  celled  infiltration  round  the 
small  vessels  of  the  brain  which  is  found  constantly  in  man.  In  chronic 
cases,  however,  this  meningo-encephalitis  is  just  as  marked  in  the  monkey 
as  in  man. 

Dogs  and  Cats. — In  Uganda  the  dogs  made  unsatisfactory  experi- 
mental animals,  as  most  of  them  died  of  ankylostomiasis  before  the  ex- 


TRYPANOSOMIASIS  477 

periment  was  finished.     Other  writers  state  that  dogs  die  about  two 
months  after  inoculation,  and  cats  seem  to  be  affected  in  much  the  same 

way  as  dogs.  ,  ,      i- 

Guinea-pigs. — These  animals  are  also  susceptible,  but  m  them  the  dis- 
ease pursues  an  extremely  chronic  course.  In  Uganda  in  two  guinea-pigs 
which  were  inoculated  more  than  once,  the  trypanosomcs  only  ai)peared 
in  the  blood  after  twelve  and  fifteen  months  respectively.  According  to 
Thomas  the  disease  is  sometimes  fatal.^  It  is  probable  that  sooner  or 
later  all  the  animals  die  of  the  infection  but  this  cannot  be  affirmed  at 
present.  Rabbits.— Incnhation  period,  according  to  Laveran  and  Mesnil, 
five  to  fifteen  days.  Duration  from  fifty  to  one  hundred  and  twenty-eight 
days,  iiafo.— Incubation  period  four  to  forty-seven  days.  Duration  from 
forty-five  to  three  hundred  and  eighty-eight  days  (average  85).  Mice.— 
Incubation  period  one  to  thirty-seven  days.  Duration  from  eleven  to 
fourteen  days.  Goats.— One  of  the  goats  in  Uganda  showed  Trypanosoma 
Gambiense  in  the  blood  about  fifteen  months  after  infection.  Sheep, 
horses,  asses  and  cattle,  are  also  very  refractory,  the  trypanosomes  appear- 
ing but  rarely  in  the  blood,  although  the  blood  may  be  virulent  if  injected 
into  susceptible  animals. 

Effect  of  Trypanosoma  Gambiense  on  Man — Symptoms— 1st  Stage — 
Trypanosomiasis. — When  the  Trypanosoma  Gambiense  gains  entrance 
to  the  human  organism  it  begins  to  multiply  and  appears  in  the  blood. 
How  long  it  is  before  it  appears  in  the  general  circulation,  is,  of  course, 
unknown,  but  in  the  monkey  it  usually  appears  about  twenty  days  after 
inoculation.  The  course  of  the  disease  is  so  slow  and  insidious  that 
months  and  even  years  may  elapse  before  any  marked  signs  manifest 
themselves.  As  an  example  of  this,  in  Uganda  in  March,  1903,  we  had 
five  natives  in  Entebbe  under  constant  supervision.  In  January,  1905, 
after  a  period  of  nearly  two  years.  Captain  Greig  informed  the  writer 
that  2  of  these  men  died  of  pneumonia  in  April  and  May,  1904,  respec- 
tively. Of  the  others,  1  appears  to  be  undoubtedly  in  an  early  stage  of 
sleeping  sickness;  he  has  gradually  developed  the  characteristic  signs  of 
the  malady  and  trypanosomes  are  now  always  found  in  his  cerebrospinal 
fluid.  The  remaining  two  present  some  of  the  features  of  the  disease,  but 
are  still  able  to  do  their  work  and  have  not  yet  shown  trypanosomes  in 
the  cerebrospinal  fluid.  Again  in  June,  1903,  80  apparently  healthy  natives 
from  the  sleeping  sickness  area  were  examined  and  trypanosomes  found 
in  the  blood  of  23.^  Captain  Greig  now  reports  that  4  have  died  of 
undoubted  sleeping  sickness,  2  died  from  pneumonia,  5  are  now  in  an  early 
stage  of  the  disease.  No  information  could  be  gained  concerning  6, 
and  the  remainder  do  not  show  any  symptoms  of  sleeping  sickness.  Dr. 
Wiggins  also  relates  the  case  of  an  "Askari"  or  native  poHceman,  sta- 
tioned at  Fort  Ternan  in  British  East  Africa  for  two  and  a  half  years 
before  he  developed  the  disease. 

All  these  facts  go  to  show  that  the  first  stage  of  this  disease,  when  the 
trypanosomes  are  found  in  the  blood  but  not  in  the  cerebrospinal  fluid, 

1  Thomas  and  Linton,  A  Comparison  of  the  Trypanosomes  of  Uganda  and  the 
Congo  Free  State,  Liverpool  School  of  Tropical  Medicine,  Memoir  XIII,  p.  75, 
1904. 

2  Bruce,  Nabarro  and  Greig,  "  Further  Report  on  Sleeping  Sickness  in  Uganda," 
Royal  Society,  No.  IV,  Report  of  the  Sleeping  SicJiness  Commission,  Harrison  & 
Sons,  St.  Martin's  Lane,  London,  1903. 


478  DISEASES  CAUSED  BY  PROTOZOA 

may  be  of  a  very  variable  duration.  If  one  may  be  bold  enough  to  put 
this  into  definite  figures,  it  may  be  said  that  this  so-called  stage  of  trypano- 
soma  fever,  this  first  stage  of  human  trypanosomiasis,  may  last  from  three 
months  to  three  years  or  more.  During  this  time  the  native  is  going  about 
at  his  ordinary  vocation.  He  says  he  feels  perfectly  fit  and  strong.  But 
there  is  one  outward  mark  which  proclaims  the  disease  and  that  is  the 
presence  of  enlarged  lymphatic  glands.  This  is  a  disputed  point,  but  in 
my  oi)inion  this  enlargement  of  the  lymphatic  glands  must  be  looked  on  as 
a  constant  and  early  feature  of  the  disease.  It  is  not  that  enlargement 
of  the  inguinal  or  femoral  glands  should  be  taken  as  a  sign  of  human 
trypanosomiasis;  there  must  be  a  polyadenitis,  and  as  a  matter  of  routine, 
the  postcervical  glands  should  be  examined  first.  Every  case  of  sleeping 
sickness  examined  by  us  in  Uganda  showed  this  glandular  enlargement, 
and  according  to  Greig  and  Gray,^  the  trypanosomes  are  readily  dem- 
onstrated on  examining  the  gland  juice.  Later  it  was  found  that  the  early 
cases  of  trypanosomiasis,  the  so-called  trypanosoma  or  Gambia  fever, 
also,  in  every  case,  presented  enlargement  of  the  lymphatic  glands,  and 
in  these  active  trypanosomes  could  readily  be  found.  The  natives  them- 
selves are  alive  to  the  fact,  that,  when  the  glands  in  the  neck  enlarge,  they 
will,  sooner  or  later,  pass  into  the  stage  of  sleeping  sickness,  and  their 
custom  is  then  to  eat  up  their  live  stock,  goats,  chickens,  etc.  This  en- 
largement of  the  cervical  glands  was  used  in  Uganda  to  guage  the  inci- 
dence of  the  disease  in  a  sleeping  sickness  area.  The  result  was  that  in 
about  three-fourths  of  the  po]:)ulation  of  the  islands  of  Sesse  and  Kome 
this  symptom  was  present.  As  to  whether  there  is  any  other  symptom 
which  can  be  depended  upon  to  point  to  the  first  stage  of  this  disease,  is  a 
question  which,  in  my  opinion,  must  be  answered  in  the  negative.  Some 
writers  state  that  there  is  fever  from  time  to  time  of  an  irregular  type,  but 
if  the  charts  of  the  men  we  kept  under  observation  in  Uganda  be  examined 
it  will  be  seen  that  they  kept  absolutely  normal  for  several  months.  The 
jBrst  stage  of  this  disease  may  be  dismissed  then  by  saying  that  the  blood 
and  lymphatics  contain  the  trypanosomes,  and  that  there  is  a  general  en- 
largement of  the  lymphatic  glands  of  the  body. 

2nd  Stage — Sleeping  Sickness. — Naturally,  in  a  disease  so  insidious  as 
this  it  is  impossible  to  say  with  absolute  accuracy  when  the  first  stage 
merges  into  the  second.  But  a  time  comes  when  a  slight  change  in  the 
man's  demeanor  becomes  evident;  when  he  is  less  inclined  to  exert  him- 
self; he  lies  about  more  during  the  day,  and  at  last  his  intimates  see  that 
he  has  the  first  symptoms  of  the  disease.  When  these  are  well  advanced 
the  expression  of  the  face  is  sad,  heavy,  dull-eyed  and  apathetic,  as  is 
well  shown  in  Plate  IV,  Fig.  1.  The  body,  however,  is  well  nourished,  and 
this  is  the  rule,  even  up  to  the  time  of  death,  if  the  patients  are  well  nursed 
and  fed.  Complaints  of  headache  or  indefinite  pains  in  other  parts  of  the 
body  are  often  made.  The  pulse  is  rapid,  shallow  and  weak,  and  the 
heart  sounds  faint  and  distant.  The  breathing  usually  presents  nothing 
abnormal.  The  lymphatic  glands  are  generally  enlarged,  and  vary  from 
the  size  of  a  pea  to  that  of  a  bean.  There  is  nothing  abnormal  about 
the  skin;    it  may  be  at  times  harsh  and  rough,  but  usually  is  smooth 

*  Greig  and  Gray,  "  Continuation  Report  of  Sleeping  Sickness  in  Uganda," 
Reports  of  Sleeping  Sickness  Commission,  No.  V,  Royal  Society,  Harrison  &  Sons, 
St.  Martin's  Lane,  London,  1905. 


PLATE    IV 


FiG.   1 


Sleeping  Sickness.    Second  Stage. 


FIG.  2 


Sleeping  Sickness.     Shortly  before  Death. 


TRYPANOSOMIASIS  479 

and  sleek,  and  any  eruption  is  quite  the  exception.  The  gait  is  weak,  un- 
certain and  shuffling.  There  is  little  strength  in  the  hand  grip  and  the 
hands  when  held  out  are  tremulous.  Tremors  of  the  tongue  are,  as  a  rule, 
well  marked.  The  voice  is  weak,  indistinct,  and  monotonous.  At  this 
time  the  temperature  is  usually  irregular,  often  normal  in  the  morning  and 
rising  to  101°  or  102°  F.  in  the  evenings.  During  this  time  the  patients  in 
hospital  are  usually  up  a  great  part  of  the  day,  sitting  in  the  open  air,  and 
to  the  casual  observer  show  little  or  no  signs  of  disease.  The  symptoms 
gradually  increase  until  after  weeks  or  months  the  patient  is  unable  to 
walk,  speak  or  feed  himself.  He  is  then  altogether  confined  to  his  bed, 
lying  in  an  absolutely  lethargic  condition  all  day  long.  It  is  at  this  time 
that  the  sick  are  often  neglected  by  their  friends  and  become  much  ema- 
ciated. The  urine  and  fpeces  are  passed  involuntarily.  During  the  last 
two  or  three  weeks  the  temperature  sinks  six  or  seven  degrees  below  the 
normal,  and,  the  condition  gradually  deepening,  the  patient  dies  in  a  state 
of  coma. 

Plate  IV,  Fig.  2,  represents  a  case  of  the  emaciated  type  taken  a  few 
days  before  death. 

Principal  Symptoms  in  Detail. — Nervous  System. — The  dull,  heavy, 
listless,  expressionless,  emotionless  physiognomy  is  a  marked  feature  of 
this  disease.  Often  when  a  patient  is  being  examined  he  stares  at  a  fixed 
point  in  a  vacant  way  with  eyes  wide  open.  The  intelligence  and  memory 
seem,  as  a  rule,  to  remain  fairly  good.  On  two  or  three  occasions  we  meet 
with  cases  showing  mental  excitement,  laughing  and  jabbering  all  day 
in  a  meaningless  way.  In  regard  to  sleep  the  usual  history  is  that  the  pa- 
tients sleep  well  at  night  and  a  good  deal  during  the  day.  The  condition 
however,  can  hardly  be  called  sleep.  It  is  rather  a  vacant,  day-dreaming, 
apathetic  condition  in  which  the  patient  remains  for  hours,  often  with 
eyes  open,  staring  unmeaningly  at  the  wall.  They  can  easily  be  roused 
from  this  state  by  touching  or  speaking  to  them.  The  speech  is  peculiar: 
weak,  slow,  tremulous  and  indistinct,  sometimes  faint  and  high-pitched, 
like  a  whimpering  child.  When  asked  a  question  some  little  time  elapses 
before  the  patient  answers;  he  gives,  as  it  were,  a  sigh,  gathers  his  wits 
together,  and  answers  with  an  evident  effort.  There  is  nothing,  as  a  rule, 
noteworthy  about  the  eyes.  There  is  frequently  {marked  tremor  of  the 
tongue,  lips,  and  hands,  but  the  tongue  alone  may  be  affected.  The  mus- 
cular nutrition  is  usually  good,  but  power  is  diminished  as  evinced  by  the 
grip.  Sensibility  to  touch,  temperature,  and  pain  is  normal  and  the  mus- 
cular sense  is  little  impaired.  In  regard  to  the  reflexes,  as  a  rule  there  is 
no  abnormality.  Sometimes,  in  the  early  stages,  the  knee-,  elbow-,  and 
wrist-jerks  are  increased;  but  in  advanced  cases  the  knee-jerks  are  often 
diminished  and  ankle  clonus  is  in  rare  cases  present  to  a  slight  extent. 

Alimentary  System. — There  is  little  or  nothing  to  be  noted  here.  The 
appetite  is  usually  good,  even  in  fairly  advanced  cases.  The  tongue  is 
moist,  flabby,  and  furred.  Inspection  of  the  abdomen  seldom  reveals  any- 
thing. There  is,  as  a  rule,  no  enlargement  of  the  liver  and  the  spleen  is 
rarely  palpable.  The  bowels  tend  to  be  constipated  and  aperients  are 
often  required.  When  the  patient  is  bed-ridden,  unless  care  is  taken,  the 
colon  becomes  full  of  hard  scybala. 

Circulatory  System.— This  is  more  important  from  a  diagnostic  point 
of  view,  as  the  heart  and  pulse  tend  to  become  affected  early  in  the  dis- 


480  DISEASES  CAUSED  BY  PROTOZOA 

ease.  In  regard  to  the  heart  no  patient  at  any  time  made  any  complaint 
as  to  pain  or  palpitation.  On  examining  tlie  cardiac  area  the  apex  beat 
was  found  usually  either  very  weak  or  imperceptible,  but  nothing  else 
abnormal  could,  as  a  rule,  be  made  out.  On  auscultation  the  heart  sounds 
arc  weak  but  regular,  antl  there  is,  in  the  great  majority  of  cases,  no  bruit. 
The  pulse  is  usually  accelerated.  It  has  a  rate,  as  a  rule,  of  from  about 
ninety  to  one  hundretl,  with  a  low  tension,  a  small  size,  easily  compres- 
sible and  regular  rhythm. 

Respiraturtj  System. — In  all  the  cases  of  sleeping  sickness  examined  by 
us  in  Uganda,  the  lungs  presented  nothing  abnormal.  The  breathing  is 
naturally  somewhat  increased  in  frequency  when  there  is  fever,  and 
there  is  some  congestion  of  the  bases  in  the  last  few  days  of  life.  Pneu- 
monia seems  to  supervene  more  frequently  in  sleeping  sickness  cases  than 
among  the  healthy.  Dr.  Cooke,  Kampala,  observes  that  the  mortality 
among  the  natives  from  pneumonia  has  greatly  risen  since  the  occurrence 
of  the  sleeping  sickness  epidemic. 

Urinary  System. — There  is  also,  as  a  rule,  nothing  noteworthy  to  be 
found  in  this  system. 

Cutaneous  System. — Sometimes  the  skin  is  harsh  and  rough,  and  the 
papilhe  prominent,  especially  over  the  legs  and  arms,  but  in  the  great 
majority  of  cases  there  is  nothing  abnormal.  In  one  case  we  noticed 
an  oedematous  swelling  over  the  shin,  but,  as  a  rule,  swelling,  puffiness 
and  eruptions  are  conspicuous  by  their  absence. 

Lymphatic  System. — In  every  case  the  superficial  lymphatic  glands  are 
slightly  enlarged,  varying,  as  a  rule,  from  the  size  of  a  pea  to  a  bean. 
The}^  are  fairly  soft  and  painless,  but  in  a  few  cases  in  the  last  stages  they 
become  inflamed,  tender,  and  break  down.  This  is  probably  due  to  a 
terminal  bacterial  invasion  and  not  to  the  trypanosomes.  This  poly- 
adenitis is  considered  to  be  one  of  the  most  characteristic  signs  of  this 
disease  and  is  only  found  among  natives  inhabiting  the  sleeping  sickness 
area.  It  may  then  be  accepted  as  the  most  marked  symptom  of  the 
disease. 

Hcemopoietic  System. — Antemia  is  not  a  feature  of  sleeping  sickness; 
in  uncomplicated  cases  no  diminution  of  the  number  of  the  red  blood 
corpuscles,  or  percentage  of  haemoglobin,  takes  place.  Greig  and  Gray 
state  that  "toward  the  end  in  a  certain  proportion  of  cases  the  number 
of  red  cells,  the  percentage  of  haemoglobin  and  the  specific  gravity,  rise. 
These  cases  did  not  present  any  signs  of  cyanosis." 

Low  and  Castellani,  on  the  other  hand,  say  that  anaemia  in  varying 
amount  is  constant,  the  average  number  of  the  red  blood  corpuscles  per 
cubic  millimeter  being  3,500,000  or  thereabout,  and  that  the  haemoglobin 
is  generally  reduced  proportionately. 

In  regard  to  the  leukocytes  Greig  and  Gray  state  that  a  lymphocytosis 
occurs  in  all  cases.  They  write  that  "enlargement  of  lymphatic  glands 
being  a  constant  feature  in  sleeping  sickness,  it  is  a  matter  of  importance 
to  determine  whether  the  lymphocytes  in  the  blood  show  an  increase  in 
numbers.  This  point  is  of  interest,  further,  because  the  most  constant 
lesion  found  in  the  nervous  system  of  sleeping  sickness  cases  is  an  accumu- 
lation of  cells  of  this  nature  in  the  perivascular  lymph  spaces."  Greig 
and  Gray  also  made  the  interesting  observation  that  all  the  cells  found  in 
the  cerebrospinal  fluid  were  lymphocytes  and  that   they  increased  in 


TRYPANOSOMIASIS  481 

number  from  23  per  Cc.  in  the  early  stage,  to  730  per  Ce.  in  the  fully 
developed  disease.  The  total  number  of  leukocytes  per  Ccm.  remains 
fairly  normal,  lying,  as  a  rule,  between  7,000  and  10,000,  sometimes  rising 
to  15,000  and  20,000.  Greig  and  Gray's  averages  work  out  for  the  red 
blood  corpuscles  at  4,707,000,  white  blood  corpuscles  11,000,  eosinophiles 
5  per  cent.,  polynuclears  39  per  cent.,  large  mononuclears  12  per  cent., 
and  lymphocytes  38  per  cent.  Needless  to  say,  among  natives  who  all 
suffer  more  or  less  from  helminthiasis  there  is  often  found  a  varying 
eosinophilia. 

The  Temperature  Curve. — There  is  nothing  very  marked  about  the 
temperature  curve  in  human  trypanosomiasis.  In  the  early  stage,  when 
the  trypanosomes  are  found  in  the  blood  and  before  symptoms  of  sleep- 
ing sickness  appear,  the  temperature  remains  normal.  The  cases  under 
observation  in  Entebbe  remained  without  any  rise  of  temperature  for 
six  or  seven  months,  and  it  is  impossible  to  say  how  long  they  harbored 
the  parasite  before  coming  under  observation.  When  symptoms  of 
sleeping  sickness  appear,  the  temperature,  as  a  rule,  becomes  irregular, 
rising  to  101°  F.  or  102°  F.  in  the  evening  and  sinking  to  normal  or  slightly 
below  normal  in  the  morning.  But  it  must  be  admitted  that  cases  occur 
with  the  temperature  fairly  normal  throughout  the  disease,  although 
there  is  always  a  certain  irregularity.  High  temperatures  may  be  said 
never  to  occur — 103°  F.  being  a  rare  exception,  and  these  are  probably 
often  due  to  an  attack  of  malaria.  There  is  one  characteristic  about  the 
curve  which  is  fairly  constant :  about  a  fortnight  before  death  the  tem- 
perature runs  rapidly  down  94°,  93°,  and  92°  F.,  and  remains  so  until 
death.  When  the  temperature  becomes  subnormal  morning  and  evening, 
the  patient  will  probably  die  within  a  fortnight.  To  recapitulate  then, 
the  few  cases  of  human  trypanosomiasis  we  have  been  able  to  follow,  up 
to  the  present,  show  a  normal  temperature  for  six  or  seven  months. 
During  this  time  the  trypanosomes  are  constantly  found  in  the  blood. 
Then  the  temperature  becomes  slightly  irregular,  the  patient  becomes 
heavier  and  duller  in  his  demeanor,  the  trypanosomes  begin  to  appear  in 
the  cerebrospinal  fluid,  and  the  stage  of  sleeping  sickness  may  be  said  to 
be  entered.  The  temperature  remains  irregular  with  two  or  three  degrees 
of  fever  in  the  evening,  until  a  fortnight  before  death  when  it  becomes 
subnormal,  running  down  to  93°  and  92°  F. 

Special  Pathology. — There  is  little  of  special  interest  to  be  noted  at  the 
postmortem  examination  of  an  uncomplicated  case  of  human  trypanoso- 
miasis. The  body  is  usually  well  nourished,  but  may  be  extremely  erna- 
ciated.  There  are  usually  bed-sores  present,  or  at  least  commencing 
bed-sores.  The  effect  of  the  long  chronic  disease  renders  the  heart 
muscle  flabby  and  the  Hver  fatty.  The  lungs  and  kidneys  present  nothing 
abnormal,  except  the  congestion  incident  to  a  failing  circulation.  In  a 
malarious  region,  naturally,  the  spleen  is  usually  somewhat  enlarged, 
pigmented  and  tough.  Of  course,  the  patient  may  die  of  some  inter- 
current malady,  such  as  pneumonia,  which  is  common  enough,  and  the 
signs  of  the  disease  will  be  present.  But  it  may  be  safely  said  that,  except 
for  the  constant  presence  of  general  enlargement  of  the  lymphatic  glands, 
there  is  nothing  in  the  naked-eye  appearances  to  proclaim  human  trypano- 
somiasis. The  lymphatic  glands,  both  superficial  and  deep,  are  enlarged. 
The  superficial  usually  vary  in  size  from  a  pea  to  a  large  bean,  and  the 

31 


482 


DISEASES  CAUSED  BY  PROTOZOA 


deep  run  somewhat  larger.  Sometimes  they  increase  very  much  in  size, 
and  on  section  are  found  to  be  caseous  or  to  contain  collections  of  pus. 
This  is  probably  due  to  some  terminal  bacterial  invasion  and  not  to 
the  trypanosomes.  But  A\hen  one  comes  to  examine  the  brain  there  is  a 
divergence  from  the  normal  and  a  pathological  picture  which  is  fairly 
regular.  On  removing  the  calvarium,  as  a  rule,  a  good  deal  of  fluid  es- 
capes. The  dura  mater  is  not  adherent,  and,  usually,  presents  nothing 
abnormal.  On  reflecting  it  the  convolutions  on  the  surface  of  the  brain 
are  found  to  be  flattened,  and  the  sulci  filled  with  opaque-looking  sub- 
arachnoid fluid,  giving  a  ground-glass  ajipearance.  The  vessels  on  the 
surface  are  injected.  On  section  the  brain  appears  normal,  but  the 
lateral  ventricles  are  dilated  and  contain  an  excess  of  fluid.  This  is  all 
that  can  be  seen  on  exposing  the  surface  of  the  brain  of  an  ordinary  un- 
complicated case  of  sleeping  sickness,  but  which,  in  my  opinion,  constitute 
an  appearance  fairly  characteristic  of  sleeping  sickness.  A  certain  per- 
centage of  the  cases  present  much  more  acute  signs  of  disease.  These 
are  the  cases  in  which  a  terminal  bacterial  infection  has  taken  place,  and 
the  brain  may  then  present  all  the  appearances  of  acute  or  purulent 
meningitis. 

Microscopic  Examination  of  the  Tissues. — It  is  to  Mott  we  owe  our 
knowledge  of  the  pathological  histology  of  sleeping  sickness.  He  states 
that  a  definite  characteristic  appearance  is  found  in  sections  of  the  brain, 
which  is  found  in  no  other  disease.  He  is  able  to  pick  out  with  certainty 
from  a  number  of  sections  of  brains  of  various  nervous  disorders,  such  as 
tabes  and  general  paralysis,  those  cut  from  sleeping  sickness  cases.  This 
is  a  condition  of  meningo-encephalomyelitis.  Throughout  the  whole 
central  system,  but  especially  in  the  medulla,  and  at  the  base  of  the  brain, 

Fig.  34. 


sections  show  the  pia  arachnoid  to  be  infiltrated  with  mononuclear  leuko- 
cytes; the  inflammation  can  be  traced  along  the  bloodvessels  and  septa 
into  the  substance  of  the  nervous  system.  The  perivascular  lymphatics 
around  both  large  and  small  vessels  are  crowded  with  these  lymphocytes. 


TRYPANOSOMIASIS  483 

Fig.  34  is  taken  from  his  paper  and  shows  this  collection  of  lympho- 
cytes in  the  perivascular  spaces.  But  this  lymphocytic  accumulation  in 
the  perivascular  spaces  of  the  brain  and  spinal  cord  is  not  restricted  to 
the  nervous  system,  but  is  found  all  over  the  body.  We  have  seen  that 
there  is  an  increase  of  the  lymphocytes  in  the  blood  and  that  the  lymphatic 
glands  are  enlarged  and  show  a  proliferation  of  these  cells.  In  sliort, 
throughout  the  body  and  especially  in  those  tissues  and  organs  rich  in 
lymphatics,  such  as  the  intestine,  this  proliferation  and  accumulation  can 
be  seen.  Human  trypanosomiasis  is  essentially  then  a  disease  of  the 
lymphatic  system,  and  the  irritation  and  proliferation  of  the  lymphocytes 
is  probably  due  to  a  toxin  secreted  by,  or  contained  in,  the  bodies  of  the 
trypanosomes.  The  characteristic  symptoms  of  the  disease  are  no  doubt 
due  to  the  accumulation  of  these  lymphocytes  in  the  perivascular  spaces 
of  the  brain,  compressing  the  arteries  and  so  interfering  with  the  normal 
nutrition  of  the  brain  cells.  The  progressive  weakness  of  the  body,  the 
tremulous  condition  of  the  muscles,  the  feeble  rapid  pulse,  the  weak 
voice,  and  uncertain  gait,  the  rise  of  temperature,  would  all  be  accounted 
for  by  this  obstruction  or  interference  with  the  circulation,  giving  rise  to 
degenerative  changes  in  the  nerve  cells,  and  proliferation  of  the  neuroglia. 
Terminal  Bacterial  Invasion. — Some  writers  are  of  the  opinion  that  the 
bacteria,  chiefly  cocci,  found  frequently  in  the  tissues  of  sleeping  sickness 
cases  after  death,  may  be  an  important  etiological  factor  in  the  disease. 
It  is  necessary  then  to  say  a  few  words  on  this  subject.  The  Portuguese 
Commission  described  a  diplo-streptococcus  which  they  found  in  the 
cerebrospinal  fluid  after  death,  and  during  life  by  lumbar  puncture. 
Castellani  in  39  cases  grew  streptococci  from  the  blood  of  the  heart  in  32 
and  from  fluid  taken  from  the  lateral  ventricles  in  30.  During  life,  he 
found  his  streptococcus  very  rarely  and  only  in  the  last  stages  of  the  dis- 
ease. He  examined  the  cerebrospinal  fluid  obtained  by  lumbar  puncture 
in  28  patients ;  in  5  he  had  positive  results,  but  only  when  the  examination 
was  made  a  few  hours  before  death,  with  the  exception  of  1  case  in 
which  he  found  it  several  days  before  death.  Greig  and  Gray  also 
made  a  number  of  observations  by  making  cultures  from  the  glands, 
blood,  and  cerebrospinal  fluid.  They  say  that  "the  result  of  these  obser- 
vations showed  that  a  number  remained  cases  of  pure  trypanosoma 
infection  to  the  end;  the  cultures  made  from  the  glands,  blood,  and 
cerebrospinal  fluid  remained  sterile.  On  the  other  hand,  in  a  propor- 
tion of  cases,  an  invasion,  chiefly  by  diplo-streptococcus,  did  occur  but, 
by  the  results  of  the  examination  at  different  stages  of  the  disease,  it 
was  possible  to  locate  it  to  the  final  stage,  when  the  patient  was  practically 
moribund.  These  cases  at  this  stage  of  the  disease  have  invariably 
numerous  foci  of  suppuration  on  the  hands  and  feet  due  to  jiggers;  also 
there  is  frequently  before  death  a  purulent  discharge  from  the  gums ;  and 
their  vitality  and  resisting  power  is  a  negative  quantity."  The  writer's 
opinion  of  the  role  played  by  the  diplo-streptococcus  has  always  been  that 
it  is  merely  a  terminal  infection  in  the  last  days,  when  the  patient  is 
practically  dead.  At  the  same  time  it  must  sometimes  hasten  the  end,  and 
the  cases  of  pneumonia,  acute  and  purulent  meningitis,  which  are  often 
met  with  at  autopsy  of  cases  of  sleeping  sickness  are  due  to  bacterial  inva- 
sions of  the  pneumococcus,  the  diplo-streptococcus,  and  other  organisms. 
In  nagana  there  is  also  frequently  found  a  streptococcal  terminal  infection. 


484  DISEASES  CAUSED  BY  PROTOZOA 

The  writer  docs  not  believe  that  the  di]:)lo-streptococciis  plays  any  more 
important  part,  and  it  may  be  relegatetl  to  the  lumber  room  to  join  the 
Filaria  Perstans,  Strongyloides,  Ankylostoma,  and  the  various  bacteria 
wliich  have  been  described  at  various  times  as  the  cause  of  sleeping 
sickness. 

Diagnosis. — From  the  description  of  the  disease  given  above,  it  will  be 
seen  that  it  is  no  easy  matter  to  diagnose  human  trypanosomiasis  in  the 
early  stages.  If  a  case  were  met  with  in  America  or  England  a  history  of 
the  patient  having  lived  in  Africa  in  the  endemic  area  within  the  last  four 
to  five  years  would  give  a  clue:  then,  in  all  probability,  at  the  time  the 
patient  sought  medical  advice  the  temperature  would  be  found  to  be 
irregular,  with  an  evening  rise  of  one  or  two  degrees;  the  pulse  also  would 
most  likely  be  suspicious,  being  quicker  than  usual  and  with  low  tension. 
The  examination  of  the  blood  Avould  show  a  lymphocytic  leukocytosis, 
which  would  help  to  exclude  some  other  diseases;  and,  lastly,  a  drop  of 
gland  juice,  removed  by  a  hypodermic  needle  from  a  cervical  gland, 
would  show  Trypanosoma  Gnmhiense,  and  so  definitely  settle  the  diag- 
nosis. In  more  advanced  cases  the  peculiar  apathetic  physiognomy,  the 
pulse,  the  temperature  curve,  the  tremors  of  the  tongue  and  hands,  the 
peculiar  speech  and  weak  shuffling  gait,  ought  to  form  a  picture  which 
cannot  be  mistaken  for  any  other  disease.  But  the  one  unmistakable 
mark  of  the  disease  is  the  presence  of  the  Trypanosoma  Gambiense  in  the 
lymphatic  glands,  blood,  or  cerebrospinal  fluid,  and  no  medical  man 
should  rest  content  with  a  diagnosis  which  does  not  include  the  demon- 
stration of  the  parasite. 

Prognosis. — Every  case  of  human  trypanosomiasis  which  shows  symp- 
toms of  sleeping  sickness  dies  sooner  or  later.  It  is  an  absolutely  fatal 
disease.  The  question  has  arisen  as  to  whether  any  of  the  natives  with 
trypanosomes  in  their  blood  are  able  to  kill  the  parasite  off  before  organic 
changes  in  the  tissues  have  been  set  up,  and  so  establish  an  immunity. 
This  question  cannot  yet  be  answered  with  certainty.  Greig  and  Gray 
remark  on  this  point,  "In  following  the  after  history  of  cases  of  trypan o- 
soma  fever  we  have  arrived  at  these  conclusions:  (1)  that  many  of  them 
terminate  fatally  as  sleeping  sickness  cases,  which  may  be  regarded  as  the 
usual  mode  of  termination;  (2)  that  a  certain  number  die  of  intercur- 
rent affections;  e.g.,  pneumonia;  (3)  that  a  certain  proportion  remain 
well  for  long  periods,  indicating  that  a  tolerance  toward  the  parasite  has 
been  obtained.  It  may  be  said  that  some  of  the  cases  may  become  in  time 
sufficiently  immune  to  destroy  the  parasite.  The  evidence  collected  so 
far  suggests  that  this  is  the  case."  The  writer  agrees  with  Greig  and 
Gray  in  everything  except  the  last  sentence  but  it  is  debatable  as  to 
whether  the  evidence  does  any  such  thing.  It  is  of  course,  a  very  impor- 
tant point,  but  we  must  wait  for  more  knowledge.  Of  the  5  cases  of 
human  trypanosomiasis  in  natives^  kept  under  observation  since  March, 
1903,  2  have  died  of  pneumonia,  1  shows  undoubted  symptoms  of  sleeping 
sickness,  and  the  remaining  2  premonitory  symptoms.  Another  case, 
a  European  brought  under  observation  at  the  same  time,  came  to  me  at 
the  beginning  of  1905  with  swollen  glands,  trypanosomes  in  his  blood, 

^ Bruce  and  Nabarro,  "Progress  Report  on  Sleeping  Sickness  in  Uganda," 
Royal  Society,  No.  I.  Report  of  the  Sleeping  Sickness  Commission,  1903,  Harrison 
&  Sons,  St.  Martin's  Lane,  London. 


TRYPANOSOMIASIS  485 

complaining  of  want  of  energy,  and,  in  my  opinion,  in  an  early  stage  of 
sleeping  sickness.  He  died  afterward  of  undoubted  sleeping  sickness. 
Of  the  23  healthy  natives  with  trypanosomes  in  their  l)lood  in  1903,  Greig 
reports  at  the  end  of  1904,  that  "it  has  been  ascertained  that  since  that 
date  3  have  died  of  undoubted  sleeping  sickness;  1  ran  away  from  his 
shamba  and  was  reported  to  have  died  of  sleeping  sickness;  2  died  from 
pneumonia  (1  was  almost  certainly  in  an  early  stage  of  sleeping  sickness) ; 
5  are  now  in  an  early  stage  of  sleeping  sickness;  no  information  has  been 
obtained  in  6  cases.  The  remainder,  6,  do  not  as  yet  present  definite 
signs  of  sleeping  sickness."  There  is  still  time  for  these  6  to  develop  symp- 
toms. The  incubation  period  may,  as  stated  above,  be  three  years  or 
more.  The  evidence  rather  goes  to  show  that  all  cases  of  human  try- 
panosomiasis go  on  to  sleeping  sickness  and  death.  Further  knowledge  is 
required  before  the  question  can  be  answered  dogmatically. 

Treatment. — It  may  be  stated  at  the  outset,  that  up  to  the  present,  medi- 
cal treatment  has  failed  to  do  more  than  prolong  life.  Arsenic  has  more 
influence  on  the  trypanosome  than  any  other  drug.  Horses,  donkeys, 
and  cattle  suffering  from  nagana  received  12  to  20  grains  of  arsenic 
daily.  The  result  was,  that  in  a  few  days,  the  parasite  disappeared  al- 
together from  the  blood,  and  remained  out  of  it  for  a  long  time — from  one 
to  five  or  six  months.  In  every  case,  however,  sooner  or  later,  the  hsema- 
tozoa  crept  back  into  the  blood,  increased  in  numbers,  and  finally  killed 
the  animal.  In  no  case  was  a  cure  effected.  In  the  most  successful  case 
death  was  delayed  for  nearly  a  year.  In  human  trypanosomiasis  the  same 
thing  seems  to  occur.  The  writer  has  no  experience  of  arsenic  in 
human  trypanosomiasis.  Low  and  Castellani  say  that  "iron,  arsenic, 
and  quinine,  especially  in  cases  complicated  with  malaria,  produced  a 
distinct  but  temporary  improvement."  Manson^  treated  his  case  with 
arsenic  in  various  forms,  both  by  the  mouth  and  hypodermically;  also 
with  methylene  blue.  The  patient  died  after  two  years,  of  sleeping  sick- 
ness. The  Liverpool  School  of  Tropical  Medicine  states  that  a  "variety 
of  drugs  have  been  used  with  more  or  less  success;  up  to  the  present 
arsenic  and  trypanroth,  an  aniline  dye  introduced  by  Ehrlich  and  Shiga, 
appear  to  be  most  useful;  the  parasite  disappears  for  a  time  from  the 
blood,  and  the  life  of  the  animal  is  prolonged,  iDut  with  neither  of  the  drugs 
is  a  cure  obtained."  Greig  and  Gray  report  several  experiments  with 
arsenic.  They  gave  10,  15  and  20  milligrams  of  arsenious  acid  daily. 
They  write  that  "the  effect  of  arsenic  on  the  trypanosomes  in  the  blood 
of  patients  in  the  early  stage  of  the  disease  has  been  observed.  The  action 
is  somewhat  remarkable.  The  parasite  disappears  first  from  the  periph- 
eral blood  and,  at  a  later  date,  from  the  lymphatic  glands.  After 
an  interval  of  varying  length  the  parasites  will  reappear  in  the  blood 
temporarily  and  then  again  disappear,  but  have  not  so  far  returned  to  the 
glands.  This  reappearance  of  the  trypanosomes  in  the  blood  and  their 
final  disappearance  suggests  that  arsenic  acts  in  two  ways:  (1)  by  ac- 
tually destroying  the  trypanosomes,  and;  (2)  the  trypanosomes  so  de- 
stroyed actively  immunize  the  individual,  the  effect  of  this  not  being 
apparent  till  later."  As  none  of  these  cases  have  been  under  observa- 
tion for  more  than  five  months  it  is,  in  the  writer's  opinion,  too  early  to 

^Manson,  "Sleeping  Sickness  and  Trypanosomiasis  in  a  European,"  British 
Medical  Journal,  December  5,  1903. 


486  DISEASES  CAUSED  BY  PROTOZOA 

generalize;  in  nagana,  it  will  be  remembered,  the  parasite  sooner  or  later 
reappeared  in  the  blood  and  caused  the  death  of  the  animal.  Greig  and 
Gray  are  also  experimenting  with  trvjxxnroth.  Concerning  the  latter  drug 
Laveran  and  jNIesnil  state  that  they  liave  had  no  success  with  it  in  the  case 
of  rats  infected  with  Trypanosoma  Gambicn.sr.  In  some  of  the  trypano- 
some  diseases,  such  as  nagana  and  surra,  every  conceivable  drug  has  been 
tried.  All  the  sera  have  likewise  been  used.  Toxins  and  cultures  of  liv- 
ing bacteria  of  many  pathogenic  organisms,  as  well  as  blood  parasites,  have 
also  been  found  useless.  In  short,  everything  likely  to  effect  a  cure  by 
interfering  with  the  well-being  of  the  trypanosome  has  been  tried,  but  not  a 
single  case  of  recovery  has  occurred.  At  present,  then,  there  is  no  reason- 
able hope  of  a  curative  agent  being  found,  and  preventive  treatment  seems 
equally  unreachable.  Laveran^  in  a  later  note  records  the  results  of  his 
observations  on  the  action  of  arsenic  and  tryjianroth  on  the  Tri/panosovia 
Gamhirnsc  in  rats  and  dogs.  The  method  which  Laveran  adopts  for  the 
administration  of  the  drugs  is  to  inject  the  infected  animal  with  arsenious 
acid  and  after  an  interval  of  forty-eight  hours  with  trypanroth.  He  thinlvs 
that  this  treatment  carried  out  three  times  at  intervals  of  eight  days  is 
sufficient  to  cure  the  disease  in  rats.  Two  rats  infected  with  Trypano- 
soma Gambiense  on  October  17,  1904,  and  treated  in  this  way  were,  in 
his  opinion,  cured,  the  trypanosomes  having  been  absent  from  the  blood 
for  ninety-one  days.  For  dogs  he  considers  that  a  dose  of  1.5  mg.  of 
arsenic  per  kilo  should  not  be  exceeded.  For  a  dog  of  ten  to  twelve  kilos, 
he  recommends  a  dose  of  14  to  16  milligrams  and  30  to  40  centigrams 
of  trypanroth.  Plimmer  tells  us  that  his  rats  infected  with  the  trypano- 
some of  sleeping  sickness  lived  for  a  year  without  showing  any  symptoms 
of  disease  and  without  the  trypanosomes  appearing  in  their  blood.  It  is 
evident  then  that  w^e  must  wait  longer  before  any  results  of  treatment  can 
be  accepted.  That  a  substance  could  be  found  with  the  power  of  destroy- 
ing the  Trypanosovia  GaviJnense  in  the  tissues  of  man  is  "a  consummation 
devoutly  to  be  hoped."  Prof.  P.  Ehrlich  is  investigating  the  subject  with 
a  view  to  this  and  the  members  of  the  Sleeping  Sickness  Commission  now 
in  Uganda  are  testing  these  drugs  on  cases  of  human  trypanosomiasis  in 
the  earliest  stage.  Some  years  must  probably  elapse  before  the  result  of 
these  experiments  can  become  known,  but  they  will  be  looked  forward  to 
with  great  interest. 

Prophylaxis. — Since  we  have  found  that  at  present  there  is  no  cure  for 
this  disease,  we  must  consider  what  means  may  be  devised  for  its  pre- 
vention. There  are  three  factors  to  be  considered;  the  human  host,  the 
parasite,  and  the  tsetse-fly.  If  this  were  a  disease  affecting  a  species  of 
the  lower  animals  it  is  evident  that  the  slaughter  of  all  those  with  parasites 
in  their  blood  would  in  all  probability  nip  an  epidemic  in  the  bud.  The 
neglect  to  take  promptly  this  stamping  out  measure  led  to  disaster  in 
Mauritius  and  the  Pliilippines,  when  surra  was  introduced  into  these 
islands.  But  we  are  dealing  with  man.  We  have  seen  that  the  disease 
only  spreads  by  means  of  the  tsetse-fly,  and  in  its  absence  there  can  be  no 
infection.  Is  it  possible  to  destroy  these  flies  ?  They  are  found  in  great 
numbers  all  round  the  lake  shore,  where  there  is  dense  forest.  There 
does  not  seem  at  present  any  means  by  wdiich  such  insects  could  be  got 

*  Comptes  rendus  des  seances  de  I'Academie  des  Sciences,  CXIV,  p.  287,  Stance 
du  30  Janvier,  1905. 


TRYPANOSOMIASIS  487 

rid  of.  The  dense  jungle  can  hardly  be  entered  except  by  the  infrequent 
native  paths.  The  vegetation  is  too  green  and  damp  to  burn.  It  is  possi- 
ble that,  if  the  life-history  of  the  fly  were  more  fully  known,  some  way 
of  getting  at  it  might  be  devised.  At  present  the  destruction  of  the  carrier 
as  a  means  of  prevention  must  be  reckoned  impossible.  If  the  Baganda 
were  an  intelligent,  civilized  race  it  might  be  possible  to  get  them  to  migrate 
out  of  the  sleeping  sickness  area,  and  this  is  what  the  intelligent  among 
them  do,  but  the  great  mass  of  them  are  half-naked,  ignorant  savages, 
who  would  rather  die  than  desert  their  shambas.  Again,  if  any  big 
scheme  of  migration  was  attempted,  it  would  be  important  that  the  dis- 
trict selected  should  be  first  carefully  examined  for  any  species  of  tsetse- 
fly.  We  have  found  that  the  trypanosomes  can  be  carried  by  more 
than  one  species.  It  would,  therefore,  be  dangerous  to  allow  of  any  move- 
ment of  natives  from  the  sleeping  sickness  area  into,  let  us  say,  the  eastern 
parts  of  British  East  Africa,  where  more  than  one  species  of  tsetse  is 
found.  But  from  what  we  have  learned  of  the  etiology  of  the  disease 
the  method  of  escaping  from  it  is  easy  in  the  extreme.  Just  as  no  one 
would  expose  his  horses  or  cattle  to  the  danger  of  passing  through  a 
nagana  "Fly  belt,"  if  he  could  possibly  help  it,  so  no  one  should  expose 
himself  to  the  danger  of  living  in  a  sleeping  sickness  area.  If  it  is  neces- 
sary to  have  a  settlement  near  the  lake  shore  much  can  be  done  to  render 
it  habitable  by  cutting  down  the  jungle  in  the  vicinity  and  bringing  the 
ground,  if  possible,  under  cultivation. 


CHAPTER  XXII. 

AMGEBIC  DYSENTERY. 
By  RICHARD  P.  STRONG,  M.  D. 

Synon5nilS. — Amoebic  colitis,  amoebic  enteritis,  amoebiasis. 

Definition. — An  infectious  disease  characterized  by  a  variable  mode 
of  onset,  a  course  of  great  irregularity,  intestinal  disturbances  consisting 
chiefly  of  intermittent  attacks  of  diarrhoea  and  constipation,  abdominal 
pain,  and  the  presence  of  amoebjie,  and  sometimes  of  mucus  and  blood 
in  the  dejecta.  Besides  man,  in  the  tropics  smaller  monkeys  and  orang- 
outangs are  attacked. 

Historical  Note. — ^^Vhile  dysentery  probably  existed  in  the  earliest 
times,  since  in  the  most  ancient  writing  upon  medicine,  the  papyrus 
Ebers,  references  are  made  to  it  and  even  in  the  time  of  Hippocrates  it 
was  regarded  as  an  independent  malady,  the  suggestion  of  the  existence 
and  the  first  step  toward  the  differentiation  of  a  variety  of  amoebic  origin 
may  be  said  to  date  back  not  earlier  than  1859,  in  which  year  Lambl 
called  attention  to  the  presence  of  rhizopoda  in  the  intestinal  mucus 
of  a  child  who  had  died  from  enteritis. 

This  was  confirmed  in  1875  by  Losch,  who  found  amoebae  in  the  de- 
jecta during  life  and  in  the  intestinal  lesions  at  autopsy  of  a  case  of 
chronic  dysentery.  Losch  gave  a  careful  description  of  the  parasite, 
which  he  named  Amoeba  coli,  and  was  able  by  rectal  injections  of  the 
faeces  which  contained  living  amoebae,  to  produce  dysentery  and  ulcera- 
tions in  the  lower  portion  of  the  large  intestine  of  a  dog.  Lewis  and 
Cunningham,  in  1870  and  1881,  on  the  other  hand,  found  these  organisms 
in  cholera  stools,  as  well  as  in  those  of  individuals  suffering  from  other 
diseases,  and  even  in  the  dejecta  of  healthy  persons.  They  inclined  to 
the  belief  that  they  bore  no  causal  relation  to  intestinal  disease.  Grassi, 
Sonsino,  Normand,  Perroncito,  Calandruccio,  Blanchard,  Koch,  and 
others,  likewise  observed  amoebae  in  the  stools  of  those  suffering  with 
intestinal  disturbances,  but  Grassi  and  Perroncito  also  ascribed  no 
pathogenic  properties  to  these  parasites.  Koch,  however,  demonstrated 
amoebae  in  sections  of  the  intestine  of  those  who  had  died  of  ulcerative 
dysentery. 

The  question  of  the  significance  of  amoebae  in  intestinal  disease  was 
uncertain  until  1886,  when  Kartulis  published  the  results  of  his  investi- 
gations upon  over  150  cases  of  Egyptian  dysentery.  Amoebae  were  found 
in  the  stools  of  every  one  of  these.  In  30  control  patients  suffering 
with  other  diseases  he  found  no  amoebae.  Kartulis  thoroughly  convinced 
himself  that  this  parasite  was  the  cause  of  tropical  dysentery  and  reported 
in  his  later  papers  his  study  of  over  500  cases.  He  also  in  1887  found 
the  parasite  in  cases  of  dysenteric  abscess  of  the  liver.  Halava  in  the 
same  year,  in  Prague,  found  amoebae  in  60  instances  of  partly  endemic 


AMCEBIC  DYSENTERY  489 

and  partly  sporadic  forms  of  the  disease.  He  experimented  upon  animals, 
injecting  faeces  containing  amoebtE  into  the  rectum,  and  obtained  positive 
results  with  both  dogs  and  cats. 

In  Baltimore  in  1890,  Osier  discovered  amoebae  in  the  contents  of  a 
liver  abscess  and  in  the  stools  of  a  patient  who  was  suffering  with  chronic 
dysentery,  which  he  had  contracted  in  Panama.  Other  cases  in  which 
amoebae  were  found  in  the  stools  were  then  reported  in  the  United  States 
by  Musser,  Stengel,  and  Dock.  In  1891  Councilman  and  Lafleur  pub- 
lished a  complete  study  of  15  cases  from  Osier's  wards.  They  de- 
scribed histological  peculiarities  by  which  this  form  of  flux  differs 
from  other  types,  and  concluded  that  amoebic  dysentery  should  be 
regarded  etiologically,  clinically  and  anatomically  as  a  distinct  disease. 
It  is  to  their  important  monograph  that  we  owe  much  of  our  present 
knowledge. 

In  1894,  Kruse  and  Pasquale  by  their  extensive  studies  in  Egypt  did 
much  towards  confirming  our  belief  in  the  existence  of  amoebic  dysentery 
as  a  separate  disease  with  a  specific  etiology;  and  Harris,  in  1898,  by 
his  investigations  also  added  important  data  in  the  differentiation  of 
the  malady  in  America.  In  1900,  the  writer  showed  that  the  prevailing 
dysenteries  of  the  Philippine  Islands  could  be  divided  into  two  distinct 
forms,  one  of  which  owed  its  origin  to  a  variety  of  amoeba  (Amoeba  dysen- 
teriae),  and  the  other  to  a  species  of  bacterium  (Bacillus  dysenterise). 
Leonard  Rogers,  in  1902  and  1903,  increased  our  knowledge  of  the  dis- 
ease as  a  separate  infection  in  India,  where  its  existence  had  previously 
been  frequently  denied,  and  showed  clearly  its  association  in  that  country 
with  liver  abscess. 

These  investigations  have  convinced  many  of  us  of  the  existence  of  a 
separate  form  of  dysentery  of  amoebic  origin,  and  from  them  and  from 
other  experimental  studies  it  seems  that  we  are  justified  in  regarding 
it  as  a  distinct  form  of  intestinal  disease  to  be  distinguished  from  other 
varieties  of  dysentery.  However,  there  is  still  much  objection  to  this, 
and  it  is  opposed  by  a  number  of  authors  who  have  had  a  wide  personal 
experience  in  tropical  intestinal  affections. 

Etiology. — Distribution  and  General  Prevalence. — While  the  disease 
is  widely  prevalent  and  occurs  sporadically  in  many  subtropical  and  tem- 
perate countries,  in  tropical  ones  it  finds  its  endemic  home  and  is  indeed 
the  usual  form  of  dysentery  encountered.  It  is  particularly  prevalent  in 
the  Philippine  Islands,  India,  and  Egypt,  and  not  uncommon  in  South 
America,  particularly  in  Brazil,  and  in  the  Southern  United  States; 
sporadic  cases  are  found  from  time  to  time  in  New  England,  and  an 
occasional  case  is  encountered  in  the  Eastern,  Central,  and  Western 
States.  In  the  Eastern  Hemisphere  sporadic  cases  have  occurred,  par- 
ticularly in  Russia,  Germany,  Austria,  Italy,  and  Greece.  In  temperate 
climates  the  disease  is  rarely  epidemic,  but  occasional  outbreaks  of 
moderate  size  have  occurred,  such  as  reported  by  Jager,  in  the  German 
Army,  in  1901,  in  East  Prussia. 

Relative  Incidence  in  the  Philippine  Islands. — In  1899-1900  an 
epidemic  of  bacillary  dysentery  occurred  in  the  Philippine  Islands,  and 
in  a  series  of  147  fatal  cases  of  both  this  and  of  the  amoebic  form  of  the 
disease,  67  per  cent,  belonged  to  the  latter  variety.  Of  the  dysentery  cases 
in  Manila  during  the  past  two  years,  over  80  per  cent,  have  been  amoebic. 


490  DISEASES  CAUSED  BY  PROTOZOA 

and  nearly  90  per  cent,  of  our  fatal  cases  of  dysentery  have  shown  at 
necropsy  lesions  of  this  form.  The  disease  is  by  far  the  most  prevalent 
one  in  the  Philippine  Islands  among  white  people.  At  the  Government 
Civil  Hospital  in  Manila  the  records  kindly  furnished  by  Dr.  G.  B. 
Cook,  for  the  summer  months  of  the  year  190-1,  show  that  over  30  per 
cent,  of  all  the  wliitc  ])atients  admitted  had  amoebic  dysentery. 

Meteorological  conditions  have  considerable  influence  upon  the  prev- 
alence of  the  disease.  In  the  Philijipine  Islands  by  far  the  greatest 
number  of  cases  is  recognized  between  June  and  September,  the  largest 
number  appearing  after  the  hea.vy  rains  have  begun.  During  the  year 
1904,  after  the  great  flood  in  INIanila  in  July,  the  disease  became  almost 
epidemic,  and  the  number  of  cases  enormously  increased.  Harris  states 
that  the  onset  of  the  malady  in  the  United  States  is  almost  invariably 
in  the  simimer  months,  ]\Iay,  Juno,  July,  and  August.  Laflcur  called 
attention  to  the  fact  that  the  disease  is  observed  most  frequently  in  dis- 
tricts approaching  the  sea-level,  namely,  the  shores  of  the  Chesapeake 
Bay,  the  Gulf  of  Mexico,  and  the  Mississippi  Valley.  This  is  true  also 
in  the  Philippine  Islands,  where  near  the  sea  coast  and  in  the  low  lands 
the  disease  is  very  prevalent,  while  in  the  mountains,  particularly  in 
Benguet,  Luzon,  which  has  an  altitude  of  over  4,000  feet  and  in  which 
place  many  of  the  springs  which  funiish  drinking  water  contain  plentiful 
numbers  of  amnebne  undistinguishable  from  those  observed  in  the  water- 
supply  of  INIanila,  the  disease,  although  occasionally  encoimtered,  is 
very  rare. 

Sex. — All  observers  agree  that  the  disease  is  much  more  prevalent 
in  males.  Harris  states  that  it  seems  to  occur  in  males  about  three  times 
as  frequently  as  in  females.  In  Futcher's  series  of  119  cases  at  the  Johns 
Hopkins  Hospital,  there  were  108  males  and  11  females.  In  the  Philip- 
pine Islands  the  disease  occurs  also  more  frequently  in  males.  In  the 
Government  Civil  Hospital  of  401  cases,  the  ratio  of  males  to  females 
is  as  4.1  to  1.  In  200  personal  cases  only  23  have  been  in  females. 
Undoubtedly  in  the  tropics  men  are  more  frequently  exposed  to  infec- 
tion than  women  on  account  of  their  more  active  life. 

Age. — In  Futcher's  series  the  greatest  number  of  cases  occurred  be- 
tween the  ages  of  twenty-one  and  thirty  years.  Of  the  writer's,  149 
among  200  were  in  the  third  and  fourth  decade;  only  4  cases  occurred  in 
the  second.  The  disease  is  common  in  children  under  ten  years  of  age. 
Futcher  calls  attention  to  11  such  cases.  Musgrave  has  encountered  21 
with  1  death  in  a  series  of  100,  and  the  writer  met  with  18.  Harris  reports 
4  cases  out  of  35,  and  many  other  observers  have  also  encountered  the 
disease  in  young  children. 

Race. — In  the  Philippine  Islands  the  white  race  is  much  more  sus- 
ceptible than  the  Malay.  The  natives,  by  reason  of  their  mode  of  life 
and  condition  of  their  drinking  water,  are  constantly  exposed  to  infection, 
yet  they  do  not  suft'er  nearly  so  often  from  it  as  Americans  and  Europeans, 
At  the  Government  Civil  Plospital  the  ratio  of  white  to  native  patients 
has  been  as  2.5  to  1,  while  the  ratio  of  amoebic  dysentery  in  the  two 
races  has  been  as  9  to  1.  Futcher  and  Harris  found  that  in  the  United 
States  blacks  were  somewhat  less  frequently  attacked  than  whites. 

Unhygienic  Influences. — Harris  states  that  amoebic  dysentery  is  an 
affection  |)reemincntly  of  the  poor,  and  is  almost  always  associated  with 


AMCEBIC  DYSENTERY  491 

filth,  bad  hygienic  surroundings  and  lack  of  proper  food.  This,  however, 
does  not  hold  good  in  the  tropics,  and  in  the  Phihppine  Islands  all  classes 
are  likely  to  be  attacked  who  do  not  take  continuous  and  extraordinary 
precautions  in  regard  to  their  drinking  water.  Susceptibility,  however, 
seems  to  depend  considerably  in  some  cases  upon  the  general  physical 
condition  of  the  individual,  although  sometimes  apparently  perfectly 
healthy  and  robust  persons  are  attacked. 

The  Amoebss  of  the  Human  Intestine. — ^These  organisms  are 
classed  under  the  rhizopoda  of  the  protozoa.  They  are  unicellular  para- 
sites possessing  an  endosarc  and  ectosarc  which  can  readily  be  distinguished 
when  the  organism  is  in  motion.  The  endosarc  is  granular,  and  usually 
encloses  several  vacuoles  of  variable  size.  The  ectosarc  is  clear  and  more 
hyaline  in  appearance.  When  seen  in  the  faeces  they  frequently  contain 
red  blood  corpuscles,  the  larger  forms  sometimes  enclosing  as  many  as 
twenty.  Pigment  granules  and  bacteria  have  also  been  observed  in 
the  endosarc. 

The  parasite  moves  by  means  of  pseudopodia;  blunt  processes  con- 
sisting of  the  ectosarc  are  first  protruded  and  into  these  protrusions  the 
protoplasm  of  the  endosarc  appears  to  flow.  The  organism  is  capable 
of  changing  not  only  its  shape  but  also  its  position  and  so  moves  about. 
It  possesses  a  nucleus  which  may  sometimes  be  observed  in  the  living 
forms  but  which  can  be  more  clearly  seen  in  colored  preparations.  It 
is  usually  placed  eccentrically  in  the  endosarc  and  contains  a  nucleolus. 
The  most  satisfactory  stain  for  bringing  out  the  structure  of  the  parasite, 
in  preparations  from  the  stools,  has  been  shown  by  Woolley  to  be  Bor- 
rell's  blue.  In  tissues  the  thionin  stain  is  more  satisfactory  for  differen- 
tiation, and  for  distinguishing  the  amoebae  from  mast  cells.  Musgrave 
recommends  Wright's  modification  of  Romanowski's  method  as  most 
satisfactory  for  staining  permanent  preparations  of  the  parasite  from 
cultures,  the  technique  employed  being  the  same  as  recommended  by 
Wright  in  staining  blood  films.  The  amoebae  multiply  by  binary  fission 
and  by  sporulation. 

The  diameter  of  the  organisms  found  in  the  human  stools  has  been 
variously  estimated  at  from  10  to  50/i.  While  they  may  vary  greatly 
in  size  in  different  cases,  in  the  same  one  they  are  usually  of  a  fairly 
uniform  diameter.  Sometimes  in  stools  that  have  remained  standing 
for  some  time,  the  amoebae  become  encysted.  They  then  appear  to  be 
surrounded  by  a  coating  of  two  layers,  and  it  is  sometimes  almost  im- 
possible to  differentiate  them  morphologically  from  other  substances. 
The  outer  layer  of  the  cyst  frequently  presents  a  warty  appearance. 

Biological  Properties. — It  is  doubtful  if  amoebae  have  been  grown 
artificially  in  pure  culture  free  from  bacteria,  though  numerous  attempts 
have  been  made  to  accomplish  this  since  the  reported  successful  results 
of  Kartulis  in  1885.  He  used  a  straw  decoction  as  a  medium,  and  thought 
that  he  had  obtained  a  pure  growth  of  the  parasites  from  an  abscess  of 
the  liver  which  was  free  from  bacteria.  In  1895,  Celli  and  Fiocca  claimed 
to  have  obtained,  after  great  difficulty,  amoebae  in  pure  cultures  upon  an 
alkaline  media  containing  fucus  crispus.  However,  the  organism  did 
not  reproduce  in  transplants.  In  1898,  Tsujitani  reported  the  pure  devel- 
opment of  encysted  cultures  of  amoebae.  He  took  old  cultures  of  a  favor- 
able symbiotic  organism,  heated  them  for  an  hour  at  60°  C,  and  then 


492  DISEASES  CAUSED  BY  PROTOZOA 

plated  to  see  if  all  the  organisms  were  dead.  These  dead  cultures  were 
then  inoculated  with  encysted  amcebfe  and  development  occurred,  though 
not  so  luxuriantly  as  with  living  bacteria. 

However,  while  the  parasites  have  not  been  successfully  cultivated 
free  from  microcirganisnis,  single  species  have  been  grown  with  pure 
cultures  of  bacteria  by  numy  workers.  INIusgrave  recommends  for  the 
cultivation  of  ama4)iTj  with  bacteria,  a  medium  composed  of  agar  20 
grams,  sodium  chloride  and  extract  of  beef  each  .3  to  .5  grams,  prei)ared 
as  ordinary  bacterial  agar  and  with  a  final  reaction  of  1  per  cent,  alkaline 
to  phenolphthalcin.  The  cultivation  of  amoebae  from  the  stools,  accord- 
ing to  him,  is  frequently  more  difficult  than  of  those  found  in  water.  It 
is  necessary  that  the  proper  bacteria  should  be  present  in  the  culture 
in  order  to  obtain  a  growth  of  the  protozoa.  He  was  unable  to  cultivate 
amccbie  which  contained  red  blood  cells,  as  these  seemed  not  to  reproduce. 
Lesage  recommends  for  cultivation  ordinary  gelatin  that  has  been  thor- 
oughly washed  with  distilled  water,  and  then  sterilized. 

Behavior  Towards  Physical  Conditions  and  Chemical  Substances. — 
AVhilc  most  observers  have  remarked  that  ama^biie  usually  lose  their 
motility  in  the  stools  at  or  below  75°  F.,  Musgrave  and  Clegg  have  not 
found  this  to  be  the  case  either  in  the  stools  or  in  cultures.  Craig  asserts 
that  a  freezing  temperature  kills  amoebfe  almost  instantly.  Tuttle  goes 
so  far  as  to  say  that  the  behavior  of  amoebjE  found  in  dysentery  differs 
greatly  from  that  of  those  found  in  fresh  water  when  exposed  to  heat  or 
cold,  and  that  it  is  this  alone  which  positively  distinguishes  the  two. 
The  latter  remain  motile  at  high  or  low  degrees,  while  the  former  are 
viable  only  at  temperatures  near  that  of  the  body.  He  states  that  a  tem- 
perature of  70°  F.  is  fatal  to  the  motility  and  life  of  the  dysenteric  amcebfe. 
However,  Kruse  and  Pasquale  found  by  employing  a  dysenteric  stool 
containing  amoebse  which  had  first  been  frozen  and  then  subsequently 
thawed  and  injected  into  the  rectum  of  a  cat,  that  a  typical  dysentery 
followed  and  that  at  necropsy  the  mucosa  of  the  large  intestine  was 
swollen  and  reddened  and  covered  with  mucus  in  which  living  amoebse 
were  found.  Harris  found  that  these  organisms  were  not  killed  in  any 
reasonable  length  of  time  by  lowering  the  temperature  of  the  fluid  in 
which  they  were  contained  to  0°  C.  Musgrave,  moreover,  has  shown 
that  extreme  cold  sometimes  does  not  destroy  this  parasite.  An  encysted 
culture  of  an  amoeba  isolated  from  a  dysenteric  stool  was  placed  in  cold 
storage  at  -  12°  C,  for  forty-five  days ;  at  the  end  of  this  time  a  transplant 
gave  a  fresh  growth  of  the  amoebae.  The  same  experiment  was  repeated 
with  another  strain  of  the  organism  isolated  from  a  dysenteric  stool  and 
with  one  isolated  from  water,  but  with  neither  of  these  did  any  growth 
result.  A  temperature  of  60°  C.  maintained  for  one  hour  usually  suffices 
to  kill  encysted  cultures,  though  considerable  variation  has  been  noted 
in  the  temperature  necessary  to  destroy  different  strains. 

The  action  of  various  chemical  substances  upon  amoebae  has  received 
attention  for  a  long  time.  Harris  found  that  amoebae  (in  the  stools)  were 
not  seemingly  affected  by  saturated  solutions  of  quinine  sulphate  or 
boric  acid,  though  1  to  300  solution  of  quinine  bisulphate  invariably 
killed  them  within  ten  minutes.  They  were  destroyed  by  weak  solutions 
of  hydrogen  dioxide,  potassium  permanganate,  toluidine  blue,  and  dilute 
acids,    Rogers  found  in  scrapings  from  the  walls  of  amoebic  liver  abscesses 


AMCEBIC  DYSENTERY  493 

that  a  solution  of  quinine,  1  to  1,000,  failed  to  kill  the  parasite  even  after 
several  hours.  On  the  other  hand,  1  to  .500  solution  stcjf)[jed  all  move- 
ment of  the  amoebfe  in  from  five  to  fifteen  miiiut(;s.  In  order  to  test 
if  such  a  strength  would  be  effective  when  applied  to  the  living  wall  of  an 
abscess,  a  piece  of  such  tissue  which  was  full  of  active  amu;ba;  was 
placed  in  a  solution  of  1  to  500  sulphate  of  quinine  in  normal  salt  solution, 
and  scrapings  examined  every  five  minutes.  In  none  of  them  were  any 
living  parasites  found.  In  very  thick  walled  abscesses,  1  to  100  solution 
of  quinine  was  more  satisfactory  than  1  to  500. 

Tuttle  found  that  1  to  10,000  bichloride  of  mercury  and  1  to  100  nitrate 
of  silver  solutions  check  the  motility  but  do  not  destroy  the  parasite 
except  after  prolonged  contact.  Saline  solutions  and  5  per  cent,  of  the 
15-volume  peroxide  of  hydrogen  in  water  also  did  not  seem  to  destroy 
the  amcebEe  at  body  temperature.  However,  in  the  hands  of  this  observer 
all  of  these  substances  when  used  at  a  temperature  below  70°  F.  proved 
fatal  to  the  motility  and  life  of  the  parasite. 

Musgrave  and  Clegg  found  that  when  a  slant  culture  of  amoebae  with 
bacteria  was  treated  with  a  1  to  2,500  solution  of  quinine  hydrochlorate, 
the  parasites  quickly  encysted  and  in  from  five  to  eight  minutes  many 
had  broken  up  and  disappeared.  Ten  minutes  later  cultures  were  made 
but  no  development  of  amoebae  occurred  in  the  fresh  inoculations,  al- 
though the  bacteria  grew  out  well.  In  another  experiment,  performed 
in  the  same  manner  but  with  another  amoeba,  a  slight  growth  was  ob- 
served. Acetozone,  1  per  cent,  acid  to  phenolphthalein,  in  solutions  of 
1  to  5,000  and  1  to  2,000,  always  killed  the  amoeba  in  cultures.  Thomas 
found  that  in  cultures  of  amoebse  in  symbiosis  with  cholera  spirilla, 
boric  acid,  eucalyptol,  ichthyol,  oil  of  cassia,  and  infusion  of  quassia, 
had  slight  if  any  effect  on  the  amoebae.  Tannic  acid,  1  to  100,  sulphate 
of  copper,  1  to  2,000,  permanganate  of  potassium,  1  to  4,000,  and  sul- 
phate of  quinine,  1  to  1,000,  had  a  distinct  moderate  effect  on  the  growth 
of  the  parasite  and  spirilla  within  thirty  minutes.  Alphozone,  1  to  1,000, 
permanganate  of  potassium,  1  to  2,000,  sulphate  of  quinine,  1  to  500, 
nitrate  of  silver,  1  to  2,000,  argyrol,  1  to  500,  and  protargol,  1  to  500, 
exercised  a  very  marked  effect  on  the  growth  of  the  cultures  within  thirty 
minutes,  and,  with  the  silver  salts  and  alphozone,  the  action  was  plainly 
due  to  the  destruction  or  inhibition  of  the  growth  of  the  symbiotic  cholera 
spirillum.  Thymol,  1  to  2,500,  applied  for  fifteen  minutes  had  the  most 
marked  effect,  in  some  instances  destroying  the  amoebse,  while  exercising 
only  a  moderate  effect  on  the  cholera  spirilla. 

In  regard  to  special  physiological  processes  of  dysenteric  amoebse,  little 
is  known.  We  are  aware  that  certain  definite  secretions  occur  in  the 
protoplasmic  body,  some  of  which  evidently  go  to  make  up  the  mantle 
which  forms  about  the  parasite  in  encystation.  It  has  been  supposed  by 
some  that  the  engulfing  of  certain  substances  in  the  protoplasm — red 
blood  corpuscles,  bacteria,  granular  material,  etc., — occurred  for  the 
purpose  of  nourishment.  Some  have  thought  that  the  pigment  masses 
which  amoebse  sometimes  contain  are  the  remnants  of  partially  digested 
red  cells.  This  may  be  true,  but  no  proteolytic  enzymes  have  as  yet 
been  isolated,  though  Mouton  has  obtained  a  proteolytic  ferment,  resemb- 
ling trypsin,  from  cultures  of  an  amoeba  isolated  from  garden  earth, 
and  grown  in  symbiosis  with  Bacillus  coli  communis. 


494  DISEASES  CAUSED  BY  PliOTOZOA 

Distribution  of  Amoebae  in  the  Body. — Besides  the  intestine  and 
neighboring  tissues,  the  iibdoniinal  cavity,  abscess  of  the  Uver,  lung,  and 
pleura,  anuvbie  have  been  found  hi  the  followhig  pathological  conditions: 
in  aschic  Huid  in  cases  of  abdominal  tumor;  in  necrosis  of  the  jaw-bone; 
in  abscess  of  the  mouth;  and  in  disturbances  of  the  bladder  and  urine. 
Celli  and  Fiocca  reported  their  cultivation  from  the  larynx  and  lungs 
in  cases  of  tuberculosis,  and  Gross  and  Sternberg  found  them  in  tartar 
scraped  from  the  teeth.  Frequently  when  present  in  the  bladder  a  sinus 
leading  into  the  rectum  (as  has  been  true  in  several  of  our  cases)  is  found, 
or  one  has  previously  existed,  but  this  is  not  always  the  case. 

Classification. — Some  observers  have  believed  that  more  than  one 
species  of  anueb;e  occur  at  times  in  the  intestine  of  man,  and  some  have 
considered  that  not  all  are  pathogenic  but  that  some  are  harmless  sapro- 
phytes. Kartulis,  in  reply  to  Grassi's  communication,  in  which  it  was 
stated  that  amoebre  had  been  found  in  the  stools  of  healthy  persons, 
asserted  that  these  organisms  were  not  of  the  same  variety  as  those  which 
he  had  found  in  dysenteric  cases  in  Egypt.  However,  he  did  not  definitely 
prove  this  assertion.  Councilman  and  Lafleur,  believing  on  account  of 
the  number  of  observers  who  had  found  amoebte  in  the  stools  of  healthy 
persons  that  there  might  be  more  than  one  species  encountered  in  the 
human  hitestine,  proposed  the  name  amwha  dijsenteriop  for  the  pathogenic 
variety,  and  reserved  the  one  of  amoeba  coli  for  the  non-pathogenic  organ- 
ism of  the  normal  intestine. 

Quincke  and  Roos,  in  1893,  believed  that  they  could  distinguish  three 
varieties  of  amoeba.  (1)  Amoeba  coli  Losch,  or  amoeba  coli  felis,  which 
measured  from  20  to  25«  in  diameter,  possessed  a  finely  granular  plasma 
and  a  spherical  nucleus,  and  contained  blood  corpuscles  in  the  endosarc. 
Its  cysts  were  spherical  and  presented  a  double  contour.  It  was  found 
in  the  stools  of  human  amoebic  enteritis,  and  upon  injection  into  cats 
was  pathogenic  for  these  animals.  (2)  Amoeba  coli  mitis  was  somewhat 
larger  than  (1),  (40/i);  its  protoplasm  was  coarsely  granular  and  con- 
tained vacuoles.  The  nucleus  did  not  have  such  a  sharp  contour  and 
its  motility  was  less.  Included  red  blood  corpuscles  were  never  seen. 
This  variety  was  also  obtained  from  the  stools  in  human  intestinal 
disturbance  but  was  found  to  be  non-pathogenic  for  cats.  (3)  Amoeba 
intestini  vulgaris  was  found  in  the  stools  of  a  healthy  man.  It  was 
morphologically  similar  to  the  second  and  not  pathogenic  for  cats;  but 
since  it  was  found  in  a  healthy  individual,  the  authors  considered  it  a 
third  species. 

Kruse  and  Pasquale,  after  numerous  inoculation  experiments  per- 
formed on  animals,  distinguished  two  varieties  of  amoebae  found  in  the 
human  intestine.  They  adopted  the  name  of  amoeba  dysenteric  (Council- 
man and  Lafleur)  for  the  pathogenic  variety,  and  amoeba  coli  for  the 
harmless  one  occurring  in  the  stools  of  healthy  persons.  The  latter  they 
observed  in  their  own  stools  when  no  symptoms  of  disease  were  present. 

Celli  and  Fiocca  have  described  six  different  varieties  of  amoebae  found 
in  the  human  stools.  (1)  Amoeba  lobosa  var.  guttula  measured  from 
2  to  4/z  in  diameter,  the  smallest  forms  from  1  to  2/i.  It  possessed  a 
hyaline  ectoplasm  and  blunt  motile  pseudopodia.  (2)  Amoeba  lobosa 
var.  oblonga  was  double  the  size  of  the  former  variety  and  contained 
one  or  two  non-contracting  vacuoles.     Its  pseudopodia  were  short  and 


AMCEBIC  DYSENTERY  495 

compact  and  oblong  in  shape.  (3)  Amoeba  spinosa  (n.  sp.).  This 
variety  was  found  in  the  healthy  and  dysenteric  stf)ols  of  man  and  also 
in  the  intestine  of  guinea-pigs  and  frogs.  It  had  little  motility.  It 
measured  from  6  to  10/i  in  size.  There  was  little  ectoplasm  and  the 
entoplasm  contained  from  1  to  7  non-contracting  vacuoles.  Cystic  forms 
were  observed.  (4)  Amoeba  diaphana  (n.sp.)  was  also  found  in  the 
dysenteric  intestine.  The  ecto-  and  entoplasm  was  very  difficult  to  dis- 
tinguish. It  showed  very  active  motility  and  measured  from  0.5  to  2/x 
in  diameter.  (5)  Amoeba  vermicularis  (Weisse)  was  found  in  the  dysen- 
teric intestine,  and  also  in  the  vagina  of  healthy  women  and  of  those 
suffering  from  carcinoma.  It  varied  from  4  to  Q/j.  in  length  and  was 
1/i  in  breadth.  No  differentiation  between  ecto-  and  entoplasm  could  be 
made  out  and  it  contained  no  vacuoles.  (6)  Amoeba  reticularis  (n.  sp.). 
The  form  of  this  species  was  very  constantly  oval;  the  pseudopodia  were 
angular  and  their  movements  slow;  the  organism  measured  from  2  to  4fi 
in  diameter.  There  was  no  visible  nucleus.  The  protoplasm  was  hyaline 
and  homogeneous.  Celli  and  Fiocca  regarded  none  of  these  species  as 
the  cause  of  dysentery. 

In  the  earlier  work  in  Manila  it  was  thought  that  at  least  two  varieties 
of  amoebae  found  in  the  human  stools  could  be  distinguished— amoeba 
dysenteriae  and  amoeba  coli.  This  differentiation  was  based  primarily 
upon  the  pathogenic  action,  as  with  one  species  found  in  the  stools  of 
dysenteric  patients  typical  lesions  could  be  produced  in  cats,  and  with 
another,  from  the  fgeces  of  persons  with  apparently  no  intestinal  disturb- 
ance, we  did  not  succeed  in  obtaining  any  lesions.  With  still  a  third 
amoeba  which  developed  in  cultures  of  straw  infusions,  no  pathological 
changes  were  produced  upon  injection  into  animals.  Having  observed 
these  differences,  other  points  of  differentiation  were  sought  for.  The 
most  striking  of  these  was  that  in  the  dysenteric  amoeba  the  distinction 
between  endosarc  and  ectosarc  could  be  readily  made  out,  and  that  in 
the  harmless  one,  the  protoplasm  of  the  ectosarc  was  not  nearly  so 
refractive.  The  nucleus  of  the  former  was  eccentrically  placed  and  could 
best  be  made  out  in  stained  preparations,  while  in  the  latter  it  was  small 
and  compact.  The  only  other  differences  noted  were  that  the  amoebae 
found  in  the  stools  of  apparently  healthy  individuals  were  never  seen  to 
contain  red  blood  corpuscles,  and  they  also  seemed  generally  somewhat 
smaller  than  the  dysenteric  amoeba,  since  in  a  large  number  of  measure- 
ments their  diameter  was  usually  less  than  25/i,  and  in  the  dysenteric 
stools  the  amoeba  sometimes  measured  as  high  as  from  35  to  50/i  in 
diameter.  Shiga  later  described  amoeba  dysenteriae  as  from  three  to  five 
times  as  large  as  amoeba  coli.  However,  the  size  of  the  parasites  cannot 
longer  be  regarded  as  an  aid  in  the  separation  of  the  species,  since  a 
number  of  competent  observers  have  reported  very  small  amoebae  as  the 
only  parasites  present  in  undoubted  amoebic  dysentery.  Moreover,  the 
size  of  the  organism  may  greatly  change  in  cultivation  and  very  small 
amoebae  may  become  large.  Further  observations  suggest  that  animal 
experiments  are  often  misleading,  as  one  frequently  encoimters  failures 
when  undoubtedly  employing  the  dysenteric  species;  and  unless  large 
series  of  inoculations  are  performed  with  each  organism,  the  results  are 
likely  to  be  doubtful  or  misleading.  Since  pure  cultures  of  amoebae  can- 
not be  obtained  except  in  the  contents  of  sterile  liver  abscesses  in  which 


496  DISEASES  CAUSED  BY  PROTOZOA 

other  toxic  material  is  probably  present,  many  observers  decline  to  accept 
the  pathogenesis  of  an  ama^ba  as  a  point  in  differentiation.  However, 
Sehaudinn^  has  described  additional  details,  particularly  in  encystation 
and  reproduction,  by  which  these  organisms  may  be  definitely  separated. 

Schaudinn  believed  that  und  jr  the  name  of  amoeba  coli,  various  authors 
have  referred  to  .two  entirely  distinct  organisms  which  differ  so  much 
in  their  manner  of  development  and  reproduction  that  they  could  even 
be  placed  in  dift'erent  genera.  One  of  these  forms  lives  commonly  in  the 
intestine  of  healthy  man  but  can  also  exist  in  the  dysenteric  intestine 
with  the  second  species.  The  latter  he  foimd  only  in  cases  of  dysentery 
of  tropical  origin  and  with  it  he  produced  ulceration  in  the  large  intes- 
tine of  cats  by  feeding  the  encysted  forms.  He  points  out  that  the  harm- 
less amoeba  is  the  one  which  has  been  carefully  studied  and  described 
by  Casagrandi  and  Barbagallo,  who  also  demonstrated  its  non-pathogen- 
icity.  From  the  description  given  by  these  authors,  Schaudinn  was  able 
to  recognize  that  he  was  encountering  the  same  amoeba,  and  he  has  been 
able  to  confirm  their  work  entirely.  Yet  he  was  unable  to  say,  from  the 
published  descriptions,  whether  the  species  which  Losch  and  other 
observers  have  described  under  the  name  amoeba  coli  was  the  same  as 
that  which  Casagrandi  and  Barbagallo  had  studied.  These  latter  authors 
named  the  form  they  encountered  entamoeba  hominis,  believing  that  it 
was  the  same  form  which  Losch  had  described.  Schaudinn  pointed  out 
that  since  it  was  necessary  to  establish  a  new  genus  and  their  description 
was  the  first  accurate  one  of  the  organism,  the  name  of  "entamoeba" 
should  stand,  but  as  they  supposed  they  had  the  same  form  as  Losch 
the  name  "coli"  should  be  substituted  for  "hominis."  Schaudinn 
infected  himself  on  two  occasions  by  ingesting  the  cysts  of  this  harmless 
amoeba.  In  both  cases  the  artificial  infection  was  controlled  by  the 
examination  of  his  stools  for  two  months.  Young  cats  were  also  infected 
for  the  purpose  of  the  study  of  cyst  formation. 

With  reference  to  the  structure  of  this  harmless  amoeba  (entamoeba 
coli),  he  emphasizes  that  during  rest  the  characteristic  differentiation 
between  ectoplasm  and  entoplasm  does  not  exist  and  that  it  is  only  in 
the  formation  of  pseudopodia  that  the  hyaline  appearance  of  the  former 
is  noted.  The  nucleus  is  vesicular,  spherical,  and  provided  with  a  thick, 
dense,  nuclear  membrane.  The  nucleolus  consisting  of  plastin  and  chro- 
matin occupies  its  centre,  while  the  remaining  granular  chromatin  is 
distributed  in  the  achromatin  network.  The  multiplication  takes  place 
either  by  simple  division  or  through  spore  formation  (schizogony).  In 
the  former  case  the  nucleus  become  contracted  in  the  centre,  assuming 
a  dumb-bell  shape,  and  parts  amitotically.  Then  the  entire  cell  divides 
after  the  separation  of  the  daughter  nuclei.  In  reproduction  by  schizog- 
ony the  chromatic  substance  of  the  nucleus  separates  into  eight  parts, 
which  after  dissolution  of  the  nuclear  membrane  become  distributed  in 
the  protoplasm  as  daughter  nuclei.  The  soft  protoplasm  then  divides 
into  eight  young  amoebse. 

Schaudinn  recommended  the  half  fluid  stools  as  most  favorable  for  the 
study  of  the  encystation  of  this  organism.  He  stated  that  there  are  few 
objects  so  favorable  for  nuclear  study  in  the  living  cell  as  these  cysts, 

^  Arbeiten  aus  dem  Kaiserlichen  Gesundheitsamte,  Bd.  19,  1903. 


AM(EBIC  DYSENTERY  497 

whose  plasma  is  entirely  clear  of  all  foreign  bodies,  and,  with  proper 
artificial  light,  the  nucleus  appears  as  sharp  and  plain  as  in  a  stained 
preparation.  Already  in  the  resting  state,  if  they  do  not  contain  many 
foreign  bodies,  the  nucleus  can  always  be  clearly  recognized.  In  encysta- 
tion  the  foreign  bodies  are  cast  out  of  the  plasma,  which  becomes  entirely 
clear  and  transparent,  and  the  nucleus  then  can  be  even  more  clearly 
seen. 

Entamoeba  histolytica  (n.  sp.);  this  was  found  by  Schaudinn  in  the 
stools  of  those  suffering  with  dysentery  contracted  in  the  tropics.  It  is 
different  from  the  harmless  form;  the  plainly  developed  ectoplasm  is 
more  strongly  refractive  and  hyaline  than  in  entamoeba  coli.  In  the 
latter  form  the  hyaline  pseudopodial  plasma  in  contrast  to  the  remaining 
plasma  is  not  well  differentiated  and  is  much  less  refractive  than  in  ent- 
amoeba histolytica,  in  which  there  is  always  a  plainly  developed  ecto- 
plasm existing  as  a  plasma  zone  and  possessing  a  stronger  refraction 
than  the  entoplasm.  Jiirgens  had  already  called  attention  to  the  glassy 
hyaline  appearance  of  the  ectoplasm  in  the  dysenteric  amoeba,  and  this 
property,  Schaudinn  stated,  is  most  important  in  the  living  amoeba 
and  to  it  may  be  attributed  special  phenomena.  The  harmless  entamoeba 
coli  with  their  soft  pseudopodia  cannot  enter  into  the  healthy  mucosa  of 
the  intestine  but  the  dysenteric  amoeba  is  able,  by  means  of  its  stiff 
hyaline  ectoplasm,  to  penetrate  between  the  epithelial  cells  and  to  sep- 
arate them  from  one  another.  Schaudinn,  in  freshly  cut  sections  of  the 
intestine  of  infected  cats,  watched  for  an  hour  the  process  by  which  this 
protozoon  separates  the  epithelial  cells  from  one  another. 

The  nucleus  of  entamoeba  histolytica  is  very  difficult  to  recognize  in 
fresh  specimens.  Its  shape  changes  very  easily  and  it  often  becomes 
stretched  out.  Its  position  is  always  eccentric.  The  parasite  multiplies 
by  division  and  budding.  Under  unfavorable  conditions  for  the  organ- 
ism, spores  are  formed.  The  usual  method  of  reproduction  is  as  follows : 
The  nucleus  expels  some  chromatin  into  the  protoplasm  and  finally 
itself  degenerates.  In  the  encystation  in  vivo  it  is,  under  the  eye  of  the 
observer,  later  expelled  and  cut  off.  Small  spherical  bodies  possessing 
a  diameter  of  from  3  to  1  p.,  and  presumably  containing  some  of  the 
particles  of  chromatin,  become  formed  in  the  cyst.  The  plasma  then 
appears  at  the  periphery  protruded  and  bulged  out  and  these  buds  are 
cut  off  finally  in  the  form- of  balls  which  show  a  concentrically  arranged 
filamentous  structure.  They  soon  secrete  an  opaque  membrane  and  all 
further  process  of  development  becomes  invisible.  The  rest  of  the 
amoeba  dies.  The  small  round  forms  Schaudinn  believed  bring  forth 
in  the  course  of  time  a  new  infection,  and  this  he  showed  by  his  experi- 
ments on  animals.  While  he  observed  spore  formation  he  never  saw  the 
eight  nuclear  cysts  in  the  development  of  entamoeba  histolytica.  On  one 
occasion  when  he  did  find  these  cysts  in  an  infection  with  entamoeba 
histolytica  he  was  able  to  prove  later  that  a  double  infection  with  both 
amoebse  existed. 

Craig  points  out  that  since  Councilman  and  Lafleur  accurately  de- 
scribed the  amoeba  dysenterise,  the  name  "histolytica"  should  be  dropped 
and  this  species  should  be  known  as  entamoeba  dysenterise.  However, 
Schaudinn  was  the  first  to  call  attention  to  the  essential  differences  by 
which  these  two  organisms  might  be  separated  from  a  zoological  stand- 
32 


498  DISEASES  CAUSED  BY  PROTOZOA 

point,  for  Lafleiir  in  his  later  paper  stated  that  no  definite  morphological 
differences  had  been  found  between  the  ama^ba  occurring  in  the  stools  of 
healthy  persons  and  in  patients  suffering  with  dysentery. 

Lesage  gives  the  same  characteristic  distinctions  for  entamoeba  histolyt- 
ica that  Schiiudinn  had  mentioned.  Upon  staining  these  amoebie  in 
cultures  by  Laveran's  method,  the  protoplasm  colored  itself  lightly  and 
uniformly  except  at  one  point  near  the  periphery  where  it  (the  nucleus) 
stained  more  deeply.  In  the  cysts  the  surrounding  membrane  did  not 
stain  and  there  was  a  clear  space  between  it  and  the  protoplasm.  The 
latter  during  development  was  sometimes  seen  to  be  almost  separated 
into  three  portions,  each  of  which  enclosed  a  lightly  stained  nucleus. 

Craig  in  his  most  recent  work  also  confirms  Schaudinn's  observations. 
He  says  in  addition  that  the  ama'ba  dysenterire  is  larger,  and  that  when 
stained  a  diagnosis  can  be  made  by  observing  that  the  ectoplasm  colors 
much  more  intensely  than  the  entoplasm,  w'hile  in  entamoeba  coli  the 
opposite  is  true.  The  latter  form  is  not  actively  motile  in  the  stools  and 
a  vacuole  is  seldom  seen. 

Occurrence  of  Amoebae  in  Healthy  Persons. — The  presence  of 
amoebre  in  the  stools  of  apparently  healthy  individuals  has  inclined  many 
authors  to  believe  that  all  amoebjie  are  without  etiological  or  pathological 
significance.  Among  the  more  striking  of  these  observations  in  recent 
times  may  be  mentioned:  Schuberg,  in  1893,  found  amoebje  in  the  stools 
of  10  out  of  20  healthy  persons  to  whom  a  dose  of  Carlsbad  salts  had 
been  given.  Kruse  and  Pasquale,  in  1894,  when  perfectly  healthy, 
observed  amoebse  in  their  own  fjeces  and  in  those  of  38  persons  either 
healthy  or  suffering  with  diseases  other  than  dysentery.  Upon  some 
of  these,  fresh  autopsies  were  performed  and  the  intestine  carefully 
examined.  In  1899,  the  writer  examined  with  Musgrave  in  the  Philippine 
Islands,  persons  who  had  no  dysentery  nor  any  history  of  the  disease 
and  found  amoebae  in  the  faeces  in  4  per  cent.  A  dose  of  Rochelle  salts 
had  been  given  by  the  mouth  previously.  Schaudinn  recently  found 
amoebae  which  he  considered  harmless  in  the  stools  of  34  of  68  healthy 
people  in  East  Prussia,  in  one-fifth  of  the  cases  examined  in  Berlin,  and 
in  256  out  of  385  in  Austria.  Schaudinn  twice  infected  himself  with  this 
amoeba  and  controlled  his  faeces  before  the  infection  for  two  months 
in  order  to  be  sure  that  his  stools  were  free  from  these  parasites.  After 
infection  he  suffered  from  no  intestinal  disturbance.  Craig  in  1905, 
examined  200  patients  not  suffering  wdth  dysentery  and  found  amoebae 
in  65.  However,  in  other  regions  observers  who  have  sought  at  random 
in  the  stools  of  healthy  individuals  for  these  parasites  have  failed  to  find 
them.  Notable  among  these  investigations  may  be  mentioned  those  of 
Dock  in  the  United  States  and  of  Zorn  in  Munich. 

There  are  periods  in  the  course  of  amoebic  dysentery,  particularly  in 
the  earlier  stages,  in  w^hich  symptoms  are  entirely  lacking.  Hence  when 
amoebae  are  found  in  the  stools  of  healthy  individuals  we  cannot  say 
that  they  are  not  suffering  wqth  an  early  or  latent  form  of  the  disease, 
or  that  the  malady  does  not  exist  in  its  incubation  period,  unless  we  follow 
them  over  long  periods  of  time  in  which  no  disease  develops.  The  writer 
had  opportunity,  among  private  patients,  to  study  some  instances. 
One  occurred  in  a  chemist  of  our  laboratory  w^ho  in  August  asked  that 
an  examination  be  made  of  his  faeces,  as  he  had  a  slight  attack  of  diarrhoea 


AMCEBIC  DYSENTERY  409 

the  day  before.  An  unusually  rich  infection  with  amoebae  was  found 
and  he  promised  to  undergo  the  usual  local  treatment  but  next  day  as 
he  felt  perfectly  well,  the  diarrhoea  having  entirely  ceased,  he  remon- 
strated against  beginning  it.  However,  he  did  take  enemata  for  about 
a  week,  but  subsequently  did  not  pursue  any  further  treatment.  His 
stools  were  many  times  examined  and  always  infection  with  amnebse 
was  demonstrated,  the  last  being  on  December  10th.  Two  examinations 
made  towards  the  end  of  January  showed  that  the  amoebae  had  dis- 
appeared. During  the  period  from  August  to  December  he  was  without 
a  single  manifestation  of  disease.  The  stools  were  formed  and  appar- 
ently normal.    He  has  been  perfectly  well  since. 

It  would  appear  that  there  are  some  individuals,  apparently  perfectly 
healthy,  who  harbor  amoebae  in  large  numbers  for  long  periods  without 
any  unfavorable  symptoms.  It  is  not  necessary  to  suppose  that  lesions 
are  always  present,  although  in  some,  lesions  may  exist  which  we  cannot 
always  be  aware  of  during  life;  and  the  questions  arise,  are  these 
instances  of  natural  resistance  or  immunity  against  the  parasite,  or  are 
they  instances  in  which  the  parasites  are  unable  to  exert  any  harmful 
action  until  the  proper  symbiotic  bacteria  appear  in  the  intestine  and  are 
only  awaiting  this  moment  to  become  pathogenic,  or  are  they  cases  in 
which  the  organisms  are  still  incapable  of  producing  any  injury  until 
through  some  mechanical  disturbance  a  small  erosion  in  the  mucosa 
occurs,  or  are  they  instances  of  infection  with  an  amoeba  harmless  to  man  ? 
With  our  present  knowledge  some  of  these  questions  are  very  difficult  to 
answer.  Some  incline  to  the  belief  that  all  amoebae  are  pathogenic  and 
maintain  that  in  every  case  in  which  infection  is  found,  even  though  there 
be  no  symptoms,  local  treatment  should  be  instituted  and  pursued  until 
the  amoebae  disappear.  Musgrave  quotes  his  recent  experiences  in  sup- 
port of  this.  He  found  in  the  examination  of  the  stools  of  300  prisoners 
in  Manila  that  101  were  infected  with  amoebae;  61  of  these  in  whom  the 
parasites  were  found  were  suffering  with  dysentery,  but  the  other  40  stated 
they  had  no  diarrhoea.  During  the  next  two  months  8  of  the  40  cases 
died  of  intercurrent  disease,  and  satisfactory  evidence  of  amoebic  in- 
fection was  present  in  all.  Three  and  a  half  months  later  all  of  the 
remaining  32  cases  (with  the  exception  of  2  discharged  from  the  prison) 
had  amoebae  in  their  stools  and  were  suffering  with  dysentery.  How- 
ever, this  does  not  disprove  the  existence  of  a  harmless  amoeba  or  the 
presence  of  such  an  organism  in  the  intestines  of  his  patients  in  con- 
nection with  the  dysenteric  amoeba.  Since  Schaudinn  has  shown  us 
that  zoologically  two  distinct  species  of  amoeba  exist  in  human  stools, 
it  is  necessary  that  careful  studies  be  made  of  each  of  these  species,  that 
the  cases  in  Avhich  they  are  present  singly  and  conjointly  be  separated 
and  carefully  observed.  Natural  immunity  should  be  considered  in 
this  study.  The  writer  has  undertaken  this  differentiation  in  cases  of 
amoebic  infection,  but  is  not  prepared  at  this  time  to  speak  with  cer- 
tainty as  to  the  entire  non-pathogenesis  of  the  so-called  entamoeba  coli. 
Theoretically  it  would  seem  not  unlikely  that  should  erosions  in  the  mucosa 
occur,  the  amoebae  might,  by  their  mechanical  movements  and  wanderings 
and  by  carrying  adherent  intestinal  bacteria  with  them  into  the  broken 
epithelial  layers,  aid  m  continuing  the  existing  lesions.  There  are, 
theoretically,  from  the  description  which  Schaudinn  has  given,  obAious 


500  DISEASES  CAUSED  BY  PROTOZOA 

reasons  for  sup])osing  tliat  entamcL^ba  histolytica  is  the  more  harmful 
organism  for  man;  but  it  seems  that  any  classification  into  pathogenic 
and  non-pathogenic  amoebix;  based  alone  upon  the  differences  in  the 
movements  and  character  of  the  ectoplasm  should  be  accepted  with 
caution.  Before  coming  to  any  more  definite  conclusion  about  the 
relative  pathogenic'ty  of  entamoeba  histolytica  and  entama^ba  coli,  a 
more  careful  investigation  should  be  made  of  the  secretory  products  of 
these  jxxrasites  and  a  search  made  for  their  enzymes,  soluble  and  endo- 
toxins, etc.  We  know  nothing  yet  of  the  relative  virulence  of  amoebae 
or  whether  their  pathogenesis  under  certain  conditions  may  be  increased 
by  long  periods  of  existence  in  the  hmnan  intestine. 

Occurrence  of  Amoebse  in  the  Stools  of  Those  Suffering  with 

Other  Diseases  than  Dysentery. — Another  argument  advanced  against 
the  etiological  significance  of  amo-bre  in  dysentery,  and  brought  forward 
as  recently  as  1902  by  Duncan,  is  the  fact  that  these  organisms  have 
been  found  in  the  intestines  of  those  suffering  with  other  diseases,  such 
as  chronic  diarrhoea,  cholera,  intestinal  tuberculosis,  typhoid  fever, 
hirmorrhoids,  etc.  In  many  of  the  reported  cases  the  htT?morrhoids  might 
probably  be  regarded  as  a  complication,  and  the  chronic  diarrhoea  as 
stages  of  pathogenic  amoebic  infection.  But  it  should  also  be  borne 
in  mind  that  in  some  of  these  the  entamoeba  coli  may  have  been  the 
form  of  protozoon  present.  Lafleur  mentions  a  case  of  malignant  dis- 
ease of  the  stomach  in  which  the  light  fluid  movements  contained  many 
active  amcebtie  but  no  ulceration  of  the  bowel  existed,  and  Kruse  and 
Pasquale  found  no  lesion  at  autopsy  in  some  of  their  patients  in  whom 
amoebae  were  present. 

In  the  tropics,  where  amoebic  dysentery  is  so  common  and  frequently  a 
chronic  disease  of  long  standing,  concomitant  occurrence  with  typhoid 
fever,  cholera,  or  tuberculosis,  is  not  so  very  uncommon.  In  the  writer's 
series  of  100  fatal  cases  of  amoebic  dysentery  in  soldiers  there  were  4  cases 
of  concomitant  infection  with  typhoid  fever,  in  1  of  which  death  occurred 
from  a  perforation  in  the  ileum.  The  third  case  of  cholera,  at  the  begin- 
ning of  the  great  Manila  epidemic  in  1902,  was  one  of  double  infection 
with  amoebic  dysentery  and  this  disease,  and  during  the  outbreak  a 
number  of  others  were  found. 

The  Non-occurrence  of  Amoebse  in  the  Stools  of  Dysenteric 
Patients. — Many  observers  have  advanced  the  argument  that  since 
amoebae  are  not  found  in  the  faeces  or  in  the  intestines  of  those  suffering  with 
tropical  epidemic,  or  sporadic  dysentery,  these  organisms  are  not  the  cause 
of  the  disease.  Shiga  in  Japan,  Flexner  and  the  writer  in  the  Philippines, 
and  Leonard  Rogers  in  India,  have  shown  that  tropical  dysentery  consists 
of  at  least  two  forms,  one  due  to  a  species  of  anKcba  and  the  other  to 
a  species  of  bacterium.  These  conclusions  have  been  confirmed  also  for 
temperate  climates  by  a  number  of  observers  in  the  United  States  and 
in  Europe.  In  addition  to  these  forms  there  is  a  third  catarrhal  dysen- 
tery, which  is  seen  occasionally  in  the  tropics  and  has  a  varied  etiology. 
It  is  occasionally  indistinguishable  clinically  from  amoebic  dysentery. 

Inoculation  Experiments. — Several  methods  have  been  chiefly  em- 
ployed. (1)  The  direct  injection  into  the  rectum  of  faeces  containing 
the  parasites.  In  this  manner  positive  results  have  been  obtained  in 
cats  and  dogs.    It  is  to  be  noted  that  in  these  experiments  not  all  the 


AMCEBIC  DYSENTERY  501 

inoculated  animals  became  infected,  and  that  single  experiments  and 
those  in  which  unsuitable  material  is  employed  are  Ukely  to  fail.  How- 
ever, there  is  no  doubt  that  lesions  may  be  produced  in  the  large  intestine 
in  cats  by  this  method,  though  there  are  often  many  difficulties.  (2)  By 
feeding  encysted  forms  of  amoebae.  Casagrandi  and  Barbagallo,  Caland- 
ruccio,  and  Schaudinn,  fed  themselves  encysted  amoebae,  produced  infec- 
tion and  reobtained  the  amoebae  from  their  stools.  They  had  no  symptoms 
of  disease  following  the  infection.  They  also  infected  cats  by  feeding 
encysted  cultures  of  this  parasite  but  obtained  no  symptoms  of  disease. 
Upon  feeding  the  cysts  of  entamoeba  histolytica  to  cats,  Schaudinn  ob- 
tained dysentery  and  ulceration  of  the  large  intestine  in  which  were 
found  numerous  amoebse.  Quincke  and  Roos  fed  stools  containing 
encysted  amoebse  to  two  cats  and  obtained  infection  and  amoebic 
ulceration,  which  they  observed  at  autopsy.  Musgrave  fed  encysted 
amoebse  in  cultures  with  bacteria  to  monkeys  and  obtained,  in  a  small 
percentage  of  the  cases,  dysentery  and  ulcerations  in  which  amoebse 
were  found.  The  bacteria  which  were  fed  with  the  amoebse  were  not 
recovered  from  the  stools,  showing  that  it  was  not  these  microorganisms 
that  had  produced  the  disease. 

Against  these  experiments,  in  which  bacteria  together  with  the  amoebse 
were  employed,  being  used  as  an  argument  in  favor  of  the  pathogenesis 
of  the  parasites,  objection  was  naturally  urged.  Therefore  attempts  were 
made  to  employ  material  in  which  amoebse  were  present  without  micro- 
organisms. Kartulis,  and  Kruse  and  Pasquale,  used  the  contents  of 
sterile  liver  abscesses  and  produced  dysentery  and  ulcerations  in  the 
intestines  of  cats  by  rectal  injections.  They,  however,  stated  that  while 
the  lesions  in  their  most  successful  experiments  bore  in  many  points  a 
striking  resemblance  to  those  seen  in  man,  they  were  not  identical.  In 
1899,  the  writer  obtained  dysentery  and  perfectly  typical  amoebic  ulcera- 
tions in  the  large  intestine  of  cats  by  the  injection  into  the  rectum  of  portions 
of  the  contents  of  a  liver  abscess  which  contained  living  amoebse  but  was 
otherwise  sterile.  These  lesions  were  perfectly  typical  of  the  lesions 
seen  in  man.  Many  of  the  ulcers  showed  a  distinct  undermining  of  the 
mucosa  and  a  round-cell  infiltration  of  the  submucosa  with  numerous 
amoebse  at  the  base  of  the  ulcers.  Some  of  these  specimens  are  now  in 
the  Army  Medical  Museum  in  Washington.  These  experiments  are 
suggestive  of  the  pathogenesis  of  this  species  of  amoeba. 

It  is  possible  that  toxic  substances  may  be  introduced  with  the  amoebse 
in  the  pus  of  these  liver  abscesses,  and  it  might  be  argued  that  these 
cause  erosions  of  the  mucosa.  However,  a  chemical  substance  alone 
could  hardly  produce  the  typical  anatomical  lesions  of  the  disease  which 
are  so  peculiar  to  amoebic  infection  alone  and  which  no  one  has  pro- 
duced without  amoebse.  Probably  as  much  as  could  be  expected  has 
been  gained  from  experiments  on  animals.  Before  leaving  the  subject 
it  is  interesting  to  note  that  both  the  lower  monkeys  and  orang-outangs 
contract  the  disease  naturally.  At  one  time  as  many  as  four  or  five  of 
our  laboratory  animals  have  suffered  with  naturally  acquired  infection. 
One  of  our  imported  orang-outangs  recently  died  of  a  natural. infection 
of  the  disease. 

Source  of  Amogbse  and  Mode  of  Infection. — In  Manila  the  greatest 
source  of  infection  is  the  water-supply.     Amoebse  were  frequently  culti- 


502  DISEASES  CAUSED  BY  PROTOZOA 

vated  from  it  in  large  numbers  in  1902,  but  no  attempt  was  made  to 
demonstrate  their  patiiogenicity.  In  1904,  INIusgrave  injeeted  directly 
into  the  exposed  civcum  of  a  monkey,  by  a  hypoilerniic  syringe,  an  old 
culture  of  ixn  amoeba  growing  with  bacteria  that  had  been  isolated  from 
the  city  water-supply.  A  month  later  violent  diarrhaa  developed,  and 
amoebre,  some  of  which  enclosed  red  blood  cells,  were  present  in  the 
stools.  The  animal  was  killed  and  small  ulcerations  were  found  in  the 
large  intestine.  However,  it  must  be  stated  that  with  cultures  of  this 
same  amoeba  he  was  unable  in  a  few  experiments  to  infect  cats  by  rectal 
injection.  From  a  practical  standpoint  it  is  demonstrated  daily  that  it 
is  very  easy  to  live  in  jNIanila  and  avoid  infection  with  amoeba^,  provided 
one  avoids  infected  drinking  water.  Those  who  never  drink  local  water 
but  use  only  the  better  imported  bottled  aerated  waters  are  not  attacked 
with  amoebic  dysentery.  Open  reservoirs  and  tanks  containing  drinking 
water  may  be  polluted  by  the  excreta  of  infected  monkeys.  Lettuce  leaves 
contaminated  with  amoebas  may  be  one  source  of  infection. 

It  is  very  probable  that  not  all  of  the  amoebne  found  in  our  water- 
supply  are  pathogenic,  and  it  is  also  probable  that  those  who  ingest  the 
pathogenic  form  do  not  all  suffer  with  the  disease  amoebic  dysentery. 
Dilute  acids  quickly  kill  the  amoeba,  and  it  is  probable  that  many  of 
those  ingested  are  destroyed  in  the  stomach.  Natural  and,  in  the  natives, 
accjuired  immunity  from  constant  exposure  to  the  disease  may  also  exist, 
and  probably  in  these  cases  the  disease  results  only  when  the  system  is 
overwhelmed  with  very  large  numbers  of  the  parasites  or  when  it  is 
weakened  by  other  disease. 

Other  Organisms  Encountered  in  Amoebic  Dysentery. — Other 
protozoal  organisms  common  in  the  intestine  in  amoebic  dysentery  are 
the  trichomonas,  Cercomonas  intestinalis,  and  Megastoma  entericum. 
These,  when  present  in  this  disease  in  very  large  numbers,  probably  by 
their  rapid  mechanical  movements,  act  as  an  irritant .  to  the  already 
inflamed  mucosa.  Other  animal  parasites  which  are  found  not  infre- 
quently in  the  intestine  of  those  who  suffer  with  amoebic  dysentery  in  the 
tropics  are  the  Tpenia  saginata,  Ascaris  lumbricoides,  the  Tricocephalus 
trichuris,  Uncinaria  duodenale,  Strongyloides  intestinalis,  and  Oxyuris 
vermicularis.  In  Egypt  the  ova  of  Bilharzia  hasmatobia  may  be  also 
present  in  the  stools.  When  these  parasites  are  present  the  cases  may 
be  regarded  as  a  multiple  infection.  Schaudinn  has  stated  that  certain 
species  of  bacteria  found  in  dysentery  apparently  exert  a  distinctly  harm- 
ful influence  upon  entamoeba  coli  and  monads  which  may  be  present  in 
the  intestine  at  the  same  time.  This,  however,  is  not  true  of  Bacillus 
dysenterise  and  the  dysenteric  amoeba,  since  in  some  cases  we  find 
both  of  these  parasites  producing  lesions  side  by  side  in  the  large 
intestine. 

Bacteriology. — Kruse  and  Pasquale  investigated  the  organisms  found 
in  14  cases  of  the  disease  and  isolated  streptococci.  Staphylococcus 
pyogenes,  typhoid-like  bacilli,  Bacillus  pyocyaneus,  and  Bacillus  clavatus. 
None  of  these  was  present  so  constantly  or  in  such  numbers  as  to  suggest 
a  specific  relation  to  the  disease.  Of  6  cases  in  which  pure  cultures  of 
Bacillus  pyocyaneus.  Bacillus  clavatus,  the  streptococcus,  or  typhoid-like 
bacilli,  were  introduced  into  the  rectum  of  cats,  in  5  the  results  were 
negative;    in  the  sixth,  where  the  streptococcus  was  employed,  there  was 


AMCEBIC  DYSENTERY  503 

no  dysentery,  but  a  catarrh  of  the  whole  intestinal  tract  and  a  general 
septicaemia. 

In  26  fatal  cases  in  plate  cultures  from  the  large  intestine  several 
varieties  of  the  colon  bacillus  were  the  only  organisms  found  constantly 
present.  We  were  unable  to  produce  dysentery  or  any  lesions  in  cats  by 
rectal  injection  of  cultures  of  the  varieties  of  the  colon  bacillus  encoun- 
tered. In  7G  fatal  cases  cultures  were  made  from  tlie  solid  organs.  The 
bacteria  encountered  were  streptococci  and  staphylococci,  Diplococcus 
pneumoniae,  colon  bacilli,  the  typhoid  bacillus,  and  Bacillus  aerogenes 
capsulatus.  The  most  striking  fact  demonstrated  by  these  examinations 
was  that  5  per  cent,  of  the  cases  succumbed  from  a  general  terminal 
infection  with  the  Staphylococcus  and  Streptococcus  pyogenes. 

Pathology. — The  Large  Intestine. — The  large  intestine  is  chiefly 
involved.  The  most  striking  feature  in  chronic  cases  is  the  great  thicken- 
ing of  its  walls.  This  may  be  confined  to  the  submucosa  or  involve  all 
the  coats.  It  is  always  more  marked  in  the  submucosa  and  is  due  to  a 
general  oedema  and  localized  areas  of  thickening.  The  other  characteristic 
lesions  consist  chiefly  of  hemorrhagic  catarrh,  of  raised  hemispherical 
areas  of  infiltration  protruding  above  the  level  of  the  surrounding  mucosa, 
and  of  at  least  three  forms  of  ulceration .  Frequently  a  diphtheritic  process 
is  added  to  the  amoebic  one.  The  lesions  may  affect  the  whole  large 
intestine  or  a  portion  only,  as  the  csecum,  the  hepatic  or  sigmoid  flexure 
or  the  rectum.  Generally  in  fatal  cases  the  large  bowel  is  affected  through- 
out. In  some  the  intestine  is  riddled  with  ulcers;  in  others  a  moderate 
number  is  scattered  through  it.  There  appears  to  be  no  particular  portion 
of  the  large  intestine  that  is  definitely  predisposed  to  the  infection. 

We  may  consider  the  lesions  from  the  beginning  of  the  pathological 
process.  The  amoebae  insert  themselves  either  between  the  cells  of  the 
normal  mucosa,  along  the  interglandular  substance,  or  into  small  erosions 
which  may  exist  in  the  intestine  from  other  causes.  They  next  generally 
work  their  way  through  the  muscularis  mucosae  by  the  lymph  channels 
and  finally  enter  the  submucosa.  Here  migration  and  reproduction  take 
place  and  infiltration  with  round  cells  and  oedema  results.  The  mucosa 
becomes  bulged  out  and  small  pin-head-sized  dots  appear  on  the  interior 
of  the  bowel.  Should  a  small  capillary  hemorrhage  result  in  these  areas, 
as  frequently  happens,  the  nourishment  of  the  overlying  epithelial  cells 
becomes  disturbed,  and  these,  perhaps  partly  by  digestion,  become 
gradually  disintegrated,  softened,  and  cast  off.  The  oedematous  sub- 
mucosa is  then  exposed,  which  may  appear  yellowish  from  infiltration 
with  round  cells  or  yellowish  red  if  the  blood  cells  still  remain  in  this 
area.  Thus  the  earliest  erosion  is  formed  and  becoming  exposed  to  the 
faecal  material  and  bacteria  in  the  intestine,  an  increased  number  of 
cells  accumulate,  and  if  pus  cocci  are  present  more  or  less  true  suppura- 
tion occurs. 

The  process  is  limited  in  extent  by  the  surrounding  tissue,  which  is 
well  supplied  with  blood  and  hence  red  margins  to  the  erosions  or  ulce- 
rations exist.  The  amoebae  on  the  surface  die  or  are  cast  off  into  the 
lumen  of  the  intestine  but  others  migrate  deeper  and  laterally  into  the 
submucosa.  Should  no  hemorrhage  occur  early  beneath  the  small  bulg- 
ings  of  the  mucosa,  the  areas  increase  in  size  through  the  oedema  and 
round-celled  infiltration;  hence  the  diameter  of  these  erosions  and  small 


504  DISEASES  CAUSED  BY  PROTOZOA 

ulcerations  when  first  seen  depends  upon  how  long  the  overlying  mucosa 
remains  intact  before  becoming  necrotic,  disintegrated,  and  cast  off. 
They  therefore  generally  vary  in  size  from  2  or  3  mm.  to  about  2  cm. 
In  some  cases  the  nodular  projections  are  intact  and  raised  above  the 
surface  of  the  mucosa,  and  on  incising  tUeni  they  may  be  observed  to 
contain  a  pale-yellow  or  grayish-yellow  viscid  material.  The  earliest 
lesions  are  obviously  rarely  seen  at  hunum  autopsies,  but  may  be  studied 
in  infected  cats  which  have  been  killed  a  day  or  two  after  inoculation. 
In  many  of  the  ulcerations  that  have  originated  from  nodules  which 
reached  1  or  2  cm.  or  more  in  size  before  opening,  we  may  see  evidences 
of  the  primary  nodular  formation  from  the  fact  that  the  margins  are 
raised  and  thickened  and  in  many  cases  undermined.  IMoreover  some 
of  the  ulcers  have  a  distinct  crater-like  appearance,  with  a  small  opening 
in  the  centre,  which  may  be  pin-head  in  size  or  so  large  as  to  freely  expose 
the  cavity.  About  the  edges  of  many  of  these  ulcers  there  exists  a  dark- 
purplish  or  reddish  ring  of  congestion.  The  mucosa  between  the  ulcers 
in  early  cases  may  appear  perfectly  normal,  but  in  later  ones  a  desquam- 
ative or  hemorrhagic  catarrh  may  be  present.  Whether  this  is  due  to 
certain  soluble  products  of  the  amoebte  acting  upon  the  surface  of  the 
mucosa,  or  to  their  mechanical  movements  upon  it,  or  to  some  other 
process,  we  do  not  know.  The  ulcerations  increase  in  size,  probably 
owing  to  the  combined  action  of  both  amoebfe  and  bacteria.  The  floors 
and  edges  become  softened,  necrotic,  and  covered  with  a  mucous  exudate. 
In  the  earlier  stages  the  ulcers  are  round  or  oval  and  placed  with  their 
long  diameters  transversely  to  the  lumen  of  the  intestine.  Later  they 
may  become  irregular  in  outline.  The  diameter  of  the  large  ones  probably 
depends  chiefly  upon  how  laterally  the  amoebae  have  spread  out  in  the 
submucosa,  and  their  depth  mainly  upon  the  depth  the  amoebae  have 
penetrated  into  it  before  the  overlying  mucosa  was  cast  off.  In  the  former 
case  the  shallow  ulcerations  of  several  centimeters  in  diameter  with 
irregular  margins  are  formed,  whose  edges  are  usually  reddened  and 
surrounded  by  apparently  healthy  mucosa  and  whose  floors  are  usually 
necrotic  and  covered  with  a  yellowish  or  greenish  more  or  less  muco- 
purulent exudate.  From  either  of  these  two  types  of  ulcer  the  more  serious 
lesions  usually  develop,  so  that  extensive  surface  ulcerations  whose  floors 
are  formed  usually  of  submucosa  result,  or  deeper  ones  with  smaller 
diameters  whose  bases  consist  of  submucosa,  muscular  coat,  or  even 
peritoneum.  It  is  in  the  ulcerations  of  moderate  depth,  owing  to  the 
burrowing  of  the  amoebae  in  the  submucosa  beneath  the  mucosa,  that  the 
characteristic  vmdermining  of  the  borders  of  the  ulcers  results.  This 
becomes  particularly  marked  owing  to  the  fact  that  the  musculans 
mucosae  is  not  infiltrated  and  destroyed  to  the  same  extent  as  the  sub- 
mucosa and  hence  holds  up  the  mucous  membrane.  In  the  more  exten- 
sive ulcerations,  necrosis  and  undermining  of  the  muscular  tissue  also 
take  place,  whereby  frequent  sinuses  are  formed  beneath  the  mucous 
membrane,  and  portions  are  dissected  out  and  cast  off  into  the  lumen  of 
the  intestine  as  sloughs. 

A  third  form  of  ulceration  sometimes  seen  is  that  in  which  the  lesion 
extends  only  partially  through  the  mucosa  and  results  from  a  gradual 
disintegration  of  the  epithelial  cells  and  not  by  necrosis  and  sloughing 
of  the  underlying  tissues.     The  bloodvessels  of  the  mucosa  are  likely 


PLATE  V 


Colon  in  Amoebic  Dysentery. 


PLATE  VI 


Colon  in  Amoebic  Dysentery. 


AMCEBIC  DYSENTERY  505 

here  to  be  more  dilated  and  filled  with  blood.  These  ulcers  may  develop 
both  laterally  in  the  mucosa  and  in  depth  into  the  submucosa;  but  there 
is  not  in  either  case  the  characteristic  undermining  that  is  observed  in 
ulcerations  of  the  other  type,  though  the  round-celled  infiltration  in  the 
vicinity  is  frequently  even  more  extensive.  When  these  surface  ulcers 
extend  only  into  the  mucous  membrane,  amoebae  are  rarely  found  in 
them,  but  are  sometimes  encountered  at  their  margins  lying  in  or  between 
the  glands.  It  seems  probable  that  this  form  of  necrosis  and  ulceration 
is  a  direct  extension  into  the  mucosa  of  the  process  which  begins  as  a 
hemorrhagic  catarrh.  It  may  be  due  to  the  'action  of  soluble  toxic  pro- 
ducts of  the  amcebse  aided  later  by  the  intestinal  bacteria.  A  somewhat 
similar  process  is  observed  in  the  liver,  which  consists  of  an  extensive 
necrosis  of  areas  of  liver  tissue  which  contain  no  amoebae  and  which  are 
situated  in  the  vicinity  of  the  abscess.  Complete  breaking  down  and 
softening  seems  to  occur  only  when  the  amoebee  actually  come  in  contact 
with  the  cells,  and  this  may  be  due  to  the  action  of  an  intracellular  toxin. 

The  amoebae  wandering  in  the  submucosa  and  carrying  with  them 
adherent  bacteria  cause  continuous  disturbance.  The  parasites  them- 
selves seem  to  be  responsible  chiefly  for  the  oedema  and  round-celled 
infiltration,  and  softening  and  breaking  down  of  the  tissues.  The  bac- 
teria cause  additional  leukocytic  infiltration  and  necrosis.  The  action  of 
the  latter  is  manifested  chiefly  in  the  more  superficial  ulcerations  where 
the  amoebae  may  be  scanty  upon  the  surface.  The  parasites  in  addition 
cause  early  infiltration  with  round  cells  of  the  walls  of  the  capillaries 
and  veins,  which  condition  is  followed  by  softening  and  complete  dis- 
organization of  these  structures.  It  is  in  this  way  that  much  blood  appears 
in  the  stools.  The  amoebae  may  even  penetrate  the  walls  of  the  veins, 
and  are  frequently  found  inside  these  vessels,  some  of  which  they  may 
have  entered  directly  or  been  carried  from  the  capillaries  through  the 
lumen  of  the  vessel.  In  this  way  the  veins  may  become  thrombosed. 
The  arteries  in  the  neighborhood  of  the  ulcer  also  frequently  show 
thrombi,  and  in  the  chronic  process  evidences  of  endarteritis  are  found. 
The  slow  inflammatory  process  in  the  submucosa  consisting  of  oedema, 
infiltration,  and  finally  of  proliferation  of  the  fixed  connective  tissue 
cells,  leads  to  great  thickening  in  the  bowel  wall  and  hypertrophy  of  the 
vessels. 

In  certain  cases  the  tissues  seem  little  able  to  resist  the  infection,  and 
large  gangrenous  ulcers  result  whose  walls  are  soft  and  whose  bases  are 
formed  of  blackish  or  greenish  sloughing  tissue  in  which  numerous 
cocci,  bacilli,  and  sometimes  amoebae,  are  found.  These  changes  are 
certainly  not  produced  entirely  by  amoebae,  but  are  probably  due  chiefly 
to  the  bacteria  which  are  present.  Another  process  which  is  sometimes 
seen  in  cases  of  this  disease  is  the  diphtheritic  one.  It  is  also  certainly 
partially  if  not  entirely  caused  by  the  action  of  bacteria.  When  Bacillus 
dysenteriae  is  present  the  origin  of  the  pseudomembrane  is  easily  ex- 
plained. Obviously  the  ulcerations  in  different  cases  and  even  in  the 
same  case  may  vary  greatly  in  appearance  in  the  active  stage,  according 
to  the  extent  and  manner  of  progression  of  the  lesions,  but  they  can 
usually  be  classified  under  one  of  the  types  which  have  been  described. 

The  process  of  healing  may  best  be  studied  in  patients  who  have  been 
under  treatment  for  some  time  with  the  intestinal  disturbance  and  pro- 


506  DISEASES  CAUSED  BY  PROTOZOA 

grossing  favorably  but  death  has  resiUtcd  suddenly  from  some  compli- 
cation. The  ulcers  may  then  be  found  with  bases  which  are  distinctly 
depressed  and  have  a  grayish  or  grayish-yellow  color.  Their  margins, 
however,  are  raised  above  the  bases,  and  are  clear  cut  but  are  not  usually 
swollen  above  the  surroinuling  mucosa.  AVhen  well  advanced  toward 
healing  they  are  no  longer  softened.  The  surfaces  of  the  ulcers  are 
bathed  in  a  serous  fluid  or  covered  with  mucus.  Healing  takes  place 
by  the  formation  of  fibrous  connective  tissue  in  the  floors  and  by  a  gradual 
covering  over  with  cpitheliiun.  If  the  lesions  have  been  extensive  old 
pigmented  scars  result. 

Peritonitis. — As  has  been  pointed  out,  the  amoebtie  may  wander  freely 
through  the  submucosa  and  into  the  circular  muscular  coat,  Avhere  they 
are  frequently  found  along  the  intermuscular  septa  and  between  the 
muscle  fibers,  which  they  have  evidently  separated.  The  fibers  them- 
selves become  swollen,  granular,  indistinct,  and  may  appear  without 
nuclei.  They  finally  become  infiltrated,  break  up,  and  disappear.  The 
parasites  also  destroy  the  bloodvessels  in  this  layer;  the  blood-supply 
is  then  cut  off  and  more  extensive  sloughs  are  formed.  They  may  next 
push  along  the  intermuscular  septa  through  the  longitudinal  muscle  and 
produce  the  same  changes.  Should  they  approach  the  serosa  similar 
changes  to  those  seen  in  the  submucosa  take  place  in  the  subperitoneal 
coat. 

In  case  many  bacteria,  particularly  the  pus  cocci,  now  ihd  their  way 
into  the  tissue,  deep  sloughing  gangrenous  lesions  are  formed  and  per- 
foration with  general  peritonitis  frequently  occurs.  In  other  cases  when 
few  bacteria  are  present  this  may  take  place  from  violent  peristalsis 
after  adhesions  are  formed.  However,  in  the  latter  instance,  particularly 
when  the  floor  of  the  ulcer  is  composed  of  muscular  tissue  and  does  not 
extend  completely  down  to  the  serosa,  the  peritoneal  coat,  owing  to  the 
action  of  the  amoebae,  becomes  greatly  thickened,  not  only  from  the 
cedema  and  infiltration  but  by  the  formation  of  considerable  fibrin. 
This  also  occurs  on  the  peritoneal  surface,  and  so  the  intestine  later 
becomes  adherent  to  loops  of  the  small  bowel  or  to  the  omentum  or  ab- 
dominal wall  and  the  adhesions  so  commonly  found  at  autopsy  in  the 
chronic  cases  are  formed.  Occasionally  general  peritonitis  will  occur 
with  no  visible  perforation,  the  amcebre  having  penetrated  the  muscular 
coat  and  serosa  and  set  up  an  inflammatory  exudate  which  consists  of 
an  opaque  gelatinous  fibrinous  fluid  in  which  the  amoebpe  may  be  found. 

It  will  be  noted  that  one  of  the  most  striking  points  in  the  pathology 
of  the  infection  is  the  absence  of  the  usual  products  of  purulent  inflam- 
mation. Polymorphonuclear  leukocytes  are  found  in  relatively  small 
numbers  in  the  tissues,  and  are  never  aggregated  together  in  large  groups 
unless  many  bacteria  are  present. 

Microscopic  study  shows  that  the  submucosa  is  very  cedematous. 
Its  interstices  are  widened  and  the  lymph  channels  engorged.  The  fixed 
connective  tissue  cells  are  swollen,  stain  poorly,  and  often  show  fatty 
degeneration.  In  places  where  extensive  necrosis  has  resulted  the  elastic 
tissue  fibers  remain  last  and  stain  well.  In  these  areas  much  amorphous 
granular  material  is  present  and  the  cells  lose  their  nuclei  and  stain 
poorly.  In  addition  there  may  be  a  general  liquefaction  of  the  tissues. 
Extensive  round-cell  infiltration  exists  in  the  submucosa  where  but  few 


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AM(EBIC  DYSENTERY  507 

polymorphonuclear  leukocytes  are  usually  seen.  Plasma  cells  are  present 
at  times  in  considerable  numbers,  and  eosinophiles  are  in  some  cases 
also  fairly  numerous.  At  the  margins  of  the  ulcers  many  of  the  epithelial 
cells  show  parenchymatous  or  mucoid  degeneration.  The  mast  cells 
are  usually  diminished  in  these  areas.  One  may  also  observe  that  the 
ulcerations  do  not  as  a  rule  begin  in  the  follicles,  but  these  may  become 
secondarily  affected.  The  amoebre  arc  found  in  large  numbers  in  the 
lymph  spaces,  in  which  case  the  endothelial  cells  in  the  neighborhood 
are  prohferated  and  there  is  sometimes  a  fibrinous  exudate  inside  the 
vessel.  The  parasites  are  also  present  in  the  ulcers,  being  most  numerous 
in  the  submucosa  along  their  bases  and  sides,  in  the  zone  of  oedema  and 
round-cell  infiltration  which  borders  the  necrotic  portion  of  the  lesion. 
Bacteria  are  always  most  numerous  in  the  upper  necrotic  layers  of  the 
ulcer,  and  when  the  pus  cocci  are  present  purulent  inflammation  fre- 
quently results.  In  these  areas  amoebae  are  seldom  found.  Bacteria  are 
also  found,  usually  in  small  numbers,  with  the  amoebae  in  the  deeper 
lesions. 

Small  Intestine. — Involvement  of  the  lower  end  of  the  ileum  some- 
times follows  from  an  extension  of  the  process  upward  from  the  caecum. 
The  mucosa  just  above  the  valve  is  frequently  hyperaemic  and  occasion- 
ally hemorrhagic.  In  only  one  of  the  writer's  autopsy  series  did  it  show 
amoebic  ulceration,  though  several  other  cases  complicated  with  typhoid 
fever  showed  typhoid  ulceration  of  the  Peyers'  patches. 

Lymphatic  Glands. — The  mesocolic  glands  are  frequently  swollen, 
particularly  where  the  lesions  are  extensive  and  extend  deeply  into  the 
muscular  coats.  They  may  occasionally  be  hyperaemic  or  oedematous 
but  are  very  rarely  hemorrhagic,  and  in  this  respect  offer  a  strong  con- 
trast to  the  condition  of  the  lymphatics  in  bacillary  dysentery.  Micro- 
scopic examination  shows  that  the  lymph  sinuses  are  more  or  less 
dilated,  and  there  may  be  some  proliferation  of  the  connective  tissue 
cells  and  a  few  plasma  cells  present.  In  rare  cases  necrosis  may  take 
place  and  bacteria  may  be  present.  The  bloodvessels  are  usually  normal. 
The  small  round  cells  are  frequently  increased  in  number. 

The  Kidneys. — ^The  chronic  cases  sometimes  show  evidence  of  par- 
enchymatous nephritis,  which  is  rarely  of  extreme  grade.  The  cells  of 
the  tubules  are  more  or  less  granular  and  stain  poorly,  and  albumin  is 
sometimes  found  in  the  glomerular  spaces.  Occasionally  the  cells  of 
the  convoluted  tubules  and  the  glomerular  epithelium  are  fatty,  and  in 
places  desquamated.  The  s-pleen  and  the  lieart  muscle  are  usually  normal, 
and  the  lungs  show  no  special  changes  peculiar  to  the  disease  except 
abscess  of  the  right  lower  lobe,  which,  together  with  the  lesions  of  the 
liver,  will  be  discussed  under  the  subject  of  hepatopulmonic  abscess. 

Musgrave  has  recently  seen  two  cases  of  general  infection  with  amoebae. 

Sjnnptoms. — General  Characteristics,  Clinical  Forms,  Mode  of  On- 
set, Course,  Duration  and  Termination. — The  symptoms  may  vary  so 
widely  that  in  order  to  discuss  the  subject  intelligently  the  cases  may  be 
grouped  for  convenience  under  the  following  divisions:  (a)  Mild  cases 
and  those  of  moderate  intensity,  (h)  Cases  with  acute  onset,  (c)  Ad- 
vanced and  chronic  forms. 

This  division  is  purely  an  arbitrary  one  since  no  sharp  lines  of  dis- 
tinction can  be  drawn  and  the  cases  may  pass  from  one  to  the  other. 


508  DISEASES  CAUSED  BY  PROTOZOA 

Moreover  instances  may  occur  which  can  be  better  considered  partially 
under  more  than  one  of  these  divisions.  While  individual  cases  may 
vary  widely  there  are  some  features  which  are  very  common  in  at  least 
the  majority.  These  are  the  irregular  course,  marked  by  periods  of 
intermission  and  exacerbation,  the  appearance  of  mucus  in  the  stools, 
and  the  tendency  to  chronieity.  A  phenomenon  that  is  peculiar  to  the 
malady  is  the  frequent  occurrence  of  the  amrpbic  liver  abscess. 

(a)  Mild  Cases  and  Those  of  Moderate  Intensity. —  Usually  the  pa- 
tients are  not  able  to  tell  exactly  when  they  began  to  realize  that  they 
were  not  in  good  health.  There  may  be  complaint  of  some  lassitude, 
of  becoming  easily  tired,  or  of  continuous  slight  headache;  more  or  less 
indefinite  abdominal  discomfort  and  dyspepsia  may  be  present.  Slight 
intestinal  disturbances  consisting  of  moderate  diarrhoea  or  of  constipation 
may  appear.  Such  symptoms  may  occur  singly  or  in  various  combina- 
tions. These  represent  patients  who,  frecjuently  in  the  tropics  among 
the  well-to-do  people,  consult  the  physicians  for  such  minor  ailments  as 
have  been  mentioned  and  generally  have  no  idea  of  the  real  trouble. 
Such  vague  symptoms  may  continue  for  months,  and  one  may  doubt 
whether  they  are  all  dependent  upon  the  intestinal  infection.  Occasion- 
ally the  abdominal  pains  become  severer,  or  there  may  be  an  outbreak 
of  diarrhoea  which  causes  the  physician  to  examine  the  stools,  when 
amoebffi,  sometimes  mucus  and  even  red  blood  cells,  are  found.  A  great 
many  of  these  infections  remain  undiscovered  for  a  long  time.  Such 
have  been  described  under  the  name  of  latent  or  masked  forms  of  the 
disease.  Robust  men  may  have  the  disease  for  a  month  or  two  without 
being  aware  that  they  are  suffering  from  a  serious  malady.  Indeed  some 
may  go  to  autopsy  with  advanced  intestinal  lesions  in  whom  the  symptoms 
have  not  been  sufficiently  prominent  to  attract  attention.  They  may 
never  advance  beyond  this  latent  stage;  either  under  some  simple  treat- 
ment by  the  mouth,  or  even  without  treatment,  the  patient  may  overcome 
the  infection  and  the  parasites  disappear  from  the  stools.  In  by  far  the 
greater  number,  however,  some  of  the  symptoms  sooner  or  later  increase 
in  severity,  and  in  the  event  of  recovery  not  taking  place  they  may  pass 
gradually  into  either  those  of  moderate  intensity  or  those  with  acute 
onset.  The  two  symptoms  most  likely  to  attract  attention  are  diarrhoea 
and  abdominal  pain.  In  those  patients  who  are  constipated  the  latter 
may  be  the  first  symptom;  or  indigestion  and  gradual  loss  of  weight 
may  be  equally  prominent.  Palpation  of  the  abdomen  sometimes  reveals 
tenderness,  but  this  is  by  no  means  constant.  As  the  lesions  in  the  large 
bowel  increase,  the  symptoms  of  intestinal  disturbance  usually  become 
more  marked,  abdominal  soreness  appears,  and  the  stools  become  more 
frequent  and  contain  mucus  and  even  blood.  If  they  are  properly 
treated  the  disease  does  not  usually  progress  to  the  chronic  stage,  and 
this  particularly  is  why  the  name  "dysentery"  is  not  an  entirely  apt  one 
for  the  malady  and  why  "amoebic  colitis"  would  perhaps  answer  better. 
Musgrave  has  proposed  the  term  Amcebiasis  to  cover  all  grades  of  the 
infection. 

Even  if  treatment  is  not  instituted  a  small  proportion  of  this  group 
may  entirely  recover,  frequently  after  several  recrudescences  of  more  or 
less  active  diarrhoea;  but  the  majority  pass  gradually  to  the  chronic 
form,  or  occasionally  acute  symptoms  develop.    Sometimes  the  abdom- 


AMCEBIC  DYSENTERY  509 

inal  manifestations  may  be  so  insignificant  as  entirely  to  escape  notice, 
or  the  appearance  of  a  liver  abscess  first  attracts  attention. 

(6)  Cases  with  Acute  Onset. — Obviously  it  is  not  correct  to  consider 
all  of  these  as  acute  cases.  Some  are  really  acute  almost  from  the  begin- 
ning, but  others  may  have  existed  for  some  time  as  latent,  mild,  or 
moderately  severe  infections.  The  symptoms  are  frequently  not  in 
accord  with  the  lesions;  ulcerations  may  exist  and  become  well  marked 
before  there  is  a  sudden  outbreak  of  the  diarrhoea.  Very  abrupt  onset 
may  occur  from  the  formation  throughout  the  large  intestine,  but  par- 
ticularly in  its  lower  portion,  of  very  numerous  small  and  superficial 
ulcerations,  or  from  secondary  infection  with  streptococci  or  Bacillus 
dysenteriee.  Cases  with  diphtheritic  or  gangrenous  lesions  may  be 
classified  clinically  under  this  division,  and  in  the  latter  instance  portions 
of  sloughing  tissue  may  be  passed  in  the  stools.  At  the  onset  there  may 
be  from  15  to  50  or  more  bloody  mucous  movements  in  twenty-four 
hours.  Colicky  pains  in  the  abdomen  with  tenesmus  develop;  fever, 
nausea,  and  vomiting  may  appear;  great  exhaustion  sets  in;  the  heart 
action  becomes  feeble  and  either  death  results,  or  the  condition  tem- 
porarily improves  and  gradually  assumes  the  chronic  form.  It  is  in  this 
form  that  wild  delirium  may  develop  before  death. 

(c)  Advanced  and  Chronic  Cases. — In  the  advanced  stages  of  the  dis- 
ease the  symptoms  become  well  developed.  The  movements  become 
more  frequent  and  usually  contain  much  mucus  and  frequently  blood. 
Their  number  may  vary  from  2  or  3  in  the  morning  to  10  or  15 
or  more  during  the  day.  There  is  aching  in  the  back,  and  at  times 
sudden  and  intense  desire  to  defecate.  As  the  disease  becomes  chronic, 
loss  of  weight  is  progressive,  and  finally  marked  emaciation  may  result. 
The  patient  becomes  anaemic  and  the  muscles  soft;  the  tongue  is  pale  and 
moist  at  first,  later  slightly  furred,  or  sometimes  heavily  coated.  There 
is  more  or  less  anorexia;  indigestion  and  flatulence  are  common.  The 
pulse  and  respirations  may  be  slightly  increased.  The  temperature  is 
normal  or  subnormal  in  the  morning  and  slightly  elevated  in  the  after- 
noon. As  the  malady  progresses  the  anaemia  becomes  more  marked, 
the  skin  dry  and  dull  yellow  in  color,  and  the  face  drawn.  The  emacia- 
tion in  some  cases  becomes  very  extreme;  the  abdomen  becomes  sunken, 
bed-sores  may  appear,  and  death  follows  from  exhaustion  or  terminal 
infections.  Another  type  of  the  chronic  form  is  that  in  which  there  is 
nothing  more  than  an  intermittent  diarrhoea  often  alternating  with  con- 
stipation, and  accompanied,  usually,  by  slow  but  gradual  loss  of  flesh. 
These  patients  sometimes  remain  in  this  condition  for  several  years. 
Occasionally  the  parasites  disappear  and  the  more  serious  lesions  heal, 
but  the  bowel  never  assumes  again  its  normal  condition.  Where  the 
destruction  of  tissue  has  been  extreme,  cicatrices  form  and  a  chronic 
catarrh  always  exists. 

The  course  of  amoebic  dysentery  is  very  variable  and  is  not  self-limited. 
The  grave  cases  with  acute  onset  may  terminate  fatally  within  a  week 
or  ten  days  in  spite  of  all  treatment.  The  mild  and  moderately  severe 
ones  may  continue  for  many  months  before  alarming  symptoms  appear. 
The  occurrence  of  complications  may  terminate  the  infection  in  death 
or  completely  alter  its  course.  If  proper  treatment  is  instituted  many 
of  the  mild  and  moderately  severe  cases  recover  entirely,  and  the  para- 


510  DISEASES  CAUSED  BY  PROTOZOA 

sites  disappear  in  a  month  or  six  weeks  Some  of  the  chronic  ones  are 
completely  restored  to  health  in  from  three  to  six  months.  Occasionally 
amoeba?  persist  after  all  symptoms  antl  sometimes  the  lesions  themselves 
have  disappeared.  Complete  recovery  is  sometimes  donbtful  owing  to 
the  fact  that  after  many  weeks  of  a{)parent  cure  patients  may  develop 
more  acute  symptoms;  sometimes  these  represent  fresh  infection,  but 
usually  they  are  merely  evidences  of  the  outbreak  of  the  original  disease. 
Cases  of  this  nature,  unless  treatment  is  pursued  until  complete  recovery 
results,  are  apt  to  sutler  with  so-called  relapses  every  few  weeks  or  months 
until  some  grave  com})lication  develops  and  carries  them  off.  Patients 
who  do  not  recover  under  continuous  local  treatment  for  six  or  eight 
months  are  likely  either  to  die  within  a  year  or  linger  on  as  incurable. 
Rarely  does  an  attack  end  in  spontaneous  recovery  after  the  dysentery 
has  existed  for  a  year. 

Death  may  occur  from  the  gravity  of  the  intestinal  lesions,  from  ex- 
haustion in  protracted  cases,  from  severe  complications,  from  a  terminal 
infection,  from  intercurrent  diseases,  or  from  severe  intestinal  hemor- 
rhage. The  severity  of  the  intestinal  lesions  and  abscess  of  the  liver 
are  the  most  frequent  causes  of  death. 

Analysis  of  the  Symptoms. — Gastro-intestinal. — Of  these,  diarrhoea 
is  the  most  important,  usually  being  intermittent  in  character,  coming 
on  abruptly,  and  subsiding  in  like  manner.  Between  the  attacks  the 
stools  may  become  formed.  The  intermissions  of  the  diarrhoea  may  last 
several  weeks  or  even  months,  or  this  symptom  may  be  absent  through- 
out the  entire  course  of  the  infection.  The  character  of  the  diarrhoea 
usually  depends,  first,  upon  the  ulceration,  whereby  increased  peri- 
stalsis results,  probably  owing  to  the  nerves  being  eroded  and  exposed; 
second,  upon  the  impaired  power  of  absorption  of  water  by  the  intestine, 
due  in  part  to  the  marked  oedema.  Ulcers  of  the  intestine  can  exist 
without  any  diarrhoea,  as  is  particularly  likely  when  they  are  superficial 
and  in  the  ceecum  or  the  adjacent  portion  of  the  ascending  colon.  When 
the  ulcers  are  very  numerous  throughout  the  intestine,  or  well  developed 
in  the  descending  colon  and  rectum,  diarrhoea  is  practically  always 
present.  In  mild  cases  the  movements  may  not  exceed  3  or  4  in  twenty- 
four  hours,  but  in  the  gangrenous  and  diphtheritic  forms  the  diarrhoea 
becomes  excessive  and  the  movements  sometimes  number  50  or  more  in 
this  time.  In  fatal  cases  before  death  they  may  diminish  to  2  or  3.  This 
has  been  explained  as  due  to  the  gradual  loss  of  expulsive  power  caused 
by  the  destruction  of  the  muscular  coat  and  nerves  situated  in  the  ulcer- 
ated areas,  and  the  general  oedema  of  the  bowel  wall. 

The  Fseces. — The  stools  vary  greatly  in  different  stages  of  the  infection 
and  in  different  cases.  Valuable  information  may  be  obtained  from  them 
of  the  condition  of  the  lesions  in  the  intestine  and  of  the  progress  of  the 
disease.  At  times  they  are  liquid,  at  times  pultaceous,  and  again  well 
formed.  In  color  they  may  be  brownish,  greenish,  reddish,  grayish  or 
variegated.  In  those  cases  with  gradual  onset  they  are  likely  at  first  to 
be  merely  more  or  less  watery  and  of  normal  color.  As  the  lesions  develop, 
mucus  begins  to  appear.  In  the  cases  with  marked  intestinal  catarrh 
and  extensive  ulceration  it  is  always  more  abundant.  The  mucus  may 
be  finely  di\nded,  shreddy  and  mixed  throughout  the  stool,  or  it  may 
appear  in  large  masses.     The  latter  condition  is  particularly  likely  to 


AMCEBIC  DYSENTERY  511 

exist  when  the  faeces  are  well  formed,  when  small  portions  of  blood- 
stained mucus  may  be  observed  over  the  surface  of  different  portions 
of  the  stool.  At  times  the  movements  may  consist  almost  entirely  of 
viscid  masses  of  blood-stained  mucus. 

Blood  may  be  present  so  that  the  color  of  the  whole  mass  is  modified, 
or  as  clotted  masses  in  portions  of  the  stool,  or  mixed  with  mucus.  It 
is  sometimes  in  such  small  amounts  as  to  be  apparent  only  upon  micro- 
scopic examination;  or  the  stool  may  consist  entirely  of  blood  mixed 
with  mucus.  It  is  probable  that  the  amount  of  blood  is  partially  depend- 
ent upon  the  rapidity  with  which  the  lesions  are  forming  as  well  as  upon 
their  position  and  extent.  The  presence  of  considerable  blood  in  the 
stool  makes  the  diagnosis  of  ulceration  very  probable;  but  we  cannot 
conclude  in  its  absence  that  ulcerations  do  not  exist.  When  the  ulcer- 
ations are  high  up  in  the  csecum  the  blood  is  apt  to  be  altered  and  brownish 
or  even  blackish  in  color. 

Pus  cells  are  found  chiefly  after  ulceration  is  well  developed  and  in 
the  diphtheritic  form  of  the  disease.  In  the  chronic  cases  it  is  not  unusual 
to  find  large  numbers  of  polymorphonuclear  leukocytes.  These  are  to  be 
distinguished  from  the  small  round  cells  so  abundant  where  a  well- 
developed  catarrhal  condition  exists  and  where  epithelial  cells  are  also 
numerous.  When  pus  is  found  in  considerable  amount  it  is  an  almost 
certain  indication  of  extensive  ulceration.  The  pus  is  frequently  found 
only  in  small  amounts. 

Shreds  of  Tissue. — As  ulceration  advances  and  becomes  more  chronic  the 
amount  of  blood  grows  less;  the  stools  become  more  copious  and  again 
more  watery ;  fragments  of  tissue  are  frequently  seen  in  the  early  stages  of 
the  chronic  cases.  In  advanced  and  particularly  in  gangrenous  cases  large 
sloughs  and  sometimes  complete  moulds  of  the  intestine  are  cast  off. 
These  are  of  a  grayish  or  brownish  color  and  have  a  very  offensive  odor. 

The  reaction  of  the  stools  is  generally  alkaline,  sometimes  neutral, 
and  occasionally  acid.  In  instances  of  recovery  the  mucus  is  the  last 
abnormal  elem^ent  to  disappear  from  the  faeces.  It  usually  persists  for 
a  long  period  and  in  many  cases  where  chronic  catarrh  remains  it  never 
disappears. 

Microscopic  examination  reveals  the  amoebae  in  addition  to  those 
elements  which  have  been  described.  These  may  be  very  plentiful  or 
scarce,  the  number  depending  upon  several  factors.  If  there  are  only 
a  few  ulcers  in  the  large  intestine  the  mucus  and  faeces  that  have  come 
in  contact  with  these  lesions  are  likely  to  contain  the  parasites  in  the 
largest  number,  and  they  will  probably  be  scanty  elsewhere.  If  the  stool 
is  liquid  the  organisms  will  be  more  or  less  evenly  diffused  throughout. 
The  gravity  of  the  lesion  is  not  always  indicated  by  the  number  of  amoebae 
found.  With  very  advanced  lesions  where  the  parasites  are  burrowing 
deep  in  the  submucosa  there  may  not  be  as  many  as  in  more  acute  con- 
ditions. In  some  instances  blood  can  only  be  recognized  microscopically. 
Numerous  epithelial  cells,  small  round  cells,  pus  cells,  eosinophiles,  and 
a  fair  number  of  Charcot-Leyden  crystals,  are  also  frequently  found. 
The  bacteria  are  usually  increased  in  number  beyond  those  seen  in 
normal  stools. 

Abdominal  Pain. — ^This  is  very  variable  and  occurs  more  acutely  in 
the  gangrenous  cases  and  where  perforation  is  imminent.    It  may  be 


512  DISEASES  CAUSED  BY  PROTOZOA 

colicky  in  character  and  very  severe;  localized  over  a  particular  ulcer, 
or  exist  over  the  abdomen  generally.  In  chronic  cases  a  tlull  aching  pain 
with  occasional  sharp  exacerbations  may  be  present.  When  this  is  con- 
stant, limited  to  a  fixed  point,  and  increased  by  external  pressure,  it  is 
suggestive  of  the  site  of  ulceration,  though  the  most  extensive  ulceration 
may  exist  without  any  pain  whatever.  Pain  which  is  produced  only  by 
external  palpation  and  pressure  suggests  areas  of  circumscribed  peri- 
tonitis. Very  excessive  {niin  on  pressure  is  usually  present  when  the 
serosa  itself  is  involved.  If  widespread  or  extensive  ulcerations  are 
present,  pain  on  pressure  may  be  elicited  along  the  whole  course  of  the 
large  intestine.  Cramp-like  and  aching  pains  frequently  occur  before 
and  after  evacuation  of  the  bowel.  A  feeling  of  abdominal  heaviness  is 
not  an  uncommon  symptom  and  is  frequently  accompanied  by  disten- 
sion and  flatulence.  Tenesmus  is  not  nearly  so  marked  or  frequent  a 
symptom  in  uncomplicated  amoebic  dysentery  as  in  the  bacillary  form. 
It  is  most  evident  in  the  grave  cases  and  in  the  gangrenous  and  diphtheritic 
forms,  where  the  sigmoid  flexure  and  rectum  are  involved.  In  the  remain- 
ing cases  it  depends  chiefly  upon  the  extent  of  the  ulceration  in  the  rectum. 
A  burning  sensation  in  the  anus  after  defecation  is  frequently  present. 

Nausea  and  vomiting  of  severe  grade  are  somewhat  rare  symptoms. 
They  may  occur  early  in  the  cases  with  acute  onset.  In  moderate  form 
they  are  most  commonly  encountered  in  the  chronic  ones.  Nausea 
sometimes  develops  in  all  classes  of  cases  as  a  result  of  the  large  and  high 
intestinal  enemas  administered  for  treatment. 

Loss  of  appetite  is  a  common  symptom  and  is  almost  absolute  in  the 
acute  cases.  In  the  moderately  severe  ones  it  may  not  be  apparent,  but 
it  becomes  very  evident  again  in  the  chronic  cases. 

Hiccough  is  seen  in  the  grave  forms  shortly  before  death  and  when  the 
peritoneum  is  involved.  The  tongue  shows  nothing  that  is  characteristic. 
In  instances  of  very  long  standing  it  is  likely  to  become  fissured  and  to 
show  small  hemorrhages  and  erosions  along  its  sides  and  tip. 

Anaemia  of  a  secondary  type  is  present  in  all  the  cases  of  long  standing 
and  is  progressive  with  the  disease.  It  is  dependent  chiefly  upon  the 
loss  of  blood  from  the  intestinal  lesions  and  the  gastro-intestinal  disturb- 
ances. It  is  possible  that  it  may  be  in  part  of  toxic  origin  due  to  absorp- 
tion. The  reduction  in  haemoglobin  is  usually  greater  than  that  of  the 
number  of  the  red  cells ;  the  hsemoglobin  varies  generally  from  50  to  80  per 
cent.  Futcher's  average  for  the  red  cells  in  38  cases  was  4,802,000.  In 
the  tropics,  in  the  advanced  and  chronic  cases,  the  red  blood  cells  some- 
times are  not  over  2,500,000.  There  is  frequently  a  slight  leukocytosis, 
and  if  a  marked  one  exists  it  is  the  polymorphonuclear  cells  which  are 
increased.  The  eosinophiles  are  not  increased  in  cases  uncomplicated 
with  other  intestinal  parasites. 

Skin. — The  skin  is  normal  in  the  mild  and  moderately  severe  cases. 
In  the  chronic  ones  it  becomes  dry  and  sometimes  glazed,  and  assumes 
a  sallow,  dirty  yellow  appearance  when  the  mucous  membranes  show 
distinct  pallor. 

Fever. — The  temperature  is  likely  to  be  elevated  in  the  cases  with 
acute  onset;  it  is  generally  higher  in  the  diphtheritic  form,  and  par- 
ticularly when  complicated  witla  Bacillus  dysenterise.  In  the  mild  and 
moderately  severe  types  there  is  usually  little  or  no  fever.    In  the  chronic 


AMCEBIC  DYSENTERY  513 

ones  the  temperature  is  frequently  subnormal  for  a  portion  of  the  day 
with  afternoon  rises  to  100°  to  102°  F.  At  other  times  it  may  be  subnor- 
mal or  normal  for  a  period  of  a  week  or  more.  In  cases  where  there  are 
many  streptococci  in  the  stools  and  advanced  lesions  of  the  intestine, 
it  may  become  septic  with  daily  rises  to  103°  to  104°  F.  Fever  becomes 
an  important  symptom  in  perforation  and  in  abscess  of  the  liver  and  lung, 
when  it  is  sometimes  accompanied  by  rigors  and  sweating. 

The  pulse  and  respiration  are  apt  to  be  increased  if  fever  is  present. 
The  pulse  is  frequently  rapid  in  the  grave  cases  with  acute  onset,  and 
may  become  thready  and  rise  to  120  to  140  or  more.  Usually  in  cases 
of  moderate  severity  it  is  not  over  100,  and  in  the  mild  and  chronic  cases- 
it  may  be  normal.  The  respirations  are  increased  particularly  in  abscess 
of  the  liver  and  lung. 

Urine. — Moderate  albuminuria  accompanied  with  a  few  hyaline  casts 
is  occasionally  seen  in  chronic  cases.  The  urine  is  then  usually  some- 
what reduced  in  amount.  Harris  noted  that  in  the  severe  forms  the 
chlorides  are  often  diminished  and  that  in  the  most  severe  instances  they 
may  be  entirely  absent.  Retention  sometimes  occurs  when  acute  symp- 
toms of  dysentery  are  present. 

Complications.— Abscess  of  the  Liver. — This  is  the  most  frequent 
and  one  of  the  most  serious  complications.  In  119  cases  reported  by 
Futcher  it  occurred  in  22  per  cent.;  in  a  series  of  100  cases  examined  at 
autopsy  by  Musgrave  and  the  writer  in  23  per  cent.;  in  74  by  Craig,  33 
per  cent.;  in  57  by  Kruse  and  Pasquale,  11  per  cent.;  in  95  by  Harris, 
15  per  cent.  It  is  much  more  common  in  males  than  in  females.  Futcher 
reports  3  cases  in  the  latter  sex.  The  writer  has  not  seen  a  case  in  a 
woman  in  the  Philippine  Islands,  and  but  1  in  a  native  of  these  islands. 
However,  Major  E.  C.  Carter  states  that  he  has  seen  1  case  in  a  woman 
here  and  3  cases  in  Filipinos.  Rogers  has  shown  that  it  is  not  uncom- 
mon in  the  natives  of  India. 

Harris  and  others  state  that  this  complication  always  arises  during  the 
acute  period  but  observations  show  that  it  may  develop  at  any  time, 
and  certainly  not  uncommonly  after  all  symptoms  of  dysentery  have 
ceased,  or  indeed,  sometimes  before  any  intestinal  ones  have  developed. 
One  patient  here  first  showed  symptoms  of  abscess  of  the  liver  after 
five  months  local  treatment  for  amoebic  dysentery.  Futcher's  statistics 
show  that  it  may  appear  at  other  times  than  in  the  very  acute  stage. 
However,  in  the  majority  the  abscess  became  evident  in  the  first  month 
after  the  onset  of  the  dysentery.  The  most  common  seat  of  the  abscess 
is  in  the  upper  and  posterior  portion  of  the  right  lobe.  Out  of  639  cases 
of  abscess  in  amoebic  dysentery  collected  by  Rouis,  70.8  per  cent,  were 
situated  in  the  right  lobe  and  13.3  per  cent,  in  the  left  lobe.  There  may 
be  single  or  multiple  large  abscesses  or  very  numerous  small  ones  scattered 
throughout.  In  Futcher's  series  out  of  18  cases,  10  were  single.  In  the 
writer's  series,  13  were  single  and  10  multiple.  In  Craig's,  9  were 
single  and  15  multiple;  and  in  Rogers's,  21  single  and  11  multiple.  The 
number  of  abscesses  is  obviously  an  important  factor  from  a  surgical 
standpoint. 

For  a  long  time  alcohol  has  been  believed  to  predispose  to  liver  abscess 
and  play  an  important  part  in  its  etiology.  In  12  cases  among  private 
patients,  8  were  alcoholics.    In  these  islands  at  least,  malaria  is  generally 

33 


514  DISEASES  CAUSED  BY  PROTOZOA 

not  a  predisposing  factor.  Kartulis  has  reported  6  cases  of  liver  abscess 
with  amoebic  appendicitis.  In  3  the  intestinal  lesions  were  most  marked 
in  the  crecnm  and  appendix.  In  1  the  appendix  was  most  extensively 
diseased  while  in  the  c;vcum  only  3  small  ulcers  existed.  He  snggcsts 
that  the  portal  of  entry  of  infection  may  sometimes  be  through  lesions  in 
the  appendix. 

The  amoebcx;  are  supposed  to  reach  the  liver  by  two  paths.  The  more 
common  is  certainly  through  the  portal  vein.  Amoeba  are  frequently 
found  in  the  veins  of  the  submucosa  and  in  the  portal  capillaries.  The 
other  method  of  transmission  is  through  the  peritoneal  cavity.  Council- 
man and  Lafleur,  and  Rogers  all  sup[)ort  this  theory  and  think  that  infec- 
tion occurs  in  many  cases  in  this  manner.  The  parasites  are  supposed 
to  migrate  through  the  intestinal  wall  and  then  invade  the  liver  from  its 
surface.  Lafleur  has  cited  an  instance  with  peritonitis  present  in  which 
amoebje  were  found  over  the  peritoneal  surface  of  the  intestines  and 
liver.  This  would  certainly  seem  to  be  one  mode  of  infection.  In  one 
of  the  writer's  cases  an  amoebic  abscess  occurred  beneath  the  right  rectus 
muscle,  the  infection  apparently  having  entered  through  the  parietal  peri- 
toneum. In  another  the  abscess  was  less  than  a  centimeter  in  diameter, 
solitary,  and  occurred  just  beneath  the  surface  of  the  right  lobe  of  the 
liver. 

Bacteriology. — In  addition  to  amoebae  the  abscesses  are  usually  infected 
with  bacteria.  In  27  cases  reported  by  Futcher  and  examined  bacterio- 
logically,  15  contained  bacteria;  of  the  writer's  23  cases  bacteria  were 
found  in  13,  and  in  37  of  Rogers's  they  were  present  in  16.  In  the  larger 
abscesses  the  bacteria  may  have  died  out,  but  a  proportion  of  even  the 
earlier  abscesses  seem  to  be  entirely  sterile.  The  organisms  most  fre- 
quently found  are  the  Staphylococcus  and  the  Streptococcus  pyogenes 
and  the  colon  bacillus;  the  Micrococcus  lanceolatus  and  the  Bacillus 
pyocyaneus  have  occasionally  been  reported.  It  is  obvious  why  bac- 
terial infection  occurs  so  frequently,  as  these  organisms  have  the  same 
opportunity  for  entering  the  liver  as  the  amoebre  and  frequently  adhere 
to  them.  Undoubtedly  the  pus  cocci  exert  an  injurious  influence  upon 
the  he]:)atic  tissue,  but  there  can  be  little  doubt  that  the  amoebae  play  a 
most  important  part  in  the  formation  of  the  abscess.  This  is  demon- 
strated by  the  very  different  character  of  the  amoebic  and  the  pure  bac- 
terial variety.  The  contents  of  the  former  vary  somewhat.  In  the 
smaller  abscesses  they  consist  of  thick,  glairy,  yellowish  masses  of  mucus 
which  are  not  fluid.  In  the  large  abscesses  the  contents  are  more  liquid, 
frequently  like  thick  gruel,  and  yellowish,  grayish-red,  brownish-red,  or 
at  times  greenish  in  color.  Frequently  shreds  of  necrotic  liver  tissue  are 
mixed  with  the  fluid  portions.  INIicroscopically  one  is  struck  usually 
with  the  absence  or  presence  in  small  numbers  only,  of  polymorphonuclear 
leukocytes.  The  contents  consist  mainly  of  fine  or  more  coarsely  granular 
material  containing  fragments  of  cells,  many  swollen  and  fatty  degen- 
erated liver  cells,  red  blood  corpuscles,  fat  globules,  and  amoebae.  The 
latter  are  sometimes  difficult  to  find  in  the  pus,  but  can  almost  invariably 
be  obtained  in  scrapings  made  from  the  abscess  wall,  though  sometimes 
repeated  examinations  are  necessary  to  detect  them. 

Special  Patholor/ij. — The  liver  may  be  of  normal  size,  but  is  frequently 
enlarged.   The  tissue  often  shows  advanced  fatty  degeneration  or  chronic 


PLATE  VIII 


FIG.  1 


Large  Single  Amoebic  Liver  Abscess. 


FIG.  2 


Hepatopulmonary  Amoebic  Abscess 


AMCEBIC  DYSENTERY  515 

passive  congestion,  or,  sometimes,  it  is  acutely  congested.  There  are 
areas  of  localized  peritonitis  where  the  abscesses  reach  the  surface  of 
the  liver,  and  the  overlying  tissues  may  then  be  bound  by  adhesions 
to  it.  The  size  of  the  abscesses  may  vary  from  several  millimeters  in 
diameter  to  that  of  a  man's  head.  In  one  of  the  writer's  cases  a  single 
abscess  occupied  the  entire  right  lobe,  only  a  shell  of  liver  tissue  remain- 
ing. The  liver  and  abscess  weighed  3,700  grams.  Very  frequently 
several  abscesses  about  the  size  of  an  orange  are  encountered.  A  some- 
what rarer  condition  is  that  in  which  very  numerous  small  abscesses  are 
scattered  throughout  both  lobes  of  the  liver.  "When  the  contents  are 
evacuated  the  walls  of  the  small  ones  generally  show  a  sharp  contour. 
Those  of  the  larger  ones  have  an  uneven  and  ragged  necrotic  appearance. 
The  liver  tissue  along  the  margin  of  the  abscess  is  softened  and  infiltrated. 
The  older  abscesses  usually  have  walls  composed  of  a  dense  layer  of 
fibrous  connective  tissue.  A  microscopic  study  of  the  periphery  of  the 
small  abscesses  shows  that  the  interlobular  areas  are  always  the  first 
to  become  disintegrated,  and  to  this  is  due  the  irregular  contour,  the 
periportal  areas  persisting  until  detached  by  the  interlobular  necrotic 
processes.  The  edge  of  the  abscess  consists  of  a  necrotic  area  of  liver 
cells  where  the  amoebse,  together  with  leukocytes,  blood  corpuscles,  and 
fibrin  filaments,  are  frequently  found.  The  capillaries  are  dilated,  filled 
with  blood,  and  frequently  contain  the  parasites.  The  latter  show  no 
indication  of  attempting  to  penetrate  beyond  the  necrotic  zone.  Outside 
this  layer  is  a  zone  in  which  great  activity  of  the  connective  tissue  cells 
is  observed  and  in  which  the  liver  cells  are  frequently  compressed  and 
atrophied;  mononuclear  small  cells  are  usually  abundant.  Finally  this 
layer  is  usually  surrounded  by  a  zone  of  more  marked  hypersemia  where 
small  hemorrhages  are  frequently  found.  In  these  latter  areas  thrombi 
may  occur  in  the  branches  of  the  portal  veins,  where  amcebse  and  bac- 
teria may  both  be  found.  Councilman  and  Lafleur,  in  addition  to  the 
abscess  formation,  have  also  described  a  widespread  necrosis  of  the  cells 
situated  round  the  central  veins  of  the  lobules  and  scattered  throughout 
the  liver.  They  suggest  that  this  is  due  to  soluble  chemical  products 
of  the  amoebse.  A  striking  point  also  observed  in  the  hepatic  lesions  is 
the  absence  of  leukocytic  infiltration,  which  usually  accompanies  suppu- 
ration of  bacterial  origin.     (Plate  VIII,  Fig.  1.) 

Diagnosis  and  Symptoms. — Liver  abscess  is  frequently  overlooked, 
and  this  is  not  strange,  for  sometimes  its  development  takes  place  so 
insidiously  that  perforation  may  be  the  first  indication.  If  the  onset  is 
more  acute  the  diagnosis  is  simplified.  Pain  is  very  common  at  some 
time.  It  is  commonly  dull  and  aching  but  may  become  sharp  and  lan- 
cinating. Its  situation  varies  greatly,  being  almost  as  frequent  in  the 
vicinity  of  the  right  scapula  and  shoulder  as  over  the  liver  itself.  In  the 
former  case  the  pain  is,  according  to  Futcher,  reflex  through  the  phrenic 
nerve  which  receives  large  branches  from  the  fourth  cervical.  The  pain 
may  occur  over  the  hypochondrium  or  epigastrium.  When  not  present 
spontaneously  it  may  be  elicited  upon  pressure  over  the  liver.  However, 
pain  is  not  constant,  and  is  frequently  absent.  Fever  is  usually  present  at 
some  time,  but  is  often  not  sufficient  to  attract  attention.  Occasionally  it 
is  continuous  and  not  over  100°  to  102°  F.  In  other  cases  it  is  remittent; 
or  it  may  be  septic  in  type  and  intermittent  and  rise  in  the  evening  tQ 


516  DISEASES  CAUSED  BY  PROTOZOA 

104°  F.  Chills  and  sweats  may  then  occur,  and  the  symptoms  simulate 
those  of  malaria.  Lafleur  calls  attention  to  sweating  as  an  important 
symptom,  and  states  that  it  is  independent  of  the  temperature.  The 
pulse  may  be  Uttle  increased,  but  in  the  cases  Avith  high  fever  it  may  be 
1-10  or  more 

Blood. — niere  is  usually  a  leukocytosis  from  15,000  to  40,000  in  which 
the  polymorphonuclear  cells  are  increased.  However  the  leukocyte  count 
may  be  normal. 

The  conjunctiva?  are  sometimes  slightly  tinged  with  yellow,  but  marked 
jaundice  is  rare.  Persistent  vomiting  may  occur.  The  skin  frequently 
assumes  a  sallow  color;  and  the  face  may  become  pale  and  yellow.  The 
facies  may  suggest  the  diagnosis.  In  certain  cases  emaciation  occurs 
rapidly;  in  others  the  flesh  is  well  retained.  The  appetite  usually  dis- 
appears and  the  tongue  becomes  coated.  Physical  examination  may 
show  enlargement  of  the  liver  which  may  even  cause  bulging  on  the  right 
side;  pain  may  be  elicited  on  pressure.  Occasionally  a  swelling  may  be 
observed  over  the  sixth  and  seventh  ribs.  Percussion  and  auscultation 
frequently  give  no  information  of  the  condition.  If  the  abscess  is  large, 
percussion  may  reveal  an  increase  in  hepatic  dulness.  A  friction  rub 
may  be  heard  over  the  liver  when  the  peritoneum  is  involved.  In  the 
diagnosis  of  liver  abscess  there  is  not  a  single  symptom  that  is  constant, 
and  proof  that  the  liver  is  involved  may  be  very  doubtful.  The  general 
condition  and  appearance  of  the  patient,  with  the  progress  of  the  case, 
rather  than  any  single  symptom,  often  suggest  the  diagnosis,  which  may 
sometimes  be  confirmed  by  aspiration. 

Spontaneous  rupture  of  amoebic  abscess  frequently  occurs  if  the  patient 
lives  long  enough  and  is  not  operated  upon.  This  is  most  often  into  the 
lower  lobe  of  the  right  lung.  Rupture  into  the  abdominal  cavity  causing 
general  peritonitis  is  also  frequent.  The  abscess  may  perforate  into  the 
pleura,  pericardium,  stomach,  colon,  small  intestine,  bladder,  vena  cava, 
kidney,  and  through  the  skin  in  the  lumbar  or  right  hypochondriac  region. 

Kartulis  has  reported  brain  abscess  in  3  per  cent,  of  his  liver  abscess 
cases.  Amoebpe  were  found  in  the  vicinity  of  the  necrotic  areas.  Jiirgens 
had  2  cases  of  thrombosis  of  the  femoral  vein,  in  1  of  which  amputation 
of  the  leg  was  necessary. 

Abscess  of  the  spleen  may  occur. 

Abscess  of  the  Lung. — Preceding  this,  the  respirations  are  usually 
increased  in  number  and  are  often  painful  and  shallow.  Before  perfora- 
tion occurs  the  physical  signs  of  pleurisy  are  usually  present.  Cough 
and  expectoration  then  appear,  and  are  generally  constant.  The  cough 
in  the  early  stage  is  hacking  and  accompanied  by  pain  over  the  liver. 
AVhen  the  abscess  discharges  into  the  pleui'al  cavity  or  into  a  bronchus, 
the  dyspnoea  becomes  less  marked.  Sooner  or  later  the  characteristic 
anchovy-sauce-like  sputum  appears,  in  w^hich  can  be  found  amoebte  with 
red  blood  corpuscles,  leukocytes,  altered  liver  cells,  alveolar  epithelium, 
elastic  tissue  fibers,  Charcot-Leyden,  tyrosin  and  hsematoidin  crystals, 
and  various  bacteria.  Small  cheesy  particles  consisting  of  granular 
material  and  oil  drops  are  also  encountered.     (Plate  VIII,  Fig.  2.) 

Special  Pathology. — In  abscess  of  the  lung  the  diaphragm  is  adherent 
to  the  liver  and  usually  to  the  base  of  the  lung.  If  the  latter  is  not  the 
case,  a  layer  of  pus  separates  the  lung  from  the  diaphragm.    Abscesses 


AMCEBIC  DYSENTERY  517 

are  never  metastatic,  and  the  lower  right  lobe  is  always  the  one  affected. 
The  diaphragm  may  or  may  not  be  visibly  perforated.  On  opening  the 
lung  abscess  it  may  be  found  filled  with  viscid  yellowish-gray  or  yellowish- 
red  partially  fluid  material;  or,  if  perforation  into  a  bronchus  or  the 
pleural  cavity  has  occurred,  it  may  be  empty.  The  walls  of  the  abscess 
are  frequently  more  uneven  than  those  of  the  liver  abscess;  in  places, 
however,  they  may  be  smooth  and  formed  of  dense  connective  tissue. 
Sections  of  the  older  abscesses  show  usually  three  zones;  first  a  necrotic 
one  containing  fragmented  nuclei,  degenerated  cells,  and  amcebse;  second, 
a  layer  composed  of  connective  tissue  fibers,  epithelial  cells,  elastic  fibers, 
sometimes  distinct  groups  of  air  cells,  and  occasionally  amoebae;  and 
third,  a  layer  of  small  round-cell  infiltration  in  which  fibrin  and  some 
proliferation  of  the  connective  tissue  fibers  is  also  visible  between  the 
air  cells.  The  walls  of  the  bronchi  are  thickened  and  infiltrated  with 
numerous  round  cells.  The  bronchi  contain  either  purulent  or  serous 
fluid. 

Hepatopulmonary  abscess  is  a  somewhat  rare  condition.  Harris 
reports  it  3  times  in  95  patients,  and  Futcher  9  times  out  of  119  with  3 
cases  in  which  the  liver  abscess  ruptured  into  the  pleural  cavity.  In 
the  writer's  series  of  100  fatal  cases,  hepatopulmonary  abscess  occurred 
but  once  with  2  cases  of  empyema.  Perforation  of  the  liver  abscess  into 
the  lung  does  not  always  occur.  The  extension  may  result  through 
the  diaphragm  without  visible  perforation.  When  rupture  into  a  bronchus 
takes  place,  the  condition  may  last  from  six  to  eight  weeks  and  terminate 
in  death  or  recovery,  or  persist  for  a  year.  The  mortality  is  usually  very 
high. 

Peritonitis. — A  local  peritonitis  may  result  from  extension  of  the 
ulceration  in  the  bowel  or  from  an  abscess  in  the  liver.  Patches  of  fibrous 
adhesions  are  of  very  frequent  occurrence;  in  chronic  cases  it  is  the  rule 
to  find  old  localized  areas  of  chronic  adhesive  peritonitis.  These  are 
very  difficult  to  diagnose  during  life.  They  may  cause  abdominal  sore- 
ness and  pain.  Peritonitis,  which  generally  proves  fatal,  may  follow 
perforation  of  a  liver  abscess  or  an  intestinal  ulcer. 

Perforation. — Perforation  of  the  intestine  results  generally  from  the 
giving  way  of  the  base  of  a  deep  sloughing  ulcer  and  is  most  frequent 
in  the  grave  and  gangrenous  cases.  The  opening  is  usually  a  large  one. 
The  perforation  occurs  frequently  in  the  csecum,  and  the  condition  has 
sometimes  been  mistaken  for  one  in  which  the  appendix  is  involved. 
Perforation  of  the  large  bowel  with  general  peritonitis  occurred  in  19 
of  the  writer's  100  autopsies.  In  2  other  cases  it  occurred  after  the 
ulcer  was  thoroughly  walled  off  from  the  peritoneal  cavity.  In  Futcher's 
series,  perforation  occurred  only  in  3  and  in  Craig's  in  4  cases.  In  the 
writer's  series  of  200  clinical  cases  it  occurred  but  3  times.  It  is  almost 
invariably  fatal.  In  one  of  the  Johns  Hopkins  series  the  patient  was 
operated  upon  three  hours  after  the  perforation  occurred,  but  died.  Death 
may  occur  in  a  few  hours  from  shock,  or  later  from  the  resulting  acute 
general  peritonitis.  Perforation  sometimes  happens  after  adhesions  have 
formed,  when  a  pericsecal  or  pericolic  abscess  may  result.  It  may  take 
place  retroperitoneally  into  the  psoas  muscle  and  may  even  open  externally. 

Appendicitis. — ^This  complication  occurred  in  7  of  my  ICO  fatal  cases. 
In  one  a  chronic  appendicitis  existed  in  connection  with  a  pericsecal 


SIS  DISEASES  CAUSED  BY  PROTOZOA 

amoebic  abscess  In  4  of  the  G,  death  resuhcd  from  general  peri- 
tonitis following  perforation  of  the  caecum  or  colon.  All  showed  extensive 
general  intestinal  lesions  and  the  involvement  of  the  appendix  merely 
followed  extension  from  the  caecum.  A  definite  diagnosis  of  the  appen- 
dicular affection  during  life  is  very  difficult  since  the  caecum  in  addition 
is  usually  extensively  diseased.  The  process  is  not  very  acute  as  a  rule. 
It  consists  of  the  formation  of  ulcerations  in  the  walls  of  the  appendix. 
In  only  one  of  the  Avritcr's  cases  was  the  appendix  perforated  at  its  tip. 

Intestinal  Hemorrhage. — Intestinal  hemorrhage  in  which  large 
amounts  of  pure  blood  are  passed  from  the  rectum  is  a  rare  complication. 
Councilman  and  Lafleur  report  but  1  case  in  which  125  Cc.  of  blood  were 
passed.  Death  was  apparently  due  to  the  bleeding.  In  1902,  the  writer 
called  attention  to  severe  intestinal  hemorrhage  as  a  fatal  complication  and 
reported  2  cases  in  both  of  which  liver  abscess  was  present  and  in  which 
death  was  due  to  severe  multi})le  hemorrhages.  It  was  suggested  that 
these  large  hemorrhages  might  perhaps  bear  some  relation  to  the  con- 
dition of  the  liver.  Shortly  afterward  Haasler  reported  from  China  3 
more  instances  of  intestinal  hemorrhages,  in  2  of  which  death  took  place 
from  bleeding.  In  both  of  these  cases  liver  abscess  also  existed.  Since 
this  time  the  writer  has  seen  2  more  fatal  cases  from  multiple  hemorrhages, 
both  with  liver  abscess,  and  therefore  a  connection  between  intestinal 
hemorrhage  and  the  hepatic  condition  is  suggested.  While  it  is  probable 
that  fatal  intestinal  hemorrhage  in  amoebic  dysentery  may  occur  independ- 
ently of  liver  abscess,  the  cases  mentioned  suggest  that  when  hemor- 
rhage occurs  in  patients  with  liver  abscess  it  is  likely  to  be  very  severe, 
and  the  bleeding  is  likely  to  recur.  Futcher  reports  intestinal  hemor- 
rhage in  3  of  his  series.  Why  is  severe  intestinal  hemorrhage  not  more 
frequent  in  amoebic  dysentery?  One  should  consider  the  following 
points:  the  thrombosed  condition  of  the  bloodvessels  in  the  zone  of  in- 
filtration and  the  oedema  which  surrounds  the  ulcers,  the  infiltration  of 
the  walls  of  the  arteries  and  the  more  or  less  marked  evidence  of  endar- 
teritis as  the  progress  is  rapid  or  slow.  In  chronic  cases  one  may  see  at 
times  the  arteries  entirely  occluded  by  this  process. 

The  frequent  occurrence  of  small  amounts  of  blood  in  the  stools  may 
be  explained  from  the  fact  that  the  walls  of  the  veins  are  early  infiltrated 
with  round  cells,  followed  by  softening  and  complete  disorganization, 
also  from  the  fact  that  amoebae  may  penetrate  the  walls  of  a  vein.  How- 
ever, thrombosis  of  the  veins  is  not  infrequent. 

Sequelae, — In  old  chronic  cases  with  extensive  ulceration  large  cica- 
trices frec^uently  form.  When  a  long-continued  catarrhal  condition  has 
been  present  a  general  atrophy  of  the  mucosa  may  take  place.  In  these 
instances  we  sometimes  find  a  clinical  condition  closely  resembling  sprue 
or  psilosis.  The  small  intestine,  owing  to  the  inanition,  ansemia,  etc., 
may  also  become  secondarily  involved  and  its  mucosa  atrophied.  The 
stools  then  are  copious,  liquid  (at  least  never  formed),  pale  in  color,  and 
usually  frothy.  The  chronic  gastric  catarrh  and  enteritis,  wdiich  fre- 
quently develop  wath  a  sore  and  fissvired  tongue  and  often  an  inflamed 
oesophagus,  complete  the  picture.  This  condition  was  observed  in  3  very 
chronic  patients  who  finally  overcame  the  amoebic  infection. 

Diagnosis. — This  is  not  difficult  by  microscopic  examination;  but 
there  are  other  forms  of  dysentery  which  clinically  it  may  be  impossible 


AMCEBIC  DYSENTERY  519 

to  distinguish  from  the  amoebic  variety,  and  any  one  who  attempts  to 
make  a  diagnosis  from  the  cUnical  manifestations  alone  will  make  fre- 
quent mistakes.  The  occurrence  of  amoebic  liver  abscess  always  con- 
firms the  diagnosis,  but  sometimes  the.symptoms  to  which  it  gives  rise  are 
the  first  ones  to  attract  attention  to  the  intestinal  disease.  The  examina- 
tion of  the  stools  should  be  made  as  soon  as  possible  after  they  are  passed, 
and  the  specimens  should  be  collected  free  from  urine.  Many  observers 
recommend  in  cold  climates  that  a  warm  bedpan  be  used  and  that  the 
microscopic  slide  be  gently  warmed.  This  is  not  necessary  in  tropical 
countries.  These  precautions  are  necessary  because  the  amoeba;  frequently 
die  in  stools  that  have  stood  for  any  length  of  time  or  that  contain  urine, 
and  their  motility  is  often  quickly  impaired  by  cold.  The  amoebai  must 
be  found  Hving  and  motile.  In  this  condition  they  are  easily  recognized 
and  cannot  be  mistaken  for  other  bodies.  After  movement  ceases  and 
death  or  encystment  results,  it  is  frequently  impossible  to  distinguish 
them  from  other  substances.  It  is  necessary  to  emphasize  that  the  amoebae 
must  be  motile,  for  upon  the  presence  of  such  forms  depends  the  diag- 
nosis of  the  disease.  Usually  the  examination  of  several  specimens 
from  one  stool  reveals  the  parasite,  but  sometimes  the  study  of  several 
upon  different  occasions  is  necessary.  If  bloody  mucus  or  small  pieces 
of  necrotic  tissue  are  present,  these  should  be  examined  first,  for  if  they 
come  from  the  neighborhood  of  an  ulcer  they  usually  contain  very  large 
numbers  of  amoebae.  If  the  movements  are  not  liquid  a  dose  of  Rochelle 
salts  should  be  given  and  the  fluid  portion  of  the  stool  examined.  Another 
very  convenient  method  of  securing  material  for  examination  is  by  the 
passage  of  the  rectal  tube.  When  the  stools  are  fluid  considerable 
amounts  may  be  obtained,  or  small  portions  of  mucus  will  be  found  in 
the  lumen  of  the  tube. 

Since  Schaudinn  insisted  upon  the  harmlessness  of  entamoeba  coli 
for  man  it  is  important  to  distinguish  between  this  and  entamoeba  histo- 
lytica. For  differentiation  Lesage  has  recommended  the  addition  of  a 
dilute  watery  solution  of  iodine  to  the  fluid  stools.  This  brings  about  in 
a  few  minutes  encystation  by  which  the  amoebae  may  be  distinguished 
from  one  another.  However  until  we  know  more  about  entamoeba  coli, 
in  any  instance  in  which  symptoms  of  intestinal  disturbance  exist  and 
amoebae  are  found,  the  diagnosis  of  amoebic  coKtis  had  best  be  made 
and  the  proper  treatment  instituted;  for,  m  an  intestine  with  erosions, 
probably  the  entamoeba  coli  may  cause  additional  disturbance  from  its 
mechanical  movements,  even  if  it  is  not  capable  of  producing  any  othei 
pathological  efl^ect.  If,  however,  one  chooses  to  attempt  the  separation 
of  the  two  forms  by  their  pathogenic  action,  extensive  animal  experi- 
ments, preferably  upon  cats,  must  be  performed  with  the  parasites 
found  in  the  stools.  Infection  with  other  disease  may  co-exist,  and  in 
cases  with  acute  onset  it  will  be  important  and  advisable  to  make  plate 
cultivations  of  the  bacteria  from  the  stool  and  search  for  Bacillus  dysen- 
teriae,  as  well  as  test  the  agglutinative  and  bactericidal  reaction  of  the 
patient's  blood  serum  with  this  organism. 

The  diagnosis  of  liver  abscess  should  be  made  only  after  a  careful 
consideration  of  all  the  existing  symptoms.  The  general  condition  of  the 
patient  and  his  faeces  together  with  the  progress  should  be  taken  into 
account.     The  blood  should  be  examined  to  exclude  malaria  and  for  a 


520  DISEASES  CAUSED  BY  PROTOZOA 

leukocytosis,  but  it  must  be  remembered  that  the  leukocyte  count  may 
occasionally  be  almost  normal.  If  no  intestinal  disturbance  exists,  an 
additional  clue  may  be  obtained  from  the  history  or  by  finding  the  amoe- 
ba^ in  the  stools.  An  absolute  diagnosis  can  frequently  only  be  made 
by  the  finding  of  ama>ba^  in  the  abscess.  This  may  sometimes  be  done 
by  asjiiration  before  spontaneous  evacuation  or  operation.  This  should 
be  done  with  a  needle  having  a  sufficiently  larg?  caliber  to  transmit  the 
thick  pus.  The  puncture  may  be  made  through  the  skin,  the  point  of 
entrance  being  over  the  suspected  area;  but  the  surgeon  must  be  at 
hand  to  operate  if  necessary.  The  method  may  fail  and  if  unsuccessful 
should  be  repeated.  ^Vhen  pus  is  obtained  it  may  contain  no  amoebie, 
but  the  absence  of  large  nund)ers  of  leukocytes  and  the  presence  of 
much  granular  material  will  suggest  that  the  origin  is  ama'bic. 

The  diagnosis  of  amoebic  he])atoi)ulmonary  abscess  may  be  definitely 
made  when  the  patient  suddenly  begins  to  expectorate  quantities  of 
reddish  brown  anchovy-sauce-like  sputum  containing  liver  cells,  haema- 
toidin  crystals,  and  amcebre.  The  latter  are  always  present,  though 
sometimes  a  prolonged  and  repeated  search  is  necessary  to  find  them. 

Prognosis. — There  is  no  doubt  of  the  gravity  of  the  disease  and  when 
well  advanced  before  proper  treatment  is  instituted  the  final  outlook  is 
often  doubtful.  The  sym})toms  in  the  majority  of  cases  yield  to  treat- 
ment in  a  short  time  and  the  patient  may  feel  quite  well.  It  is  in  this  con- 
dition (when  he  falls  into  the  hands  of  those  not  thoroughly  familiar  with 
the  malady)  that  he  is  frequently  discharged  only  to  return  sooner  or  later 
with  a  recurrence.  This  may  happen  a  number  of  times,  and  among  this 
class  of  patients  the  mortality  is  always  high.  In  untreated  patients  who 
are  exposed  to  hardships,  the  death-rate  is  very  great.  Out  of  78  collected 
cases  (Harris)  in  the  United  States  there  were  30  deaths.  In  the  Johns 
Hopkins  series  of  119,  28  terminated  fatally;  however  in  both  of  these 
series  it  seems  probable  that  many  were  well  advanced  before  treatment 
was  instituted,  since  patients  in  America  do  not  as  a  rule  enter  hospitals  in 
the  earlier  stages  of  the  disease  vmless  the  symptoms  are  severe.  One  might 
expect  a  somewhat  different  outcome  if  treatment  were  instituted  early. 

In  the  writer's  series  of  200  treated  cases,  which  included  all  stages  of 
the  disease  and  from  which  accurate  data  were  obtained,  there  have  been 
12  deaths  and  4  are  chronic  invalids;  the  remainder  have  recovered. 
Tuttle  has  recently  reported  73  cases  in  the  United  States  with  70  recov- 
eries. In  children  the  prognosis  is  almost  always  good.  Amberg  and 
INIusgrave  each  rejiort  1  death.  Adding  together  these  cases  we  have  44 
cases  in  children  with  2  deaths,  a  mortality  of  4.5  per  cent.  In  the  un- 
complicated cases,  those  with  acute  onset,  including  the  gangrenous  form, 
usually  have  the  gravest  outlook.  The  writer  cannot  agree  with  Lafleur 
that  a  mild  onset  is  no  indication  of  a  favorable  course,  for  when  local 
treatment  is  instituted  early  these  cases  usually  progress  favorably. 

In  liver  abscess  the  outlook  is  always  very  grave.  Futcher  reports  19 
deaths  out  of  27  cases;  17  of  these  were  operated  upon  but  only  5 
recovered.  In  the  writer's  clinical  series  of  200,  abscess  of  the  liver 
Occurred  in  12,  3  of  whom  recovered  after  operation.  The  prognosis 
when  hepatopulmonary  abscess  exists  is  perhaps  even  graver. 

Immunity. — While  in  many  instances  there  seems  to  be  a  natural 
resistance  to  the  disease,  it  would  appear  doubtful  if  there  is  any  acfjuired 


AMCEBIC  DYSENTERY  521 

immunity  against  it.  The  apparent  natural  resistance  may  depend  upon 
the  fact  that  the  parasites  are  killed  before  reaching  the  large  intestine,  or 
that  they  do  not  find  favorable  conditions  for  life  and  reproduction.  The 
amoebse,  after  the  development  of  the  disease,  may  disai)pear  from  the 
stools  independently  of  treatment,  but  this  may  be  brought  about  by 
unfavorable  conditions  in  the  intestine  rather  than  by  any  acquired 
immunity.  Our  knowledge  of  immunity  in  amoebic  dysentery  amounts 
to  almost  nothing.  Perhaps  further  light  may  be  thrown  ujion  it  from 
the  study  of  the  secretory  products  of  the  parasites,  their  enzymes,  endo 
and  soluble  products,  etc.,  as  well  as  by  the  application  of  other  methods 
which  have  been  employed  in  the  study  of  immunity  in  bacterial  diseases. 
Work  of  this  nature  has  already  been  commenced  in  the  laboratory  in 
Manila. 

Treatment. — Prophylactic. — Since  the  disease  is  only  acquired  by  the 
ingestion  of  the  amoebee  in  food  or  drink,  it  is  a  preventable  one,  and  may 
be  avoided  even  when  the  malady  exists  endemically.  Drinking  water  is 
the  most  usual  medium,  and  hence  only  that  which  has  been  sterilized 
is  safe  to  use.  A  reliable  bottled  imported  aerated  water  is  the  safest  to 
use  in  localities  where  the  general  water-supply  is  infected.  Salads  and 
uncooked  fruits  are  sometimes  a  possible  means  of  conveyance  and 
should  be  avoided  unless  prepared  with  great  care,  particularly  since 
they  also  may  be  a  source  of  infection  with  other  intestinal  parasites. 

General,  Dietetic,  and  Symptomatic. — Patients  with  acute  onset  or 
acute  exacerbations  of  the  disease  should  be  confined  to  bed.  In  the 
most  severe  forms  when  very  frequent  bloody  mucous  stools  are  being 
passed,  the  diet  should  at  first  consist  of  nothing  but  rice  or  albumin 
water.  Later  milk  may  be  added.  Rest  is  most  essential,  and  for  this 
hypodermic  injections  of  morphia  sulphate  (gr.  \,  gm.  0.016)  may  be 
given  every  three  or  four  hours.  Its  use  should  be  pushed  if  necessary. 
Local  treatment  in  this  stage  is  contra-indicated.  The  essential  point  is 
to  secure  rest  for  the  patient  and  for  the  acutely  inflamed  bowel.  If  this 
can  be  accomplished  the  condition  usually  improves.  As  the  symptoms 
begin  to  abate,  Dover's  powder  (gr.  10,  gm.  0.6)  may  be  substituted  for 
the  morphia.  This  should  be  continued  until  the  acute  symptoms  have 
subsided,  when  local  treatment  may  be  commenced.  If  the  patient  be 
seen  before  the  symptoms  are  very  acute  a  saline  purge  may  be  given, 
but  if  the  severe  symptoms  have  set  in  this  is  contra-indicated.  In  the 
mild  attacks  and  those  of  very  moderate  severity  it  has  become  the 
custom  in  Manila  not  to  confine  the  patient  to  the  house  but  to  allow 
him  to  be  about  and  to  enjoy  a  liberal  diet.  There  is  no  doubt  that  this 
is  frequently  a  mistake,  but  as  the  majority  of  these  do  not  feel  ill,  they 
also  feel  that  they  are  unable  to  remain  away  from  their  work  and  take 
the  advised  rest.  Many  of  them  it  is  true  are  better  off  when  not  confined 
to  bed  for  the  reason  that  they  are  likely  to  retain  their  strength  better 
when  up;  but  rest  at  home  is  usually  advisable,  though  an  occasional 
drive  in  the  afternoon  is  often  beneficial  for  its  general  effect. 

Where  any  intestinal  irritation  exists  the  diet  should  be  restricted. 
Fresh  milk,  when  obtainable,  should  be  chiefly  employed.  It  may  be 
necessary  to  peptonize  it,  and  this  should  be  done  if  curds  appear  in  the 
stools.  If  it  is  not  well  borne,  other  liquid  nourishment  may  be  substi- 
tuted.   It  is  of  course  advisable  to  feed  the  patient  frequently  and  in 


522  DISEASES  CAUSED  BY  PROTOZOA 

small  quantities.  As  the  symptoms  improve,  other  licjuids  and  soft  food 
may  be  gradually  added.  Not  until  the  stools  appear  perfectly  normal 
should  general  diet  be  permitted.  Any  lesions  of  the  intestine  will  cer- 
tainly be  more  disadvantageously  affected  by  solid  than  by  li(juid  food. 

Nausea  and  vomiting  are  frequently  very  annoying  symptoms.  They 
may  result  from  the  treatment  or  be  one  of  the  results  of  the  disease 
itself.  The  vomiting  Avhile  annoying  is  very  rarely  persistent  or  con- 
tinued. The  alkaline  carbonated  waters  will  sometimes  give  relief,  and 
strychnine  sul[)hute  nuiy  be  employed  in  tonic  doses.  Pepsin,  hydrochloric 
acid,  and  pancreatin  arc  rarely  of  benefit.  In  some,  sodium  bicarbonate 
in  combiiuition  with  bismuth  gives  the  best  results. 

The  use  of  bismuth  is  not  contra-indicated  in  the  treatment  of  amoebic 
dysentery.  Some  writers  have  thought  that  it  may  interfere  with  the 
local  treatment.  This  may  be  true  where  it  is  allowed  to  accumulate  in 
the  bowel.  It  occasionally  is  of  service  when  diarrhoea  persists,  for  by 
its  use  in  one-dnim  doses  every  three  or  four  hours  constipation  may  be 
produced  and  a  condition  of  the  intestine  brought  about  in  which  the 
amoeba^  die  out.  Just  why  the  parasites  cease  to  multi})ly  and  to  exist 
it  is  difficult  to  say.  Obviously  one  must  not  be  led  away  with  the  idea 
that  because  the  diarrhoea  has  stopped  the  lesions  are  healed  and  the 
parasites  have  disappeared.  Repeated  examination  of  the  stools  must 
be  made  to  ascertain'  if  the  amoebse  have  really  died  out.  Ipecac  and 
opium  may  sometimes  bring  about  the  same  results.  In  cases  where 
bismuth  is  employed,  a  saline  cathartic  followed  by  a  high  rectal  enema 
should  be  given  at  least  once  or  twice  a  week. 

In  some  instances  of  the  disease  an  acute  attack  of  diarrhoea  has 
brought  the  patient  for  treatment.  They  have  been  confined  to  bed  for 
a  few  days,  several  doses  of  Dover's  powder  administered,  and  local 
treatment  instituted.  The  parasites  may  never  be  found  in  the  stools 
after  the  first  week,  though  numerous  in  the  first  examination.  The 
symptoms  will  subside  during  this  time  and  a  recurrence  does  not  take 
place.  In  other  cases  with  identical  treatment  the  parasites  may  persist 
for  weeks  or  months.  Certainly  the  destruction  of  the  parasites  in  the 
former  instance  is  not  brought  about  by  the  direct  action  of  the  medicine 
administered  by  the  mouth,  nor  is  their  early  disappearance  probably 
always  dependent  upon  the  direct  action  of  the  quinine  administered 
in  the  enemata.  The  only  explanation  is  that  in  one  instance  conditions 
in  the  intestine  unfavorable  to  the  life  and  propagation  of  the  amcebse 
are  brought  about,  and  in  the  other  we  fail  to  produce  them. 

Abdominal  pain  may  be  very  troublesome.  It  may  be  relieved  by 
turpentine  stupes  and  hot  fomentations;  or,  if  severe,  opium  may  be 
administered.  When  ulcers  exist  in  the  rectum  and  there  is  much  tenes- 
mus, local  treatment  with  argyi'ol  or  some  other  astringent  or  antiseptic 
substance  may  be  applied  through  the  speculum  after  the  administration 
of  a  small  enema  containing  cocaine  or  morphia.  Enemas  of  starch 
and  opium  sometimes  have  a  very  soothing  effect.  If  the  anaemia  is 
advanced  some  iron  preparation  is  necessary;  and  when  there  is  much 
lassitude  and  anorexia,  a  course  of  strychnine  and  alcohol  in  modera- 
tion is  often  of  value.  A  change  of  climate  is  frequently  beneficial  during 
convalescence,  and  patients  who  after  a  long  time  seem  to  make  no  pro- 
gress in  the  tropics  are  often  improved  by  a  bracing  cool  atmosphere. 


AMCEBIC  DYSENTERY  523 

Curative  Treatment. — During  the  writer's  first  year  in  the  PhiHppine 
Islands  he  employed  ipecac,  and  saw  it  used  extensively,  but  concluded 
that  it  is  not  in  any  sense  curative,  and  that,  probably,  the  subsidence  of 
the  acute  symptoms  which  sometimes  takes  place  after  its  use  is  due 
more  to  the  effect  of  the  opium  which  is  administered. 

Intestinal  antiseptics  by  the  mouth  have  practically  no  effect  upon  the 
parasites  in  the  large  intestine,  or  over  the  course  of  the  disease.  Calomel 
in  divided  doses  has  many  advocates.  It  may  be  employed  with  good 
results  when  the  usual  symptoms  indicating  its  use  appear;  but  has  no 
definite  influence  upon  the  parasites  in  the  intestine.  When  the  patients 
have  no  stool  except  after  the  enema,  or  in  cases  with  constipation,  either 
small  doses  of  calomel  or  a  saline  purge  should  be  administered  at  least 
once  a  week.  The  administration  of  quinine  by  the  mouth  on  account 
of  the  effect  it  may  have  upon  the  amoebae  in  the  tissues  has  been  advo- 
cated, but  its  use  in  enemata  seems  to  be  equally,  if  not  more,  advanta- 
geous. 

Local  treatment  by  rectal  injections  and  irrigations  is  by  far  the  most 
efficacious.  After  employing  many  substances,  the  writer  concluded 
that  quinine  solutions  give  the  best  results.  A  reservoir  of  a  capacity 
of  two  liters  is  advisable,  which  during  use  should  be  placed  at  a  height 
of  four  to  five  feet  above  the  patient.  The  rectal  tube  should  be  at  least 
three  or  four  feet  in  length,  and  not  so  soft  as  to  fold  too  easily,  or  too 
stiff  as  to  be  apt  to  injure  the  bowel  in  introduction.  It  should  be  covered 
with  vaseline  before  use  and  introduced  if  possible  its  whole  length. 
The  fluid  should  be  allowed  to  enter  slowly  and  the  hips  should  be  ele- 
vated. The  solution  may  be  1  to  5,000  or  1  to  1,000  to  begin  with,  and 
after  a  few  days  should  be  increased  to  1  to  500  and  used  continuously 
at  this  strength.  The  amount  injected  should  usually  be  about  two 
liters;  some  patients  will  be  able  to  take  more  and  some  less.  The 
enema  should  be  retained  if  possible  fifteen  minutes,  and  at  least  five 
minutes.  Difficulty  may  be  encountered  in  giving  these  large  injections, 
and  in  passing  the  rectal  tube  its  whole  length.  The  attending  phy- 
sician should,  for  a  few  days,  either  administer  the  enemas  himself  or 
have  a  trained  assistant  do  so.  The  writer  has  never  seen  an  accident 
result  from  this  treatment.  It  is  sometimes  necessary  when  the  rectum 
is  very  irritable  to  introduce  a  cocaine  suppository  first;  or  the  irriga- 
tions may  be  suspended  for  a  day  or  two. 

Harris  recommends  hydrogen  peroxide  in  preference  to  quinine,  and 
nitrate  of  silver  solution  30  grains  to  the  quart,  corrosive  sublimate  1 
to  3,000,  benzoyl-acetyl-peroxide  (acetozone),  and  disuccinyl  peroxide 
(alphozone)  1  to  2,000;  slightly  acid  solutions  have  also  been  recom- 
mended. Recently  Tuttle  has  obtained  very  favorable  results  with  ice- 
water,  particularly  when  the  temperature  is  below  45°  F.  Harris  reported 
in  his  first  paper  that  not  in  a  single  instance  did  improvement  follow 
injections  of  ice-water. 

One  or  two  enemas  daily  are  usually  sufficient.  In  certain  cases  in 
robust  individuals  as  many  as  three  may  be  employed.  A  greater  number 
than  this  will  probably  always  do  more  harm  than  good.  It  is  prob- 
able that  the  mere  flushing  out  and  cleaning  of  the  colon  plays  an  im 
portant  role  in  the  treatment,  and  many  recover  when  saline  solutions 
or  ordinary  water  enemas  are  employed.    It  is  obvious  that  this  washing 


524  DISEASES  CAUSED  BY  PROTOZOA 

out  must  not  be  performed  too  often  or  the  general  condition  of  the 
patient  may  suffer,  and  the  mucosa  itself  be  injured  and  healing  delayed. 
There  are  a  number  of  cases  in  which  the  parasites  persist  even  after 
all  symptoms  have  disappeared  and  we  are  not  able  to  rid  the  patient 
of  them  by  any  known  means.  Every  physician  who  carefully  and 
repeatedly  examines  the  stools  of  his  patients  before  discontinuing  the 
local  treatment  will  hnd  this  to  be  the  case.  Still,  in  other  instances  the 
parasites  appear  to  persist,  chiefly  owing  to  their  burrowing  in  the  sub- 
mucosa  where  we  are  not  able  to  reach  them  by  local  treatment.  In 
those  cases  in  which  the  lesions  have  healed  and  the  parasites  still  persist, 
the  time  to  discontinue  treatment  is  important.  If  it  is  decided  to  inter- 
rupt the  treatment,  the  enemas  should  be  gradually  reduced  to  one  or 
two  a  week  before  their  complete  withdrawal,  and  the  stools  carefully 
watched  for  blood  cells  or  other  evidences  of  intestinal  disturbance.  Of 
course  the  prolonged  local  treatment  for  several  months  usually  brings 
about  a  catarrhal  condition  of  the  large  intestine  which  may  exist  for  a 
long  time  or  never  disappear. 

In  patients  with  suspected  lesions  in  the  coecum  which  do  not  yield 
to  treatment  by  the  rectum,  colostomy  has  been  recommended,  or  the 
appendix  has  been  drawn  out  and  amputated  and  the  irrigations  given 
directly  through  the  Cfecum.  The  writer  has  seen  only  one  advanced  case 
treated  by  this  method.  The  patient  was  not  apparently  benefited  by  it 
and  succumbed  about  a  month  later. 

Treatment  of  the  Complications.— Abscess  of  the  liver  should  be 
opened  and  drained  as  soon  as  the  diagnosis  is  made,  unless  it  has 
already  perforated  into  the  lung  and  is  being  freely  discharged  through  a 
bronchus.  If  the  abscess  is  opened  it  should  be  frequently  irrigated 
with  quinine  solution.  If  it  is  not  found  or  no  operation  is  performed 
the  medical  treatment  indicated  is  the  usual  one  for  septicaemia.  Per- 
foration of  the  bowel  also  demands  surgical  aid  if  the  condition  of  the 
patient  warrants  it;  there  is  practically  very  little  hope  of  recovery, 
since  in  those  cases  which  perforate  the  remainder  of  the  bowel  is  so 
extensively  diseased  that  the  patient  usually  succumbs  from  the  gravity 
of  the  lesions,  or  asthenia,  if  not  from  the  general  peritonitis.  Morphia 
should  be  administered  for  the  pain.  Local  peritonitis  without  perfora- 
tion requires  rest  and  the  application  to  the  abdomen  of  ice  or  hot  fomen- 
tations, with  opiates  by  the  mouth.  For  serious  hemorrhage,  morphia 
should  be  given  and  ice  applied  locally  to  the  abdomen.  Ice-cold  or 
hot  enemas  containing  tannin,  silver  nitrate,  or  calcium  chloride,  may 
be  tried  in  extreme  cases.  Stimulants  and  subcutaneous  or  intravenous 
injections  of  salt  solution  should  be  employed  when  their  use  is  indicated. 


PART   VII. 
THE  Z00-P4BASITIC  DISEASES  OF  MAN. 

(EXCLUSIVE  OF  PROTOZOAN  INFECTIONS). 


CHAPTER  XXIII. 

GENERAL  DISCUSSION. 
By  CHARLES  WARDELL  STILES,  Ph.D.,  D.Sc. 

Nature  and  Kinds  of  Animal  Parasites.— A  parasite  is  ar.y  or- 
ganism which  lives  in  or  upon  any  other  organism,  called  the  host,  and 
generally  belonging  to  a  widely  distinct  species,  at  whose  expense  it  derives 
Its  nourishment  and  habitation.  Thus  the  prime  ideas  m  parasitism 
are  food  and  association. 

1  Food.— No  distinct  line  can  be  drawn  between  a  parasite  and  a 
predaceous  animal,  although,  as  a  rule,  the  parasite  attacks  organisms 
which  are  larger,  stronger,  and  more  intelligent  than  itseli,  and  does  not 
immediately  kill  and  devour  its  host,  while  the  predaceous  animal  attacks 
animals  which  are  smaller,  weaker  and  less  intelligent  than  itselt,  and  it 
kills  and  devours  its  prey. 

2.  Association.— Association  of  animals  is  one  of  the  most  common 
biological  phenomena,  and  may  occur  between  individuals  of  the  same 
species  or  between  individuals  of  different  species.  In  the  former  case 
we  usually  have  to  deal  with  an  association  such  as  pairing  (birds),  or 
colonization  (bees),  resulting  in  a  propagation  and  protection  of  the  species, 
and  a  higher  specialization  of  structure,  but  rarely  with  parasitism.  _  in 
the  latter  case,  however,  when  organisms  of  different  species  associate 
together,  we  rarely  have  to  do  with  partnership  for  the  purpose  of  propaga- 
tion (hybrids),  but  usually  with  a  case  of  parasitism,  involving  a  speciali- 
zation but  degradation  in  structure.     Such  association  may  present  an 

instance  of —  ,  . 

(a)  Mutualism,  when  the  partnership  results  in  benefat  to  both  parties, 
as  in  the  case  of  the  sponge  growing  on  the  back  of  a  crab,  or  m  the  case 
of  some  of  the  bacteria  in  the  mouth;   or 

(6)  Commensalism,  when  the  association  results  in  a  benefat  to  one 
party  (the  messmate),  but  neither  benefit  nor  injury  to  the  other  (the 
host),  as  in  the  case  of  the  non-Tp&thogemc  Entamoeba  coh  (not  E.  hzstolyt^ 
ica)  in  man;  or  ^„^ 


526  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

((•)  True  para-siti^'im,  \\\\cu  the  as.socialioii  results  in  a  benefit  to  the 
parasite,  but  an  injury  to  tlie  host,  as  in  the  patiiogenie  Entamoeba  kisto- 
lijika,  or  triehintv,  hook-worms  or  the  tapeworms  in  man. 

A  parasite  may  visit  its  host  only  at  intervals  to  take  up  temporary 
residence  and  to  obtain  food;  such  animals  (mosquitoes,  bed-bugs,  etc.), 
are  called  temporary  parasites.  Others  are  more  or  less  stationary  with 
their  hosts,  and  are  therefore  called  .stationar;/  parasites;  of  these,  we  mav 
have  periodical  i)arasites,  wiiich  spend  a  given  jK'riotl  of  their  life  with 
their  hosts  (as  bots  under  the  skin,  or  Strongijhrides  .stercoral i.s  in  the  intes- 
tine of  man),  or  we  may  have  permanent  parasites,  such  as  trichinte,  in 
which  the  entire  life-cycle  is  parasitic. 

Some  parasites,  as  the  pinworm,  eelworm  and  hookworm,  require  only 
one  host  to  complete  their  life-cycle;  others,  such  as  the  large  tapeworms, 
recpiire  two  hosts — an  mtermcdiate  host  in  which  the  larval  stage  lives,  and 
a  definite  or  final  host  which  harbors  the  sexual  stage. 

All  cases  thus  far  cited  are  examples  of  simple  parasitism,  but  we  may 
have  parasites  which  are  parasitic  in  or  upon  other  parasites,  a  phenom- 
enon known  as  lii/perparasitism,  aiul  important  from  an  agricultural  point 
of  view. 

We  may  further  have  ectoparasites  (as  lice),  which  live  upon  animals, 
and  enduparasites  (as  tapeworms),  which  live  in  animals.  The  term 
cntozoa  refers  primarily  to  the  cndoparasites,  and  helminthes  refers  especi- 
ally to  the  parasitic  Avorms,  while  hehninthology  is  that  part  of  zoology 
wiiich  deals  with  worms,  especially  the  parasitic  forms,  and  helminthiasis 
denotes  an  infection  with  parasitic  worms. 

Chance  parasites,  or  pseudoparasites,  are  animals  which  are  usually 
free-living  but  are,  by  chance,  living  as  parasites  (as  the  vinegar  eel  in  the 
human  bladder,  mosquito  larvre,  and  Gamviarus  pulex  in  the  stomach),  or 
parasitic  animals  which  by  chance  are  not  in  their  normal  host  (as  Fasci- 
ola  hepatica  in  man). 

Spurious  parasites  are  objects  which  are  described  as  parasites  or 
mistaken  for  such,  but  which  in  reality  are  creations  of  the  imagination 
(Furia  injernalis,  Vermis  umhilicalis) ,  or  half-digested  food  {Diacanthos 
pohjcephalus;  Striatula;  banana  cells  mistaken  for  tapeworm  segments, 
etc.),  or  objects  introduced  into  the  body  by  hysterical  patients  in  order 
to  confuse  the  physician  (frogs,  earthworms — Spiroptera  hominis  is  a  par- 
asite, Ascaris  capsidaria  of  fish,  introduced  by  a  girl  into  her  vagina  to 
confuse  her  physician,  etc.). 

Frequency.^ — As  a  general  rule,  the  smaller  a  parasite  is,  the  more 
individuals  there  may  be  in  a  patient;  compare,  for  instance,  Tcenia 
saqinata,  Ascaris  lumhricoides,  Oxyuris  vermicularis,  Entamoeba  coli, 
Lamblia  duodenalis. 

There  is  no  species  of  animal,  and  no  race  or  class  of  man  known  to  be 
free  from  parasites.  We  may,  however,  lay  down  certain  general  rules 
covering  the  frequency  of  infection : — 

1.  Certain  parasites  are  more  common  among  people  of  careless  per- 
sonal habits  than  among  those  of  more  careful  personal  habits;  thus,  as  a 
rule,  dwarf  tapeworms,  eelworms,  and  pinworms  are  more  common  in 

^See  also,  Stiles  and  Garrison,  1906  a,  pp.  1-77,  "A  Statistical  Study  of  the 
Prevalence  of  Intestinal  Worms  in  Man."  Bulletin  28,  Hygienic  Laboratory 
U.  S.  Public  Health  and  Marine  Hospital  Service,  Washington. 


GENERAL  DIHCU^HION  527 

children  than  in  adults,  and  whipworms  are  more  common  in  negroes 
than  in  whites. 

2.  Certain  parasites  (eelworms)  are  said  to  be  more  common  among 
people  who — as  in  villages — drink  unfiltered  water  than  in  townspeople 
who  have  a  filtered  water-supply.  The  difference  in  frequency  is  influ- 
enced, however,  by  the  disposal  of  faeces  by  a  better  sewage  system  in 
cities  than  in  villages. 

3.  Certain  parasites  (trichinse,  pork  tapeworms)  arc  likely  to  })e  more 
common  among  people  who  (as  East  Prussians  and  Saxons)  cat  raw  or  rare 
pork  than  among  people  who  (as  South  Germans,  French,  Americans)  eat 
their  pork  well  cooked. 

4.  Certain  parasites  (hydatids)  are  more  common  among  pco[)le  who 
(as  in  Iceland)  keep  large  numbers  of  dogs  and  live  more  intimately  with 
them,  than  among  people  who  keep  fewer  dogs  in  proportion  to  the 
population. 

5.  In  general,  animal  parasitism  increases  from  temperate  to  tropical 
climates. 

6.  All  intestinal  and  some  hepatic  parasites  decrease  hand  in  hand 
with  the  increase  of  care  exercised  in  a  proper  system  of  latrines  or  sewers. 

Age  and  Sex  of  Patient. — Some  parasites  (eelworms,  pinworms)  are 
more  common  among  children,  while  other  species  (large  tapeworms  and 
hydatids)  are  more  common  among  adults  of  from  twenty  to  forty  years 
of  age;  some  parasites  (large  tapeworms,  hydatids,  head-lice)  are  more 
common  among  women  than  among  men,  while  other  species  (lung-flukes, 
pubic-lice)  are  more  common  among  men. 

Fertility  of  Parasites. — Most  parasites  are  exceedingly  fertile,  some  of 
them  almost  representing  egg-machines.     This  fertility  is: 

1.  A  natural  result  of  their  environment,  since  they  live  in  the  midst 
of  their  food,  which  their  hosts  provide  for  them;  hence  energy  which 
might  otherwise  be  expended  in  seeking  necessary  food,  may  here  be 
turned  to  growth  and  reproduction ;  thus  it  is  estimated  that  the  fat  tape- 
worm (Tcenia  sagtnata)  increases  at  the  rate  of  thirteen  segments  per  day, 
growing  3  cm.  per  day  for  the  first  month  and  averaging  14  cm.  per  day 
for  the  second  month,  and  producing  150,000,000  eggs  per  year. 

2.  Subject  to  natural  selection,  for  the  life-cycles  are  often  very  com- 
plex, hence  in  such  cases  the  chances  that  any  one  egg  has  of  reaching 
sexual  maturity  are  very  small,  so  that  individuals  which  are  only  slightly 
fertile  would  probably  not  be  represented  by  many  generations. 

3.  In  accordance  with  the  general  biological  law  (not  without  excep- 
tions) that  the  smaller  an  animal,  the  more  fertile  it  is ;  we  should  there- 
fore naturally  expect  a  pinworm  to  be  more  fertile  than  a  cow. 

Resistance  of  Parasites. — Some  parasites,  especially  in  their  egg  and 
encysted  stages,  are  exceedingly  resistant  to  external  influences:  the 
Persian  argas  may  live  five  years  without  food ;  Cysticercus  cellulosoe  may 
live  four  weeks  or  so  after  its  host  is  dead ;  trichinse  may  live  for  months 
after  their  host  (hog)  is  slaughtered;  eggs  with  thick  shells  (eelworms, 
whipworms,  Taenia)  are  more  resistant  than  eggs  with  thin  shells  (hook- 
worms, pinworms,  dwarf  tapeworm). 

Seasonal  Periodicity. — Some  parasites  show  a  decided  seasonal  perio- 
dicity :  hookworms  have  a  better  chance  to  develop  in  warm,  moist  months 
than  in  cold  or  hot  dry  seasons;   and  in  general  this  obtains  for  vronns 


528  THE  ZOO-PARASITIC  DISEASES  OF  iMAN 

Avhieh  do  not  require  an  intermediate  host.  For  certain  worms  (as  treni' 
atodes)  which  do  require  an  internietliate  host  (as  snails)  tiie  seasonal 
periodicity  depends  upon  the  seasonal  activity  of  this  host,  and  this  ac- 
tivity may  de])entl  ui)on  various  factors,  such  as  moisture  and  warmth. 
Origin  of  Parasites. — Parasites,  like  other  animals,  have  two  origins: 
namely: 

1.  The  ontogeuiitc  origin,  or  origin  of  the  individual  Contrary  to 
ideas  held  some  decades  ago,  it  is  now  known  that  there  is  no  such  ])henom- 
enon  as  a  spontaneous  generation  of  parasites,  but  it  is  known,  on  the 
contrary,  that  every  animal  parasite  proceeds  from  some  former  genera- 
tion of  parasites  and  that  it  came  into  being  either  through  sexual  or  non- 
sexual reproduction. 

2.  The  'phijlogcnciic  origin,  or  origin  of  the  species.  To  assume  that 
all  parasites  Avere  created  in  the  beginning  as  they  exist  to-day,  would  be 
to  stamp  Adam  as  a  most  remarkable  helminthological  museum,  suffering 
from  many  parasitic  diseases,  of  which  any  one  of  several  could  have  been 
fatal.  The  zoologist  holds  that  parasites  have  gradually  evolved  from 
free-living  animals,  that  numerous  connecting  links  between  the  two  exist 
and  that  this  process  of  evolution  is  still  going  on. 

Heredity  of  Parasites. — From  the  strict  embryological  point  of  view,  it 
would  be  impossible  to  fulfil  the  condition  necessary  to  demonstrate  the 
heredity  of  any  infectious  disease  in  man,  and  when  we  speak  of  the  hered- 
ity of  these  maladies  in  the  higher  animals  it  should  be  recalled  that  we 
are  using  the  term  "heredity"  rather  loosely.  No  parasitic  disease  is 
known  to  be  hereditary  in  man,  though  we  know  of  several  diseases  in 
lower  animals  (as  in  insects  and  ticks)  which  are  hereditary  in  a  stricter 
sense  of  the  term;  namely,  the  sexual  products  are  infected  before  fer- 
tilization occurs. 

Influence  of  Parasites  upon  their  Hosts. — Views  regarding  the  inju- 
rious effects  of  parasites  have  passed  from  extreme  to  extreme,  some 
authors  going  so  far  as  to  attribute  to  some  parasites  injurious  actions 
Avhich  they  surely  do  not  have,  and  others  going  so  far  in  the  opposite 
direction  as  to  see  in  the  parasites  a  supposed  advantage  or  even  a  neces- 
sity to  the  host.  Let  us  recall,  however,  that  the  injury  done  may  vary 
with  the  species,  size,  location,  and  number  of  the  parasites,  and  with 
the  condition  and  age  of  the  host.  This  injury  may  be  accomplished  in 
various  ways: 

(1)  Nourishment  is  taken  which  should  go  to  the  host,  (2)  blood  is 
taken  by  the  parasite  as  food ;  (3)  mechanical  pressure  irritates  or  causes 
atrophy  of  organs  or  parts  of  organs;  (4)  natural  channels  may  be  ob- 
structed; (5)  the  wandering  of  the  parasite  may  cause  irritation;  (6) 
substances  may  be  excreted  which  have  a  toxic  influence,  and  which  may 
change  the  natural  condition  of  body  fluids  (blood);  (7)  injury  to  the 
intestinal  mucosa  or  to  the  skin  may  form  points  of  entrance  for  bacterial 
and  protozoan  infections. 

Such  injury  does  not,  as  a  rule,  go  on  increasing  indefinitely  in  any  geo- 
metrical progression  because  of  succeeding  generations  of  parasites,  for 
the  general  rule  obtains  (with  a  few  exceptions,  as  in  infections  with  cer- 
tain protozoa  and  with  the  vinegar  eel)  that  for  every  adult  animal  para- 
site fmind  in  the  human  body  a  separate  embryo  or  larva  must  enter.  Thus, 
hookworms  do  not  multiply  generation  after  generation  in  the  intestine, 


GENERAL  DISCUSSION  529 

but  the  eggs  must  leave  the  patient  and  the  resulting  larvae  reenter  the 
body  in  order  to  become  adult. 

Greneric  and  Specific  Infections. — In  the  following  discussion,  refer- 
ence will  be  repeatedly  made  to  infections  as  being  identical  or  distinct 
generically  or  specifically.  These  terms  are  used  in  their  zoological 
sense,  to  express  more  accurately  the  relation  which  the  diseases  of  man 
bear  to  those  of  animals.  Thus,  it  has  been  reported  that  Trjonia  .solium 
occurs  in  both  man  and  dog.  If  this  statement  were  correct,  the  dog 
would  be  a  very  important  factor,  from  a  public  health  point  of  view,  in 
spreading  Tcenia  solium  and  cysticercosis.  The  reported  presence  of  this 
parasite  in  dogs  is  however  based  upon  an  error  of  identification,  for  there 
is  a  tapeworm  belonging  to  the  genus  Tcenia  which  does  occur  in  dogs  but 
which  belongs  to  a  species  {Tcenia  hydatigena)  specifically  distinct  from, 
but  quite  closely  (generically)  related  to,  Twnia  solium.  Hence,  man 
and  dogs,  in  this  instance,  have  infections  which  are  generically  identical, 
since  both  parasites  belong  to  the  same  genus,  but  .specifically  distinct, 
since  the  two  worms  represent  distinct  species  ( T.  solium  and  T.  hydati- 
gena). On  the  other  hand  there  is  a  specifically  identical  tapeworm- 
infection  {Dipylidium  caninum)  which  is  common  to  dogs  and  cats  and 
which  may  occur  in  man. 

Diagnosis  of  Parasitic  Diseases. — ^The  general  rule  may  be  laid  down 
that  the  best  method  of  diagnosing  most  parasitic  diseases  is  by  a  micro- 
scopic examination :  examine  sputum  for  suspected  parasitic  diseases  of 
the  lungs;  joeces  for  suspected  parasitic  infections  of  the  intestine 
and  liver;  urine  for  suspected  parasites  of  the  kidney  or  bladder; 
blood,  fcBces,  and  urine,  for  suspected  parasitic  diseases  of  the  circulatory 
system;  blood  and  muscle  for  suspected  infections  of  the  muscle;  blood 
for  suspected  infections  of  the  lymphatic  system.  In  some  cases  a  diag- 
nosis may  be  made  by  a  gross  examination  of  the  faeces.  In  some  para- 
sitic diseases,  diagnosis  may  be  safely  made  upon  symptoms,  especially 
if  the  patient  is  within  the  infected  area  of  a  given  malady.  It  will  be 
necessary  to  discuss  further  the  question  of  diagnosis  in  connection  with 
the  different  infections,  but  the  technique  of  fsecal  examinations  can  best 
be  given  here 

In  gross  examinations  of  the  stools  (for  pinworms  or  expelled  hook- 
worms, etc.),  the  fseces  should  be  shaken  up  well  with  warm  water  and 
allowed  to  settle;  pour  off  any  floating  material  and  wash  the  stool  in  this 
manner  several  times;   the  worms  will  thus  be  concentrated. 

For  microscopic  examination  of  fseces,  take  a  small  portion  of  faecal 
matter  on  the  end  of  a  match  or  toothpick,  using  a  separate  one  for  each 
stool;  smear  this  in  a  drop  of  water  on  a  slide;  the  large  2X3  slide  is  more 
convenient  than  the  ordinary  1X3;  cover  with  an  ordinary  coverglass, 
avoiding  unnecessary  pressure,  and  examine  ten  such  preparations. 

For  eggs  with  thick  shells  (whipworms,  large  tapeworms,  flukes),  use 
a  strong  illumination;  for  worms  Avith  thin  shells  (hookworms,  pinworms, 
etc.),  use  a  more  moderate  illumination;  examine  first  with  medium 
magnification  (8  mm.  or  J-inch  focal  length),  later  wdth  higher  power. 

To  make  permanent  mounts  of  eggs,  preserve  the  material  in  alcohol; 
then   transfer   to    95    parts    alcohol    plus   5  parts    of   glycerine;  allow 
the  alcohol  to  evaporate  slowly,  and  when  evaporated  to  glycerine,  mount 
the  material  in  glycerine-jelly, 
34 


530  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

Treatment. — The  general  rule  may  be  laid  down  that  for  verminous 
infections  of  the  brain,  bones,  muscles,  eye,  lungs,  liver,  kidneys,  spleen, 
blood  and  lymphatics,  there  is  no  satisfactory  specific  medicinal  treat- 
ment, although  some  of  these  cases  may  be  treated  surgically.  Intestinal, 
bladder,  and  some  skin  infections  by  parasites  may  be  treated  medicinally. 
For  further  details,  see  under  the  different  parasites. 

Prevention. — S(3  far  as  most  verminous  ])arasites  in  temperate  climates 
are  concerned,  ordinary  habits  of  cleanliness — such  us  are  found  in  the 
educated  American,  English,  and  French  families;  ordinary  care  in 
preparing  food — as  followed  by  good  housekeepers;  ordinary  methods  of 
meat  inspection — as  carried  on  by  the  federal  government;  a  pioper 
disposal  of  alvine  discharges — as  in  sewers,  or  properly  constructed 
privies;  and  a  recognition  of  the  fact  that  the  dog  is  not  a  human  being, 
are  in  themselves  sufficient  to  prevent  serious  trouble  (in  form  of  epi- 
demics) from  most  parasites  in  Australia,  Canada,  England,  and  the 
United  States.  In  warm  countries  protection  against  mosquitoes  will 
reduce  certain  verminous  affections  (filariasis). 

Personal  Rules  of  Hygiene. — (1)  The  use  of  spring,  boiled  or  filtered 
water  will  decrease  certain  protozoan,  fluke  and  roundworni  infections; 
(2)  proper  care  of  meat  (protection  from  flies)  and  thorough  cooking 
will  protect  against  certain  dipterous  larvfe,  certain  tapeworms  and 
trichinosis ;  (3)  avoidance  of  depraved  tastes  for  insects  will  aid  in 
protecting  against  certain  tapeworms;  (4)  keeping  the  hands  and  nails 
clean,  especially  after  handling  dogs,  will  aid  in  protecting  against  a 
certain  tapeworm  and  hydatid  disease;  (5)  personal  cleanliness  after 
defecation  will  aid  in  protecting  against  auto-infection  with  pin  worms  and 
Cysticercus  celhdosoe;  (6)  wearing  shoes  in  infected  areas  will  help  to 
protect  against  hookworm  infection  and  the  burrowing  flea. 

Public  Rules  of  Hygiene. — (1)  If  ^sewage  is  used  for  fertilizing,  it  is 
best  to  grow^  upon  the  land  so  fertilized,  only  such  vegetables  as  are  sub- 
jected to  cooking  before  eating;  (2)  properly  dispose  of  all  fseces,  espe- 
cially in  schools,  asylums,  hospitals;  (3)  interdict  nuisances,  especially  in 
warmer  climates,  and  upon  plantations,  in  mines  and  in  digging  tunnels 
and  canals;  (4)  meat  inspection  in  the  local  slaughter  houses  (the  federal 
inspection  covers  only  the  abattoirs  engaging  in  interstate  trade) ;  (5) 
segregate  local  slaughter  houses  and  place  them  under  the  supervision  of  a 
competent  veterinarian,  who  might  well  be  a  member  of  the  local  board 
of  health;  (6)  keep  swine  in  a  less  swane-like  manner, — especially  see 
that  the  privy  is  not  near  the  pig-pen ;  (7)  swine-offal  and  swill  should  be 
first  cooked  in  case  they  are  fed  to  hogs ;  (8)  destroy  all  ownerless  dogs  and 
keep  dogs  away  from  slaughter  houses — the  dog  pound  is  an  institution 
of  practical  hygienic  importance. 

CLASSIFICATION  OP  ANIMAL  PARASITES. 

Contrary  to  early  ideas,  the  parasites  do  not  represent  a  group  of  ani- 
mals closely  related  to  each  other  systematically,  but  rather  several  diverse 
groups,  more  or  less  widely  separated  but  with  somewhat  similar  biological 
habits.  For  the  details  of  classification  the  reader  is  referred  to  Avorks 
on  systematic  zoology;  for  the  purpose  of  this  article,  we  may  divide 
the  animal  parasites  as  follows; 


GENERAL  DISCUSSION  531 

1.  Unicellular  animals,  as  the  parasites  of  malaria Protozoa. 

Pluricellular    animals;     metazoa 2 

2.  Body  more  or  less  flattened  dorsoventrally 4 

Body  ordinarily  round  in  transverse  section 3 

3.  Body  never  annulated;   never  provided  with  legs;   no  jaws  present. . .       5 
Body  annulated,  or  at  least  provided  with  mouth  parts;  usually  breathe 

through  a  tracheal  system;    adults  with  jointed  legs 7 

4.  Intestine,  but  no  anus,  present;   one  or  two  suckers  present;   body  not 

segmented;  parasitic  in  liver,  lungs,  blood,  intestine,  occasionally 
elsewhere;  flukes Trematoda,  p.  535 

Intestine  absent;  two  or  four  suckers  on  head;  body  of  adults  segmen- 
ted; adults  (tapeworms)  parasitic  in  intestine;  larvaj  (bladder 
worms)  parasitic  elsewhere Cestoda,  p.  557 

Intestine  and  anus  present;  ventral  sucker  on  posterior  end;  body 
annulated  like  an  earthworm;  parasitic  in  upper  air-passages,  or 
externally;  leeches,  bloodsuckers Hirudinei,  p.  626 

5.  Intestine  absent;  armed  rostellum  present;  very  rare  in  man,  in  intes- 

tine; thorn-headed  worms Acanthocephali,  p.  604 

Intestine  present;    no  armed  rostellum 6 

6.  Intestine  rudimentary  in  adult;  rare,  accidental  parasites  in  intestine  of 

man;   hair  snakes  or  horse-hair  worms Gordiacea,  p.  604 

Intestine  present;    parasitic  in  intestine,  muscles,  lymphatics,  etc.; 

very  common  and  important;  roundworms Nematoda,  p.  582 

7-  Six  legs  present  in  adult ;  wings  present  in  most  species;  larva  annula- 
ted much  like  an  earthworm ;  breathe  through  trachea;  adults  ecto- 
parasites; occasionally  larva  is  parasitic  under  skin,  or  in  wounds, 
or  an  accidental  parasite  in  the  intestine;  insects Insecta,  p.  632 

Eight  legs  present  in  adult,  six  legs  in  larva;  head  and  abdomen  coa- 
lesced; ectoparasites;  some  burrow  under  the  skin  or  live  in  the 
hair  follicles;    acarines Acarina,  p.  626 

Four  claws  around  the  mouth;  larva  encysted  in  various  organs;   adult 
occasionally  parasitic  in  nasal  passages;    tongueworms 
Linguatulidce,  p.  632 

Numerous  legs  present;  occasionally  accidental  parasites  in  nasal 
passage  or  intestine;  thousand-leggers Myriapoda,  p.  632 

Organ  distribution  of  parasites,  according  to  their  more  common  habitat. 

More  or  Less  General. — Trematoda:  Paragonimus,  p.  536;  Schistosoma 
eggs,  p.  550.  Cestode  larvae:  Taenia  solium,  p.  574: \  Echinococcus,  p.  576;  Spar- 
ganum,  p.  581.     Arachnida:    Linguatula,  p.  632;    Porocephalus ,  p.  632. 

Intestinal  Tract. — Trematoda:  Fasciolopsis,  p.  549;  Heterophyes,  p.  549; 
GastrodiscuSjTp.  549;  Cladorchis,  p.  549.  Adult  cestoda:  Taenia,  p.  558;  Hymeno- 
lepis,  p.  564;  Davainea,  p.  566;  Dipylidium,  p.  567;  Dibothriocephalus,  p.  567;  Dip- 
logonoporus,  p.  569.  Nematoda:  Ascaris,  p.  596;  Oxyuris,  p.  599;  Trichostrongylu^, 
p.  602;  Agchylostoma,  p.  584;  Necator,  p.  583;  Uncino.ria,  p.  583;  Physaloptera, 
p.  602;  Strongyloides,  p.  595;  Trichuris,  p.  602;  Trichinella,  p.  605.  Gordiacea, 
p.  604.    Acanthocephali:  Gigantorhynchus, -p.  604.     Insecta,  p.  632. 

Liver. — Trematoda:  Fasciola,  p.  543;  Opisthorchis,  p.  540;  Dicrocoelium,  p. 
545.    Cestoda:  Echinococcus,  p.  576. 

Lungs. — ^Trematoda:  Paragonimus,  p.  536.  Nematoda:  Metastrongylus,  p. 
610. 

Uro-genital  System. — Nematoda:  Anguillula,  p.  624;  Leptodera,  p.  624; 
Dioctophyme,  p.  624. 

Lymphatic  System. — Nematoda:    Filaria,  p.  613. 

Blood. — Trematoda:  Schistosoma,  p.  550.  Nematoda:  Filaria,  larvae,  p. 
613. 

Muscles. — Nematoda:    Trichinella,  p.  605. 

Subcutaneous. — Nematoda:  Dracunculus,  p.  611;  Filaria,  p.  613;  AgdmofUa- 
ria,  p.  623;    Rhabditis,  p.  611;    Gnathostoma,  p.  611.     Insecta,  p,  632. 

Ectoparasites. — ^Acarina,  p.  626.    Insecta,  p.  632. 


532  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

NOMENCLATURE  AND  TERMINOLOGY. 

To  the  biologist,  nomcncJaiurc  deals  with  the  7iamcs  used  to  designate 
systematic  units,  such  as  families  {Tccniidcc),  genera  {Tocnia),  species 
{Tocnia  saginata),  etc.  As  systematic  zoologists  are  obliged  to  use  thou- 
sands upon  thousands  of  such  names,  it  is  advisable  that  these  should  be 
removed,  so  far  as  possible,  from  the  influence  of  individual  or  national 
tastes  and  prejudices;  and,  in  order  to  make  them  international  in  char- 
acter, Latin  has  been  adopted  as  the  basis  for  all  technical  names  (as 
opposed  to  vernacular  names).  The  acceptance  or  rejection  of  names 
and  the  method  of  writing  them  are  governed  by  "codes  of  nomencla- 
ture," which  may  in  a  certain  sense  be  compared  with  the  medical  "code 
of  ethics."  For  the  zoologists,  the  International  Congress  has  adopted 
an  "International  Code,"  ^  (1905)  prepared  by  a  permanent  international 
commission  of  fifteen  members.  This  code  is  based  primarily  upon  the 
rules  proposed  by  Linnpeus,  in  1751,  modified  to  meet  the  advances  in 
science.  In  order  that  no  revolutionary  principle  may  be  suddenly  intro- 
duced, the  rules  of  the  Congress  provide  that  no  proposition  for  chang- 
ing the  code  can  be  adopted  unless  submitted  to  the  Commission  at  least 
one  year  prior  to  the  tri-annual  meeting  of  the  Congress.  The  chief  points 
in  the  code  are:  (1)  The  "law  of  priority,"  which  provides  that  the 
valid  name  for  any  genus  or  species  is  its  oldest  available  name;  i.  e., 
available  under  the  code;  thus,  Ascaris,  1758,  is  an  older  name  than 
Fusaria,  1800,  for  the  eelworm.  (2)  The  "rule  of  homonyms,"  which 
provides  (a)  that  when  two  generically  distinct  animals  have  received  the 
same  generic  name,  this  name  is  available  only  for  the  earlier  genus 
(thus,  when  Trichina  was  proposed  for  a  genus  of  worms  by  Owen  in  1835, 
it  was  already  in  use  for  a  genus  of  insects,  1832,  hence  the  name  cannot 
be  adopted  for  the  worm) ;  and  (h)  that  when  two  species  in  any  given 
genus  have  received  the  same  specific  name,  it  is  available  only  in  its 
earlier  use  (thus.  Taenia  murina,  1845 — ITymenoIepis  nana,  1852, — 
is  antedated  by  Toejiia  murina  Gmelin,  1790 — Cysticerciis  fasciolaris — 
hence  murina,  1845,  is  not  available  as  name  for  the  dwarf  tapeworm,  and 
nana,  1852,  its  oldest  synonym,  becomes  valid).  (3)  No  name  can  be 
changed  because  of  its  inappropriateness  or  for  any  subjective  reason, 
as  names  are  not  definitions,  hence  the  introduction  of  Amoeba  dysenterice 
ioT  Amoeba  coli  was  not  permissible  under  the  code. 

Physicians  are  urged  to  acquaint  themselves  with  the  code,  before  they 
publish  or  change  zoological  names,  as  it  is  often  difficult  to  understand 
whether  or  not  a  physician  is  using  a  new  name  in  a  zoological  sense,  and 
further  because  names  are  too  frequently  proposed  contrary  to  zoological 
customs. 

The  question  is  frequently  asked,  why  zoologists  do  not  adopt,  for  the 
parasites,  the  names  already  known  to  physicians.  The  answer  is  simple: 
(1)  The  animals  known  in  medicine  form  an  almost  insignificant  frac- 
tion of  one  per  mille  of  the  animals  with  which  we  have  to  deal,  and  it 
would  be  a  very  dangerous  precedent  to  make  exceptions  for  this  group; 

^See  Stiles,  190.5,  pp  1-50,  the  "International  Code  of  Zoological  Nomencla- 
ture as  applied  to  Medicine."  Bulletin  24,  Hygienic  Laboratory  U.  8  Public 
Health  and  Marine  Hospital  Service,  Washington 


GENERAL  DISCUSSION  533 

(2)  when  physicians  discover  that  two  diseases  have  been  confused  under 
one  name,  or  one  disease  has  been  given  two  or  ten  names,  they  do  not 
hesitate  to  straighten  out  the  terminology,  yet  the  terms  used  by  physi- 
cians go  only  into  the  thousands,  while  the  names  in  zoology  run  into  the 
millions,  hence  zoologists  must  be  even  more  rigid  than  physicians  in 
respect  to  technical  names.  Would  any  physician  to-day,  for  instance, 
claim  that  trichinosis  should  be  called  typhoid,  on  the  ground  that  before 
1860  the  two  diseases  were  confused  ?  (3)  Advance  in  microscopic  tech- 
nique and  instruments  has  made  as  great  changes  in  zoology  as  it  has  in 
medicine,  and  zoologists  are  adapting  their  nomenclature  to  the  changes 
in  classification  rendered  necessary  by  the  new  discoveries.  We  do  not, 
to-day,  speak  of  Toenia  lata  and  Bothriocephalus  latus  for  the  simple  rea- 
son that  the  species  in  question  is  now  known  to  belong  neither  to  Toenia 
nor  to  Bothriocephalus. 

Terminology,  in  distinction  to  nomenclature,  deals  with  the  technical 
terms  of  parts,  organs,  functions,  conditions,  etc.  No  recognized  code  of 
rules  governs  the  names  of  the  muscles  of  the  body  or  the  names  of  dis- 
eases. A  man  adopts  a  technical  term  because  it  has  been  taught  to  him, 
or  he  changes  it,  if  a  better  name  occurs  to  him,  and,  finally,  men  adopt 
the  names  best  known  to  them.  Thus,  terminology  is  largely  subjective  and 
such  incongruities  occur  as  using  a  term  like  "spotted  fever"  for  two  or 
three  different  diseases;  while  in  the  United  States  "typhus"  refers  to  one 
disease,  in  Germany  it  is  frequently  used  for  another  malady  (typhoid). 

For  parasitic  diseases,  we  may  distinguish  three  different  kinds  of  terms 
in  particular:  (1)  Latin  terms  based  upon  the  zoological  generic  names 
(as  distomatosis,  tcBniasis,  trichinosis,  acariasis,  etc.);  (2)  vernacular 
terms  based  upon  some  symptom,  geographical  locality,  etc.,  (itch, 
Egyptian  haematuria);  (3)  vernacular  terms  based  upon  a  vernacular 
name  of  ^the  parasite  (hookworm  disease) .  For  international  use,  Latin 
terms  are  by  all  means  preferable,  as  they  do  not  need  to  be  translated, 
but  for  current  use  vernacular  terms  are  often  very  convenient. 

Bibliography.— In  a  short  article  of  this  kind  it  is  impossible  to  give  a 
full  bibliography,  for  which  the  reader  is  referred  to  Huber's  Bihlio- 
graphie  der  klinischen  H ehninthologie  (1895,  1898,  1899-1900),  or  Stiles 
and  Hassall's  Index  Catalogue  of  Medical  and  Veterinary  Zoology  (Bull. 
39,  TJ .  S.  Bureau  of  Animal  Industry)  and  Looss  (1905). 

For  annual  reviews  of  literature  on  parasites,  see  especially  Zoological 
Record  and  Archiv  fiir  Naturgeschichte.  For  current  literature,  with 
original  articles,  reviews,  and  current  bibliographies,  see  especially,  ^ re A- 
ives  de  Parasitologic,  Centralblatt  fur  Bakteriologie,  Parasitenkunde  und 
Infektionskrankheiten,  Zoologischer  Anzeiger,  and  Zoologisches  Central- 
blatt. The  current  zoological  references  can  be  purchased  in  card  form 
from  the  Concilium  Bibliographicum,  Zurich.  The  most  extensive  card 
catalogue  on  the  subject  is  the  combined  index  in  the  Zoological  Divis- 
ions of  the  U.  S.  Public  Health  and  Marine  Hospital  Service  and  the 
U.  S.  Bureau  of  Animal  Industry. 

Determination  of  Specimens. — Specimens  of  animal  parasites  of 
man  are  determined  for  physicians,  free  of  charge,  by  the  Di\asion  of 
Zoology,  Hygienic  Laboratory,  U.  S.  Public  Health  and  Marine  Hospi- 
tal Service,  Washington,  D.  C.  Such  material  should  be  forwarded  in 
alcohol  (about  50  to  70  per  cent.). 


534  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

Government  Publications.— For  U.S.  government  publications  on 
animal  parasites,  applieatic^i  should  be  made  to  the  "Keeper  of  Public 
Documents,  Washington,  D.  C,"  or  (either  directly  or  through  a  Sena- 
tor or  Congressman)  to  the  Chief  of  the  Bureau  by  which  the  document 
was  issued. 


CHAPTER  XXIV. 

DISTOMATOSIS-TREMATODE  OR  FLUKE  INFECTIONS.^ 

By  CHARLES  WARDELL  STILES,  Ph.  D.,  D.  Sc. 

Terminology. — The  general  term  distomatosis  or  distomiasis  is  based 
upon  Distoma  which  has  been  used  by  many  authors  as  the  collective 
genus  for  the  trematodes,  more  especially  for  the  so-called  digenetic 
forms.  As  a  generic  name  for  these  parasites  Distoma  is  not  valid  and  the 
species  which  have  been  included  in  this  genus  are  now  distributed  over  a 
large  number  of  well  defined  genera.  Upon  the  names  of  these  more  re- 
stricted genera,  Latin  terms  have  been  based  to  designate  infections  with 
species  of  the  respective  genera  (as  fascioliasis,  opisthorchiasis,  parago- 
nimiasis). The  word  "distomatosis"  has  been  combined  with  the  name 
of  the  organ  affected  (as  pulmonary  distomatosis) ;  while  for  some  of  the 
diseases,  there  are  well-known  vernacular  terms  (liver-fluke  disease,  liver 
rot,  etc.). 

DifEerent  Kinds  of  Trematode  Diseases  in  Man. — In  man  there 
are  four  difi^erent  clinical  classes  of  trematode  diseases  which  may  be 
regarded  as  typical,  in  the  sense  that  in  these  four  instances  the  infection 
of  man  by  certain  trematodes  is  more  or  less  normal  in  the  life-cycle  of 
the  parasite  under  consideration.    These  cases  are: 

L  A  pulmonary  distomatosis,  with  cerebral  or  other  infection  as 
secondary; 

2.  An  hepatic  distomatosis,  with  splenic  or  intestinal  infection  as 
secondary; 

3.  An  intestinal  distomatosis;  and 

4.  A  venal  distomatosis.  In  addition  we  find  recorded  rare  instances 
of 

5.  An  ophthalmic  distomatosis,  which  may  be  an  accidental  secondary 
form  of  hepatic  distomatosis. 

All  of  the  parasites  in  question,  with  the  exception  of  the  blood-flukes, 
are  hermaphrodites,  and  possess  an  oral  or  an  oral  and  a  ventral  sucker, 
a  mouth,  and  two  blind  intestinal  caeca.  The  life-cycle  is  quite  com- 
plicated and  may  involve  two  or  more  generations  which  live  outside  of 
man.  The  parasites  may  require  an  intermediate  host  or  in  some  cases 
indications  are  not  lacking  that  direct  infection  may  perhaps  occur. 

*  For  more  detailed  zoological  descriptions,  in  English,  of  these  parasites,  see 
Stiles,  1904,  pp.  1-66,  figs.  1-48;  "  Illustrated  Key  to  the  Trematode  Parasites  of 
Man."  Bulletin  17,  Hygienic  Laboratory,  U.  S.  Public  Health  and  Marine  Hos- 
pital Service,  Washington.  For  the  most  recent  general  discussion  of  trem- 
atodes, in  English,  see  Ward,  1903,  pp.  860-873;  for  keys  (in  English)  to  the 
numerous  new  genera  of  trematodes,  see  Pratt,  1900  and  1902. 

535 


536  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

PULMONARY  DISTOMATO SIS. —LUNG-FLUKE  DISEASE. 

Paragonimiasis  or  Parasitic  Haemoptysis.^— Geographical  Distri- 
bution.— The  Asiatic  rc^non,  ])articularly  Jai)an  and  China,  appears  to 
be  the  special  home  of  this  disease  in  man,  ahliough  a  generically  related 
if  not  specifically  identical  infection  occurs  also  as  an  endemic  disease  in 
hogs  in  the  United  States.  It  is  reported  also  for  the  Phili]i]nnes,  For- 
mosa and  Korea  and  occasionally  imported  cases  are  found  in  various 
other  places. 

Zoological  Distribution. — It  is  difficult  at  present  to  determine  the 
original  host  of  this  disease  but  it  is  known  to  occur  more  or  less  frequently 
in  man,  cats,  tigers,  dogs,  swine;  and  Looss  (1905)_says  it  occurs  in  cattle. 
Generically  identical  but  supposedly  specifically  distinct  infections  occur 
in  the  Brazilian  otter  and  the  Indian  ichneumon.  Pulmonary  distoma- 
tosis  is  occasionally  found  in  cattle  as  an  accidental  manifestation  of 
fascioliasis,  and  lung  infection  with  other  genera  of  flukes  is  exceedingly 
common  in  snakes,  toads,  and  frogs. 

The  Parasite. — Paragonimus  ivestermaniv'  (Kerbert,  1878)  is  a  plump, 
depressed,  oval,  or  pyriform,  pinkish  to  reddish-brown  (live  specimens), 
spinose  fluke  7.5  to  IG  mm.  long  by  4  to  8  mm.  broad  by  2  to  5  mm.  thick; 
with  branched  testicles  and  ovary  but  unbranched  intestinal  cseca;  eggs 
yellow,  77  to  102.5  by  40  to  75/(  with  distinct  operculum  but  con- 
taining no  miracidium  when  discharged.  The  adult  parasites  are  found 
in  cysts,  one  to  three  together,  in  the  lungs,  especially  in  upper  lobes, 
occasionally  in  the  pleura,  liver,  abdominal  cavity,  brain,  orbit,  lower 
eyelid,  cervical  glands,  scrotum  and  various  other  parts  of  the  body. 

Source  of  Infection. — Unknown.  The  eggs  develop  a  ciliated  mira- 
cidium (embryo)  in  water  in  four  to  eight  weeks;  this  probably  enters 
some  snail.  The  infecting  stage  probably  enters  man  with  contaminated 
food  or  water;  Katsurada  thinks  it  may  pass  directly  from  the  mouth  to 
the  bronchi,  or  if  swallowed,  from  the  stomach  up  the  oesophagus  and 
down  into  the  lungs,  or  perhajjs  from  the  stomach  through  the  stomach 
wall  to  the  mesenterium  and  from  there  by  the  lymphatics  to  the  final 
point  of  rest. 

Frequency. — ]\Iore  frequent  in  mountainous  localities  (Katsurada); 
chiefly  in  peasants,  more  common  in  males  than  in  females  (88.57  per 
cent,  to  11.4.3  per  cent,  in  481  collated  cases)  and  between  the  ages  of 
sixt:;en  and  thirty  years;  in  some  localities  20  to  73  per  cent,  of  the  lung- 
fluko  patients  give  a  history  of  other  cases  in  the  same  family  (Katsur- 
ada), while  in  other  places  the  family  history  is  reported  as  negative. 
It  is  stated  that  in  certain  parts  of  Formosa,  15  per  cent,  of  the  in- 
habitants are  aft'ected;  in  one  Japanese  village  nearly  all  the  inhabitants 

*  For  a  more  detailed  discussion  in  English,  with  bibliography,  see  Stiles  and 
Hassall,  1900,  pp.  560-611. 

2  Synonyms. — Distoma  westermanii  Kerbert,  1878;  Distoma  nngeri  Cobbold, 
1880;  Distoma  pulmonis  Kiyona,  Suga,  and  Yamagate,  1881;  Distoma  md- 
monnle  Balz,  1883;  Distoma  jmlmonum  (Bselz)  Tomono  Hidekata,  1883;  Dis- 
tomum  cerebrale  Yamagiwa,  1890. 

In  the  lists  of  synonyms  given  in  this  paper,  only  the  more  common  or  the  newer 
names  are  mentioned;  for  full  lists  of  synonyms  the  reader  is  referred  to  the 
special  literature  on  the  various  species. 


DISTOMATOSIS-TREMATODE  OR  FLUKE  INFECTIONS      537 

harbor  the  parasite  (BjcIz).  In  a  hospital  in  Okayama,  0.4  per  cent, 
of  the  20,793  patients  from  1891  to  1897  showed  infection  (Inouye). 
Various  Japanese  physicians  report  that  from  2  to  14  per  cent,  of  their 
patients  suffering  from  res{)iratory  troubles  harbor  this  fluke.  Inouye 
(1903)  has  collected  19  cases  of  brain  infection.  Frequency  doubt- 
less varies  with  occupation  leading  to  exposure  to  infection.  In  Okayama, 
7  of  130  dogs  examined  showed  infection.  From  2  to  28,  perhaps  more, 
parasites  occur  in  each  patient. 

Duration. — The  longevity  of  the  individual  parasite  is  not  established 
but  cases  are  reported  with  histories  extending  over  ten,  twenty  and  even 
thirty  years,  these  prolonged  cases  probably  being  due  to  repeated  in- 
fections. 

Symptoms. — ^The  symptoms  vary  according  to  the  location  and  number 
of  the  parasites  present. 

(a)  Lung  Infection,  Parasitic  HoBmoptysis. — This  is  the  usual  and  un- 
complicated (primary)  form  of  the  disease  and  represents  the  typical 
paragonimiasis  or  pulmonary  distomatosis  as  found  in  man.  The  onset 
may  be  so  gradual  that  the  beginning  can  not  be  recognized  with  certainty. 
The  only  constant  and  specific  characteristic  is  the  presence  of  the  eggs 
in  the  sputum;  it  is  estimated  that  as  many  as  12,000  ova  may  be  ex- 
pectorated daily.  The  sputum  is  yellow  to  red  or  rusty  brown,  due  to  the 
presence  of  the  microscopic  eggs,  and  has  a  peculiar  odor,  partially  due  to 
blood;  poor  in  water  and  rich  in  mucus,  it  varies  from  a  small  amount  to 
100  Cc.  daily;  blood  is  common  but  not  constant,  being  present  in  points, 
strings,  or  larger  amounts;  while  severe  hemorrhages  are  not  common, 
Bselz  reports  a  case  with  a  loss  of  a  pound  of  blood  within  a  few  hours; 
the  amount  of  blood,  which  is  always  arterial  (Taylor),  increases  after 
violent  exertion,  irregularities  in  diet,  use  of  alcohol,  brain  strain,  excesfe 
in  venery,  tobacco  smoking  and  in  cold  weather;  intense  ansemia  may 
result;  the  sputum  is  often  discharged  in  spirals,  resembling  Cursch- 
mann's  asthma  spirals,  and  contains  eggs,  blood,  pus,  mucus  threads, 
alveolar  and  bronchial  cells,  numerous  Charcot's  crystals;  Taylor  and 
Mimachi  have  each  observed  an  expelled  worm.  There  may  be  hoarse- 
ness or  a  chronic  cough,  usually  light,  rarely  so  severe  as  to  disturb  sleep 
and  most  urgent  in  the  morning  upon  rising. 

As  the  disease  progresses  the  periods  of  cough  and  haemoptysis  become 
more  frequent  and  prolonged,  tending  more  or  less  toward  permanency 
and  the  amount  of  expectoration  increases  from  a  slight  quantity  at  the 
onset  to  a  much  greater  quantity  later — as  much  as  10  to  12  ounces 
in  a  few  hours.  All  symptoms  increase  after  physical  exertion.  Physical 
examination  does  not  usually  reveal  anything  abnormal  except  in  severe 
cases;  Inouye  (1903)  reports  retractio  thoracis  as  among  the  most  com- 
mon changes  noticed,  with  contraction  of  the  infrascapular  portion;  as 
the  patient  fails,  auscultation  shows  diminished  respiratory  murmur,  the 
breath  sounds  being  vesicular  but  rarely  weak,  occasionally  bronchial  in 
character  with  dry  or  moist  rales.  Scheube  observed  repeatedly  that  one 
side,  probably  the  infected,  expands  less  than  the  other.  Inouye  reports 
unilateral  or  bilateral  signs  appreciable  on  percussion  in  86  per 
cent,  of  92  patients  examined;  only  1  of  these  had  tuberculosis.  The 
temperature  is  normal  or  but  slightly  elevated  even  in  severe  cases. 
The  patient  may  become  exhausted  by  cough  and  hemorrhage;  he  also 


538  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

becomes  deeply  anaemic,  and  suffers  from  dyspna^i  on  slight  exertion. 
Slight  oedema  often  occurs.  There  is  a  sensation  in  the  chest  variously 
described  as  of  oppression  or  of  heat  or  of  mere  irritation.  Occasionally 
there  are  wandering  pains  in  the  chest,  "most  probably  neuralgic." 
Inouye  reports  chest  pains  in  37  per  cent,  of  92  cases  examined;  in 
28  of  these  (82  per  cent.)  retractio  thoracis  was  present ;  the  pains 
were  due  to  fresh '  or  old  pleurisy.  After  rest  in  bed  all  symptoms 
may  abate  except  the  cough  and  expectoration  and  months  may  pass 
before  a  relapse  occurs.  Gradually  the  constitution  becomes  under- 
mined, convalescence  becomes  less  complete,  periods  of  rest  become 
shorter,  those  of  prostration  longer  and  more  severe,  oedema  and  anaemia 
increase  and  at  last  the  exhausted  patient  dies. 

The  lethaJltij  of  the  uncomplicated  form  of  the  disease  does  not  seem 
to  be  established  but  it  doubtless  varies  with  the  intensity  of  the  infection. 
{h)  Brain  Injeciion. — If  the  worms  or  their  eggs  gain  access  to  the  brain, 
a  cerebral  distomatosis  develops,  resulting  in  epileptiform  attacks  ( Jackson- 
ian  or  cortical  epilepsy).  It  does  not  appear  to  be  established  in  ^\hat 
percentage  of  cases  tins  complication  appears  but  it  is  an  extremely 
serious  and  fatal  form;  Inouye  (1903)  reports  that  of  92  patients 
with  paragonimiasis,  3  showed  brain  symptoms  (headache,  dizziness, 
weak  memory),  2  epilepsy,  and  1  epilepsy  and  left  hemiplegia;  he  has 
collected,  in  all,  19  cases;  of  these,  8  showed  general  spasms,  4  dextral,  2 
sinistral  spasms,  5  had  hemiplegia,  5  spasm  w^ith  weakness  of  the  same 
side,  other  symptoms  (paresis  of  right  arm,  color  ring,  etc.)  being  less 
frequent.  The  epileptic  attacks  may  at  first  be  a  month  or  so  apart 
but  they  gradually  increase  in  frequency  and  severity  until  death. 

(c)  Infection  in  Eyelid. — Several  cases  have  been  reported  in  which 
the  parasite  lodged  in  the  eyeUd,  forming  a  tumor  which  resulted  in 
obstruction  to  the  sight  and  to  movement  of  the  eye. 

{d)  Liver  Injection. — A  purely  accidental  hepatic  distomatosis  may 
occur  in  connection  with  pulmonary  distomatosis,  in  that  eggs  of  the  lung- 
fluke  may  be  found  in  the  liver.  Such  occurrence,  however,  can  hardly 
result  in  a  typical  hepatic  distomatosis  and  it  is  possibly  an  open  question 
whether  some  of  these  cases  were  not  due  to  the  newly  recognized  Japan- 
ese blood-fluke  (see  p.  550). 

(f)  Injection  oj  Oilier  Organs. — Cysts  of  lung-fluke  eggs  may  also  occur 
in  the  mesentery,  omentum,  etc.,  but  thus  far  such  lesions  do  not  appear 
to  have  produced  any  serious  symptoms. 

Pathology. — (a)  Lung  Injection. — Occasionally  deep,  more  commonly 
superficially  in  the  lung,  or  directly  under  the  pleura,  are  found  roundish 
or  flat  cysts  about  as  large  as  the  end  of  the  little  finger,  and  containing 
from  one  to  three  parasites  or  in  some  cases  only  caseous  contents.  Kat- 
surada  (1900)  is  of  the  opinion  that  these  cysts  represent  dilated  bronchi, 
although  he  does  not  deny  that  cavities  in  the  lung  tissue  may  form  inde- 
pendently of  the  bronchi ;  the  lumen  communicates  with  the  neighboring 
bronchi  by  one  large  or  numerous  small  openings  and  the  different  cysts 
may  communicate  with  each  other  by  means  of  direct  or  long  irregular 
tubes;  the  septa  between  the  tunnels  may  break  down  and  a  considerable 
cavity  be  thus  formed  (Manson) ;  the  wall  of  the  cyst  is  rather  stout, 
grayish-white,  about  1  mm.  thick;  the  inner  surface  is  usually  smooth, 
and  the  lumen  may  contain  a  reddish  or  brownish-green  slimy  fluid. 


DISTOMATOSIS-TREMATODE  OR  FLUKE  INFECTIONS       539 


Fig.  35, 


Katsurada  (1900)  states  that  at  first  the  changes  are  a  more  or  less  intense 
bronchitis  and  peribronchitis  of  a  catarrhal,  hemorrhagic  or  more  puru- 
lent character.  When  the  worms  settle  in  the  bronchi,  the  walls  undergo 
an  inflammatory  infiltration,  a  richly  vascularized  granulation  with  con- 
nective tissue  forms,  and  the  original  structure  of  the  bronchi  becomes 
lost.  The  bronchitis  is  caused  not  only  by  the  worms  but  also  by  their 
eggs.    An  adhesive  pleuritis  may  develop. 

(b)  Brain  Injection. — Yamagiwa  reports  disseminated  circumscribed 
foci  of  trematode  eggs,  usually  also  with  giant  cells,  in  the  cortical  sub- 
stance of  the  occipital,  parietal  and  central  lobes  of  the  brain;  surrounded 
by  connective  tissue  and  round-cell  infiltration;  thickening  of  the  wall 
of  the  bloodvessels,  especially  of  the  adventitia,  and  obliteration  of  some 
of  the  branches;  associated  with  lesions  in  the  lungs  containing  eggs  of  the 
same  parasite  and  giant  cells. 

(c)  Liver  Infection. — Yamagiwa  reports  cirrhosis  of  the  liver  resulting 
from  emboli  of  eggs  in  the  portal  area  (or  perhaps  co-existence  of  these 
fluke-egg  emboli  with  cirrhosis  due  to  other  causes).    See  also  p.  538. 

{d)  Injection  oj  Other  Organs. — Cysts  containing  these  fluke-eggs,  and 
fibrous  nodules  have  been  found  in  the  mediastinum,  diaphragm,  mesen- 
terium,  and  walls  of  the  intestine;  Otani  is  said  to  have  found  abscesses 
in  the  cervical  and  inguinal  regions  caused  by  trematodes.  Eggs  have 
been  noticed  in  the  contents  of  the  intestine  but  these  may  have  resulted 
from  swallowed  sputa. 

Clinical  Diagnosis. — This  disease  was  long  con- 
fused with  tuberculosis  from  which  it  may  be 
readily  distinguished  by  microscopic  examination 
of  the  unstained  sputum  to  find  the  characteristic 

egg- 
Treatment. — No  specific  treatment  is  known. 
Inhalations  have  proved  unsatisfactory.  By  send- 
ing the  patient  to  an  uninfected  locality  further 
infection  is  avoided  and  with  the  lapse  of  time  (the 
length  of  which  is  not  known)  the  parasites  may 
finally  die  and  become  disintegrated  or  may  be 
coughed  up.  Surgical  interference  has  been  sug- 
gested for  cases  in  which  the  parasite  can  be 
definitely  located. 

Prevention. — (1)  Destruction  of  infected  spu- 
tum; destruction  of  cats  and  dogs  showing  the 
same  disease;  destruction  of  the  lungs  of  swine 
showing  the  same  infection.  (2)  Use  of  filtered  or 
boiled  drinking-water;  thorough  washing  of  vegetables;  thorough  cook- 
ing of  snails  when  these  are  used  for  food.  These  latter  precautions  are 
based  upon  analogy,  as  nothing  positive  can  be  stated  in  this  line  until  the 
life-history  of  the  parasite  is  known. 

Pulmonary  Distomatosis  Due  to  Fasciola  Gigantica. — One  case  of 
pulmonary  distomatosis  in  man  has  been  reported  as  due  to  Fasciola 
gigantica.  This  was  doubtless  a  case  of  chance  parasitism,  as  man  is  not 
known  to  be  a  normal  host  for  Fasciola  and  as  the  liver,  not  the  lungs,  is 
the  normal  organ  in  which  Fasciola  occurs.  The  parasite  in  question  is 
common  in  Africa  in  the  liver  of  buffalo,  cattle,  sheep  and  goats;  it  was 


Egg  of  lung-fluke  showing 
ovic  cell,  yelk  cells  and 
operculum.  X  100.  (Kat- 
surada.) 


540  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

originally  dcscnbcd  for  the  girafl'e;  it  is  similar  to  /•'.  hepaiica  in  structure, 
but  much  narrower,  measuring  25  to  75  mm.  long  by  3  to  12  mm.  broad; 
eggs  145  to  190  by  75  to  90^<. 


HEPATIC  DISTOMATOSIS.— LIVER-FLUKE  DISEASE. 

At  least  six  different  species  of  liver-flukes,  representing  three  different 
genera  {Opifiilwrchi.'i,  Dicrocccliuin  and  Fasciola),  have  been  found  in 
connection  with  hepatic  distomatosis.  Infections  with  Opistit orchis  are 
common  to  man,  dogs  and  cats,  and  are  much  more  frequent  in  man  than 
are  infections  with  Dicroccclium  and  Fasciola,  which  man  has  in  common 
with  certain  food  animals,  particularly  cattle  and  sheep.  Of  the  six 
specific  infections  in  question,  one  (an  Asiatic  disease)  is  much  more 
important  than  all  the  rest  combined. 

Source  of  Infection. — For  only  two  of  these  infections,  namely  for 
the  fascioliasis,  due  to  Fasciola  hepaiica,  and  opisthorchiasis,  due  to  Opis- 
thorchis  jcUncus,  is  the  source  of  infection  known  (see  pp.  541,  546) ;  for 
all  of  the  others,  this  is  a  matter  of  speculation  based  upon  analogy  and 
circumstantial  evidence. 

Clinical  Diagnosis. — This  is  identical  for  all  six  infections.  Make  a 
microscopic  examination  of  the  unstained  ffcces  for  eggs ;  also  of  the  sputum 
and  urine,  as  the  ova  in  pulmonary  and  venal  distomatosis  may  be  dis- 
charged per  anuni;  hence,  finding  eggs  in  the  fseces,  without  excluding 
pulmonary  and  venal  distomatosis,  may  lead  to  error. 

Treatment. — There  is  no  specific  treatment  know-n  for  any  form  of 
hepatic  distomatosis;  remove  the  patient  to  a  non-infected  area  or,  if  he  be 
kept  at  home,  avoid  further  infection  and  give  good  nourishing  food. 

Prevention. — The  same  general  principles  apply  to  all  six  infections. 


Opisthorchiasis. 

The  term  opisthorchiasis  has  been  introduced  by  Looss  (1905)  to 
designate  infection  with  flukes  belonging  to  the  genus  Opisthorchis,  a 
group  characterized  chiefly  by  the  position  of  the  testicles  near  the 
posterior  extremity  of  the  body.  In  man  w^e  may  distinguish  at  present 
three  distinct  infections  by  species  of  this  genus;  in  order  of  importance 
these  are  the  Asiatic,  the  European  and  the  Indian  species. 

Asiatic  Opisthorchiasis  or  Japanese  Liver-Fluke  Disease — Geo- 
graphical Distribution. — This  infection  is  endemic  in  Asia,  more  es- 
pecially in  Japan  and  China,  but  it  is  also  found  in  the  Philippines, 
India,  Formosa,  INIauritius,  Annam,  Tonkin  and  Korea,  and  imported 
cases  are  occasionally  reported  for  other  parts  of  the  world.  About  twenty 
imported  cases  have  been  recorded  in  the  United  States. 

Zoological  Distribution. — So  far  as  can  be  judged  at  present,  man  must 
be  considered  one  of  the  normal  hosts  of  this  parasite,  but  cats  and  dogs 
also  appear  to  be  normal  hosts.  Generically  identical  but  specifically 
distinct  infections  are  found  in  quite  a  number  of  other  animals. 


DISTOMATOSIS-TREMATODE  OR  FLUKE  INFECTIONS       541 

The  Parasite. — The  Asiatic  liver-fluke  disease  is  caused  by  Opisihor- 
chis  sinensis,^  an  elongate,  lanceolate,  non-spinose  trernatode,  9.7  to  20 
mm.  long  by  2  to  5  mm.  broad.  Its  chief  anatomical  characteristic  is  the 
branched  condition  of  the  testicles.  Eggs,  24  to  30  by  15  to  17.5/^, 
exceptionally  35  by  19,  20  by  15.7,  or  22.5  by  15/i;  the  eggs  are 
somewhat  thicker  than  those  of  0.  jelmcus,  dark  brown,  with  sharply 
defined  operculum,  occasionally  with  small  knob  at  posterior  end  and 
containing  a  ciliated  miracidium  at  oviposition.  The  adult  worm  inhabits 
particularly  the  gall-ducts  but  may  be  found  in  the  gall-bladder  and  in  the 
pancreatic  duct  and  (probably  in  the  act  of  wandering)  also  in  the  duo- 
denum and  stomach.  Katsurada  (1900)  found  it  in  the  pancreas  in  9 
out  of  67  infections. 

Source  of  Infection. — ^The  life-history  of  species  of  the  genus  Ojyis- 
i/iorcAi?  is  unknown  (except  0.  felineus,  contracted  from  eating  raw  fish), 
hence  the  source  of  infection  can  not  be  definitely  stated  but  the  micro- 
scopic anatomy  of  the  embryo  shows  that  at  least  part  of  its  life  is  spent 
in  water;  it  probably  enters  some  snail.  The  probabilities  are  that  infec- 
tion of  man  takes  place  either  directly  from  water  by  swallowing  the  free 
cercaria  or  indirectly  through  eating  some  water-animal  (snail  or  fish)  or 
through  food  contaminated  by  infected  water. 

Frequency. — According  to  Taylor,  some  native  practitioners  in  the 
infected  villages  estimate  that  1  in  7  or  1  in  5  of  the  entire  local  popula- 
tion is  infected,  irrespective  of  age,  sex  or  physical  condition,  and 
where  one  member  of  a  family  is  infected  several  members  are  likely 
to  harbor  the  worm.  Katsurada  (1900)  recognized  654  cases  of  infection 
in  1,075  persons  examined  (namely  60.8  per  cent.)  in  three  villages 
engaged  chiefly  in  rice  culture  and  in  a  region  abounding  in  canals  with 
dirty  water.  It  is  also  said  that  in  Japan,  in  certain  littoral  regions  where 
the  water  is  poor,  20  per  cent,  of  the  inhabitants  are  infected,  \vhile  in 
localities  a  few  miles  distant  and  with  better  w^ater  the  parasite  is  com- 
paratively rare.  In  some  patients  only  a  few  parasites  are  present  while 
in  others  large  numbers  are  found.  Thus  Katsurada  (1900)  reports  that 
of  72  cadavers  examined,  4  contained  from  2,216  to  4,361  worms  each, 
and  Blanchard  (1901)  reports  1  infection  with  over  10,000  parasites. 

Duration. — Cases  of  infection  of  two  to  five  years  standing  seem  to  be 
common,  but  the  longevity  of  the  individual  parasite  does  not  seem  to  be 
determined. 

Symptoms. — To  a  certain  extent  these  depend  upon  the  number  of 
parasites  present,  so  that  light  infections  may  escape  attention  unless  a 
chance  microscopic  examination  is  made.  Usually  there  is  at  first  in- 
creased, exceptionally  decreased,  appetite.  In  heavy  infections,  one  of  the 
first  and  most  pronounced  symptoms  is  the  enlargement  and  tenderness 
of  the  liver,  preceded,  attended,  or  followed  by  diarrhoea;  the  stools  be- 
come irregular;  the  diarrhoea  is  at  first  irregular  and  intermittent,  the 
attacks  becoming  more  and  more  frequent  and  prolonged,  until  after  two 
to  five  years  there  may  be  hardly  any  interval  between  them;   the  stools 

^Synonyms. — Distoma  sinense  Cobbold,  1875;  Distomum  spathulatum  Leuck- 
art,  1876  (not  Creplin,  1849;  for  spatulatum  Rudolphi,  1819);  Distomum  spatu- 
latum  Cobbold,  1879  (not  Rudolphi,  1819);  Distoma  japonicum  R.  Blanchard, 
1886  or  1888;  Opisthorchis  sinensis  (Cobbold,  1875)  R.  Blanchard,  1895;  Di- 
crocoelium  sinense  (Cobbold)  Moniez,  1896. 


542  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

may  be  light,  or  dark  and  bloody  and  may  roach  twelve  per  day;  in  some 
cases  blood  is  present  only  at  irregular  intervals,  in  others  the  bloody 
diarrhoea  becomes  almost  constant.  The  liver  continues  to  increase  in 
size,  in  some  cases  reaching  the  navel,  though  at  times  it  apparently 
diminishes  temporarily;  there  may  be  tenderness  over  the  hepatic  region 
or  more  or  less  dull  pain  and  pressure  may  result  in  excruciating  agony; 
jaundice,  sometimes  intermittent,  is  a  frecjucnt  symptom;  there  is  gener- 
ally a  dark  ashen  discoloration  of  the  skin.  The  temperature  may  be 
normal  or  may  increase  to  100°  F.  After  a  time  anasarca,  likewise  inter- 
mittent, appears  and  affects  the  legs  especially.  Night  blindness  is  likely 
to  occur.  Epistaxis  is  rather  conniion.  Ascites  often  occurs,  may  in- 
crease for  a  time,  then  gradually  tliminish,  to  appear  again  and  again. 
The  patient  is  reduced  by  diarrhoea,  becomes  emaciated  and  grows 
antiemic  and  weak,  but  the  appetite  is  usually  preserved.  It  frequently 
happens  that  the  patient  is  reduced  so  low  that  life  is  despaired  of,  yet  he 
may  gradually  rally  and  apparently  become  almost  well  (Taylor,  1884). 
Later,  however,  relapse  occurs  and  the  same  process  is  repeated  again  and 
again,  ground  being  lost  each  time,  until  at  length,  worn  out  and  ex- 
hausted, the  patient  dies  after  many  years  of  illness.  In  some  cases 
enlargement  of  the  spleen  is  noticed  and  occasionally  a  chronic  gastro- 
intestinal catarrh  is  reported.  In  prolonged  cases  the  liver  becomes 
smaller. 

Lethality. — Of  1,495  cases,  compiled  for  the  province  of  Okayama, 
Katsurada  (1900)  reports  238  as  fatal  (16  per  cent.). 

Pathology. — As  the  parasites  are  situated  chiefly  in  the  liver,  we 
naturally  expect  this  to  be  the  chief  seat  of  the  lesions;  in  fresh  cases  it  is 
enlarged,  sometimes  hyperperaic,  in  prolonged  cases  normal  or  decreased 
in  size  and  of  more  or  less  cirrhotic  appearance.  The  superficial  gall-ducts 
are  prominent,  white,  opaque,  and  irregularly  thickened;  worms  may  be 
pressed  out  singly  or  in  bunches  in  the  thick,  slimy,  yellow  to  dark  brown 
bile.  The  lesions  are  particularly  of  two  kinds,  involving  the  biliary  canals 
and  the  hepatic  parenchyma.  When  the  worms  enter  the  bile  canals  they 
obstruct  the  lumen  more  or  less  completely;  the  first  result  is  a  bile  stasis 
with  resulting  dilatation  of  the  canals;  the  latter  acquire  considerable 
dimensions,  while  both  epithelial  and  subepithelial  layers  undergo  pro- 
lound  modifications.  Opinion  has  been  expressed  that  these  changes  are 
due  to  mechanical  causes;  without  doubt  these  are  important  but  the 
parasites  seem  to  do  other  damage  than  acting  simply  as  foreign  bodies, 
for  in  case  of  infection  with  Fasciola  hepatica,  Railliet  has  shown  that  the 
parasites  suck  blood  from  the  capillaries  in  the  walls  of  the  canals.  The 
lining  of  the  ducts  shows  catarrhal  irritation;  the  discharged  mucus  con- 
tributes to  the  occlusion  of  the  canals;  the  glands  undergo  considerable 
hypertrophy  which  increases  progressively  and  develops  an  extended 
adenoma;  the  newly-formed  bile  canaliculr  are  numerous  at  the  side  of  the 
chief  canal  with  which  they  communicate;  in  sections  nodules  of  several 
millimeters  in  thickness  may  be  found  which  contain  sections  of  a  number 
of  canals.  The  connective-tissue  layer  of  the  canals  undergoes  very  active 
proliferation  and  may  attain  an  enormous  thickness,  its  outer  layer  show- 
ing more  or  less  small  cell  infiltration;  it  pushes  before  it  the  epithelium 
and  thus  contributes  to  the  obliteration  of  the  canal;  it  also  compresses 
the  hepatic  tissue  at  the  expense  of  which  it  lodges  and  which  then  under- 


DISTOMATOSIS-TEEMATODE  OR  FLUKE  INFECTIONS       543 

goes  secondary  lesions  A  cirrhosis  develops  which,  with  time,  acquires 
considerable  proportions.  The  hepatic  tissue  undergoes  granular  and  fatty 
degenerations  and,  little  by  little,  atrophies.  The  lesions  have  a  marked 
influence  on  the  general  nutrition;  the  arrest  of  bile  causes  digestive 
trouble;  compression  of  the  branches  of  the  portal  vein  causes  stasis 
toward  its  origin  from  which  ascites  results  (Blanchard,  1901c);  Kat- 
surada  (1900)  reports  ascites  in  15  out  of  76  cases  as  a  result  of  the 
parasitic  interstitial  hepatitis  or  of  the  stasis  in  the  portal  vein.  Of 
the  76  cases  reported  by  Katsurada,  2  had  gall-stones  in  the  gall- 
bladder (compare  also  a  similar  instance  reported  by  Kirch ner  for 
infection  with  Dicroccelium  lanceatum)  and  2  showed  primary  malig- 
nant growths  in  the  liver,  1  of  which  was  carcinoma;  the  parasites  had 
caused  a  hepatitis  in  the  course  of  which  carcinomatous  growth  developed 
from  the  epithelium  of  the  newly-formed  gall-ducts.  The  gall-bladder 
may  be  greatly  enlarged.  The  spleen  was  enlarged  in  6  of  the  15 
cases  in  which  ascites  was  present,  but  in  1  case  this  organ  was  con- 
siderably reduced  in  size.  In  especially  severe  cases  Katsurada  fre- 
quently found  catarrhal  changes  in  the  stomach  and  intestine.  Of 
76  cases,  9  (11.8  per  cent.)  either  showed  or  gave  a  history  of  icterus;  of 
the  15  cases  with  ascites,  icterus  was  present  in  7  (46.6  per  cent.). 

Clinical    Diagnosis. — Microscopic    examination     of  pm^  35, 

unstained  faeces  to  find  the  egg  of  the  parasite  is 
necessary.  When  in  an  infected  locality  a  case  of 
enlargement  of  the  liver  and  bloody  diarrhoea  is  seen, 
careful  examination  of  the  faeces  is  usually  rewarded 
by  finding  the  eggs. 

Treatment.  ^ — No  specific  treatment  is  known. 
Whether  any  severe  cases  ever  fully  recover  is  not 
stated  but  it  seems,  a  'priori,  that  a  change  of  locality 
to  uninfected  districts,  thus  preventing  further  infection 
of  the  patient,  should  be  attended  by  at  least  a  pro- 
longation of  life.  Taylor  (1884)  says' that  it  is  doubt-  Egg  of  Asiatic  liver- 
ful  whether  recovery  takes  place  after  one  becomes  a  larged.  (Katsur- 
victim  of  this  disease,  by  which  he  probably  does  not  ^ 
refer  to  the  light  infections.  Katsurada  (1900)  suggests  the  advisability 
of  laparotomy  in  some  cases,  in  order  to  press  the  parasites  out  of  the 
gall-ducts  into  the  intestines. 

Prevention. — (1)  Destruction  of  all  cats  and  dogs  affected  with  this 
parasite,  and  disinfection,  by  heat  or  by  drying,  of  all  faeces  from  infected 
persons.  (2)  Until  the  life-history  of  the  parasite  is  known,  the  pre- 
cautions mentioned  under  Prevention  (2),  p.  539. 

Siberian  Opisthorchiasis  or  Siberian  Liver-fluke  Disease. — Geo- 
graphical Distribution. — The  parasite  in  question  is  reported  for  France, 
Germany,  Holland,  Italy  and  Russia,  but  cases  in  man  are  known  only  for 
Prussia  (Germany)  and  Siberia.  The  reported  presence  of  this  parasite 
in  the  United  States  is  based  upon  a  misdetermination  (QpistJiorchis 
pseudofehneus) . 

Zoological  Distribution. — The  cat,  and  possiby  the  dog,  the  fox  (Vulpes 
vulpes),  and  the  glutton  {Gulo  horealis)  form  the  natural  hosts  for  this  in- 
fection ;  it  is  not  yet  thoroughly  established  whether  man  is  a  natural  or  a 
chance  host  for  the  parasite  though  indications  point  to  the  latter  condition. 


544  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

The  Parasite. — This  particular  infection  is  caused  by  the  European 
cat-fluke  {Oph'thurchlfi  fclincu.s),  a  lanceohite,  non-spinose  \vorm,  measur- 
ing from  8  to  15,  rarely  to  18  mm.  long  by  1.25  to  2.5  mm.  broad;  the 
testicles  are  lobate,  but  not  branched;  eggs  oval,  yellow-brown,  26  to  30 
by  11  to  15;/,  one  side  slightly  flatter  than  the  other;  with  sharply 
defined  operculum  on  the  more  acute  pole  and  containing  a  ciliated 
miracidium  at  oviposition.  The  adult  parasites  inhabit  the  gall-ducts 
but  nre  occasionally  found  in  the  pancreas  and  duodenum. 

Source  of  Infection — The  embryo  does  not  hatch  in  water  but  it 
hatches  in  snails  belonging  to  the  genus  Limnwa,  although  it  does 
not  develop  further  in  this  host.  From  circumstantial  evidence  suspicion 
has  fallen  upon  raw  fish  as  a  source  of  infection  and  Askanazy  (1906)  has 
traced  the  infection  to  the  dace  (Lcucu'cus  rutilus)  and  the  ide  or  orf 
{Idus  idufi). 

Frequency. — This  is  an  exceedingly  common  parasite  of  cats  in  some 
parts  of  Europe.  Winogradoff  (1892)  reports  8  cases  of  infection 
(6.45  per  cent.)  in  man  in  124  autopsies  at  Tomsk,  Siberia;  Askanazy 
(1900b)  reports  5  cases  (all  males)  from  Heydekrug  district,  Prussia;  and 
Kurimoto  (1900)  and  Kholodovsky  are  authority  for  1  case  in  St.  Peters- 
burg, Russia,  in  a  patient  who  had  been  in  Siberia.  Thus,  recent 
literatui'e  shows  that  this  is  by  no  means  a  rare  parasite  in  man.  In 
the  cases  reported  for  man,  there  were  several  to  a  thousand  (Askanazy, 
1901)  parasites  present. 

Winogradoff  has  reported  an  additional  case  of  infection  with  a 
small  spinose  fluke  which  he  supposed  was  a  young  0.  felineus.  Braun 
has,  however,  pointed  out  that  this  might  perhaps  be  a  Metorchis 
truncatus,  a  small  spinose  fluke  which  occurs  in  the  dog,  cat,  fox,  glutton, 
and  seal. 

Duration. — Unknown.    In  one  case  probably  nearly  three  years. 

Symptoms. — The  cases  that  have  been  found  have  not  all  been  care- 
fully studied  from  a  clinical  point  of  view.  In  general,  approximately  the 
same  clinical  picture  can  be  expected  which  is  found  in  corresponding  in- 
fections with  the  Asiatic  fluke,  for  the  worms  are  very  closely  related  and 
the  lesions  more  or  less  identical.  According  to  Askanazy  (1900b), 
Winogradoff  reported  icterus  in  5  of  his  cases,  decreased  liver  in  5 
cases,  enlarged  liver  in  2  cases,  ascites  in  3  cases.  In  Askanazy's  third 
case  he  reported  (1901)  icterus  and  bilirubinuria  in  a  cachectic  man 
with  a  very  large,  hard  growth  in  the  liver,  enlargement  of  the  gall-bladder 
and  colic-like  pains. 

Lethality. — In  none  of  the  cases  reported  is  the  parasite  given  as  the 
direct  cause  of  death. 

Pathology. — In  general  this  is  similar  to  that  of  Asiatic  opisthorchiasis, 
except  that  no  such  severe  infections  have  been  studied.  Askanazy 
(1900b)  summarizes  the  pathology  as  cholangitis  catarrhalis  and  peri- 
cholangitis fibrosa  or  as  Virchow  described  it  in  fascioliasis,  as  a  chronic 
choleportitis  and  fibrous  periportitis.  Bossuat  (1902)  summarizes  the 
condition  as  an  irritation  of  the  Avails  of  the  biliary  canals,  a  thickening 
with  pisiform  dilatations,  followed  by  a  veritable  cirrhosis.  In  two  of  the 
cases  studied  by  Askanazy,  he  reports  (1901)  carcinoma  (c/.  above,  p.  543) 
of  the  liver  which  he  believes  was  indirectly  caused  by  the  parasites.  The 
free  eggs  in  the  ducts  were  surrounded  by  eosinophile  pus  cells  (Askau- 


DISTOMATOSIS-TREMATODE  OR  FLUKE  INFECTIONS       545 

azy,  1900b).  The  pancreatic  duct  showed  the  same  changes  as  the  gall- 
ducts.     Charcot's  crystals  were  present  in  the  f'ajces. 

Clinical  Diagnosis  and  Treatment. — See  p.  543. 

Prevention. — See  p.  543.  In  view  of  the  fact  that  fishes  form  the  in- 
termediate host,  it  will  be  well  to  avoid  eating  raw  fish.  This  avoidance 
also  recommends  itself  on  general  principles  in  connection  with  the  pre- 
vention of  infection  with  the  broad  Russian  tapeworm. 

Indian  Opisthorchiasis  or  Indian  Liver-Fluke  Disease — Geo- 
graphical Distribution. — Thus  far  reported  only  for  Calcutta,  India,  unless 
Winogradoff 's  ninth  case  (which  Braun  thinks  may  perhaps  have  been  due 
to  Metorchis  trmicatus)  belongs  here  (?).  Ijima  reports  a  spinose  fluke 
for  cats  in  Japan  which  might  perhaps  be  identical  with  this  species.^ 

Zoological  Distribution. — Man  and  dogs.  It  is  not  yet  known  whether 
these  are  the  normal  or  merely  chance  hosts  for  this  infection.  The  view 
that  this  parasite  occurs  in  the  North  American  red  fox  {Canis  fulvus)  is 
based  upon  an  error  of  identification. 

The  Parasite. — The  Indian  liver-fluke,  Opisthorchis  noverca  Braun, 
1903,  is  a  lanceolate,  spinose  fluke,  9  to  12.5  mm.  long  by  2.5  mm.  broad, 
which  lives  in  the  gall-ducts.     Eggs  oval,  34  by  19  to  21//. 

Symptoms. — ^In  general,  these  are  probably  the  same  as  for  other  species 
of  this  genus,  see  p.  541. 

Source  of  Infection,  Duration,  Lethality,  and  Prevention. — Unknown. 

Frequency. — Only  two  cases  (McConnell,  1876  and  1878)  known. 


LANCET  FLUKE  INFECTION. 

Geographical  Distribution. — This  infection  seems  to  be  primarily  one 
of  Continental  Europe.  Its  exact  distribution  can  not  be  stated,  as 
there  has  been  considerable  confusion  in  the  determinations  of  infections 
with  this  and  other  lanceolate  parasites.  Aside  from  Europe,  it  is 
reported  also  for  Northern  Africa,  Siberia,  Turkestan,  and  North  and 
South  America.  American  specimens  have  never  been  seen  by  the 
writer. 

Zoological  Distribution. — The  same  confusion  noticed  in  connection 
with  the  geographical  distribution  also  exists  in  reference  to  the  hosts. 
Apparently  cattle  and  sheep  are  the  normal  hosts  for  this  disease,  which 
is  also  reported  for  the  goat,  deer  (Hirsch),  horse,  ass,  hog,  hare,  rabbit, 
and  man.  Certainly  many  and  possibly  all  of  the  reported  occurrences  of 
this  infection  in  carnivorous  animals  (dogs  and  cats)  are  based  upon 
errors  of  identification,  as  pointed  out  by  Braun  (1893e  and  f). 

The  Parasite. — -The  lancet  fluke  (Dicroccelium  lanceatum  Stiles  and 
Hassall,  1896)  is  a  non-spinose,  lanceolate  trematode,  4  to  9  mm.  long 
by  2  to  2.4  mm  broad,  characterized  by  the  anterior  position  of  the 
testicles,  which  are  between  the  acetabulum  and  the  ovary,  and  by  the 
posterior  position  of  the  uterus.  Eggs,  dark  brown,  thick-shelled,  38  to 
45  by  20  to  30/<,  with  a  distinct  operculum  and  containing  a  ciliated 
miracidium  when  oviposited;  the  embryo  is  provided  with  two  dark 
spots  in  posterior  portion. 

^Looss,  1905,  p.  91. 
35 


546  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

Source  of  Infection. — Unknown.  Embryos  hatch  in  tlie  intestine  of 
slugs  (Arionidie)  but  not  in  water;  they  do  not,  liowever,  develop  further 
in  these  mollusks. 

Frequency. — While  the  parasite  is  quite  common  in  cattle  and  sheep, 
only  7  cases  of  its  occurrence  in  man  have  been  reported.  It  is  doubt- 
less purely  an  accidental  parasite  for  man. 

Duration. — Unknown. 

Symptoms,  Lethality,  and  Pathology. — Probably  not  serious,  as  only 
light  infections  are  likely  to  occur  in  man.  Kirchner  reports  1  case  with 
gall-stones.  It  seems  not  impossible  that  Mehlis's  case,  in  which  a  woman 
vomited  50  si)ocimens  of  this  parasite  and  9  of  Fasciola  hepatica,  re- 
sulted from  eating  infected  liver  which  was  not  thoroughly  cooked. 

Clinical  Diagnosis,  Treatment,  and  Prevention. — See  p.  543. 

FASCIOLIASIS— INFECTION  WITH  FASCIOLA. 

Fascioliasis  is,  properly  speaking,  distomatosis  caused  by  species  of 
the  genus  Fasciola.  While  the  liver  is  the  normal  habitat  for  these 
worms,  it  occasionally  happens  that  fascicles  infest  other  parts  of  the 
body.  In  man  fascioliasis  is  probably  always  due  either  (1)  to  a  purely 
chance  infection  by  the  larva?  which  then  develop  in  the  liver  or,  in 
rare  cases,  some  other  part  of  the  body,  as  the  lungs  (p.  539),  the  eye 
(p.  556),  or  the  veins  {Hexathyridium  venarum),  etc.;  or  (2)  to  acci- 
dental infection  -with  the  adult  worm,  due,  as  Khouri  (1904)  has  recently 
shown,  to  eating  raw  liver  containing  these  parasites. 

Geographical  Distribution. — The  common  liver-fluke  is  reported  with 
a  very  wide  distribution  but  as  the  parasites  on  different  continents  are 
studied  more  carefully  it  is  found  that  the  infections  alleged  to  be  due  to 
this  species  are  specifically  distinct,  although  generically  identical.  On 
account  of  these  changes  in  ideas  regarding  classification  this  entire  sub- 
ject must  be  restudied.  Europe  is  to  be  considered  the  type  locality  of 
Fasciola  hepatica  and  the  same  parasite  seems  to  occur  in  North  America 
and  Australia.    It  is  also  reported  for  Asia,  Africa  and  South  America. 

Zoological  Distribution. — ^This  infection  is  reported  from  more  animals 
than  are  probably  actually  infected  with  it  but  its  normal  hosts  seem  to 
be  cattle,  goats  and  sheep;    it  is  also  reported  for  many  other  animals. 

The  Parasite. — Fasciola  hepatica^  Linnaeus,  1758,  is  a  flat,  leaf-like, 
spinose  worm  measuring  18  to  30  mm.  (reported  to  51  mm.)  long  by  4 
to  13  mm.  broad;  the  intestine,  testicles,  ovary,  and  vitellogene  glands 
are  profusely  branched.  Eggs,  yellow-brow^n,  oval,  130  to  145  by  70  to 
90/i,  with  distinct  operculum,  not  containing  embryo  when  oviposited. 

Source  of  Infection. — Snails  of  the  genus  Limnoea  (L.  truncatula,  L. 
oahuensis,  L.  rubella)  form  the  intermediate  host,  and  infection  takes 
place  normally  by  swallowing  the  encysted  cercaria. 

Frequency. — While  this  infection  is  rather  common  in  cattle  and  sheep, 
especially  those  pasturing  in  marshy  districts,  it  seems  to  be  purely  ac- 
cidental in  man.  Not  every  case  reported  as  Fasciola  hepatica  is  to  be 
accepted  as  such.     One  source  of  error  is  to  mistake  single  segments  of 

'SYNOivrYMS. — Distoma  hepaticum.  (Linnaeus)  Abildgaard;  Fasciola  humana 
Gmelin,  1790;   Hexathyridium  venarum  Treutler,  1793. 


DISTOMATOSIS-TREMATODE  OR  FLUKE  INFECTIONS       547 

tapeworms  for  liver-flukes;  the  writer  has  seen  several  cases  in  which 
this  had  been  done.  Blanchard  has  carefully  collated  the  authentic  cases 
reported  for  man  and  Moniez  has  added  several  to  Blanchard's  list.  The 
parasite  has  been  reported  for  the  liver  by  several  observers.  One  recent 
case  for  Poi-to  Rico  is  known  to  the  writer;  but  while  the  parasite  is  a 
Fasciola,  he  believes  that  it  represents  a  new  species.  Cases  have  been 
reported  for  the  blood  and  in  subcutaneous  tumors. 

Besides  these  cases,  attention  may  be  directed  to  the  fact  that  the  eating 
of  raw  liver  infected  with  F.  hepatica  may  be  a  much  more  serious  matter 
than  has  heretofore  been  supposed  and  may  cause  in  man  a  condition 
which,  in  certain  localities  at  least,  is  apparently  more  common  than  is  the 
presence  of  the  common  liver-fluke  in  the  human  liver. 

Halzoun. — According  to  Khouri  (1904),  there  exists  in  northern  Liban, 
Syria,  a  disease  known  as  "  halzoun,"^  which  he  attributes  to  Fasciola  hepat- 
ica c  ntracted  through  eating  raw  goat-liver  infested  with  the  parasite.  His 
experiments  upon  rabbits,  as  well  as  clinical  observations,  indicate  that 
the  parasites  attach  themselves  to  the  pharyngeal  mucosa  where  they 
gorge  themselves  with  blood  after  the  manner  of  leeches ;  Khouri  thinks 
that  the  parasites  may  secrete  a  substance  which  acts  as  a  vasodilator. 
After  gorging  themselves  with  blood  the  flukes  loosen  their  hold,  reach 
the  stomach,  or  are  expelled  with  the  vomit.  There  are  two  sets  of  symp- 
toms; namely,  congestive  (a  more  or  less  intense  cedematous  congestion 
of  the  buccopharyngeal  mucosa,  of  the  larynx,  nasal  fossae,  tonsils, 
Eustachian  tube,  ear,  conjunctivae,  and  lips)  and  mechanical  (dyspnoea, 
dysphagia,  aphonia)  resulting  from  the  first  phenomena.  The  mechani- 
cal symptoms  are  proportional  to  the  .severity  of  the  congestive  conditions; 
they  are  less  constant  but  of  more  serious  prognostic  import.  The  symp- 
toms appear  a  few  minutes  to  an  hour  after  eating  the  suspected  liver  and 
are  localized  in  the  cephalic  region  of  the  body;  vomiting  may  result  in 
expelling  one  or  several  worms  and  the  severity  of  the  attack  varies  with 
the  number  of  worms  present. 

Subjective  Symptoms. — ^After  eating  the  infected  raw  liver,  the  patient 
experiences  an  itching  sensation  deep  in  his  throat;  soon  he  feels  more  or 
less  malaise;  the  itching  increases,  extending  to  the  ears  and  becoming 
painful;  a  buzzing  in  the  ears  follows  and  a  sensation  of  auricular  tension 
exasperates  the  patient.  Two  or  three  hours  after  onset  the  itching 
lessens;  deglutition  and  dysphagia  become  painful;  dysphonia  develops 
and  may  extend  to  complete  aphonia.  The  most  alarming  symptom  is 
the  dyspnoea,  varying  to  orthopnoea  in  severe  cases  or  asphyxia  in  fatal 
cases.  The  patient  complains  of  a  sensation  of  suffocation  or  of  violent 
constriction  of  the  throat,  and  of  headache,  usually  frontal,  which  is  some- 
times extreme. 

Objective  Symptoms. — The  aspect  of  the  patient  is  typical;  the  face 
is  congested,  the  lips  thick,  cyanotic  and  livid;  an  abundant  saliva  flows; 
the  eyes  are  highly  congested  and  there  may  be  lachrymation;  the 
conjunctivse  are  injected  and  cedematous;  photophobia  and  exoph- 
thalmia  are  common;  the  sight  remains  normal.  The  nose  is  large, 
red  and  shining;  the  pituitary  mucosa  is  of  an  intense  red- violet  color, 
thickened,  sometimes  closing  the  nasal  passages;    usually  it  secretes  a 

^A-ra.t>ian  word  for  spiral  or  snail, 


548  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

yellowish,  ropy  mucus,  sometimes  very  abundant.  In  severe  cases  the 
neck  is  swollen  and  cedematous;  palpation  shows  a  variable  submaxillary 
and  cervical  adenopathy  and  a  diii'use  pufhness;  the  oedema  invades  the 
cervical  cellular  tissue,  in  serious  cases  extending  to  the  clavicle.  Ex- 
amination of  the  throat  shows  congestion  and  a  more  or  less  intense 
oedema  of  the  pharyngeal  mucosa,  of  the  palate  and  especially  of  the 
uvula  and  tonsils;  "the  latter  are  considerably  enlarged  and,  in  severe 
cases,  may  meet  in  the  median  line,  leading  rapidly  to  asphyxia.  Laryngo- 
scopic  examination  shows  an  unusually  narrowed  superior  larynx,  of  red- 
violet  color,  the  vocal  cords  are  slightly  cedematous,  but  the  opening  of  the 
glottis  is  not  seriously  restricted.  There  is  rather  an  intense  reddening  of 
the  external  auditory  canal  and  especially  of  the  tympanum. 

Somatic  Symptoms. — The  tem{)erature  usually  remains  normal  but 
the  pulse  increases  with  the  dyspnoea.  Examination  of  the  lungs  and  urine 
is  negative. 

Forms. — Besides  the  common  form,  described  in  the  foregoing,  one  may 
distinguish  light,  grave,  and  fatal  cases.  In  the  light  cases,  dysphonia 
and  distinct  dyspnoea  are  not  observed;  the  duration  is  short,  varying  from 
a  few  hours  to  two  or  three  days.  In  the  grave  form  the  symptoms  reach 
their  maximum;  the  incubation  is  only  five  to  twenty-five  minutes;  after 
ten  to  eighteen  hours,  the  pharyngolaryngeal  symptoms  are  intense  ;  if 
the  symptoms  do  not  ameliorate  by  the  end  of  thirty-six  hours,  to  continue 
for  four  or  five  days  in  benign  form,  death  is  inevitable;  usually  this  attack 
lasts  five  to  eight  days.  In  the  fatal  form  the  symptoms  develop  very 
rapidly. 

Complications. — As  complications  may  be  found:  abscess,  especially 
in  the  external  auditory  canal  and  in  the  mastoid  region,  which  may  be 
treated  surgically,  suppurative  otitis  media,  followed  by  perforation  of  the 
tympanum,  and  peripheral  facial  paralysis  which  disappears  after  eight  or 
ten  days. 

Duration. — Attacks  vary  in  length  from  a  few  hours  to  ten  days.  Most 
patients  recover,  death  being  exceptional. 

Diagnosis. — As  a  rule  this  is  not  difficult  but  some  cases  may  be  con- 
fused temporarily  with  diphtheria,  oedema  of  the  glottis,  cardiac  or  pul- 
monary dyspnoea  and  acute  iodism. 

Treatment. — Vomiting  dislodges  and  expels  the  parasite,  and  should  be 
encouraged;   it  is  more  effective  if  the  stomach  is  well  filled. 

Prevention. — ^Avoid  eating  raw  liver. 


INTESTINAL  DISTOMATOSIS. 

The  entire  subject  of  intestinal  distomatosis  in  man  is  one  which  needs 
a  careful  restudy.  Undoubtedly  the  infections  are  much  more  common 
than  is  ordinarily  assumed  but  we  cannot  as  yet  say  for  which  infections 
man  forms  a  normal,  and  for  which  an  accidental  host. 

Geographical  Distribution. — So  far  as  the  writer  has  records,  intestinal 
distomatosis  in  man  is  reported  only  of  Asiatic  and  African  origin. 

Zoological  Distribution. — Similar  infections,  some  of  them  generically 
identical  with  those  found  in  man,  are  exceedingly  common  in  other 
a,nimals  but  of  the  infections  which  occur  in  man,  only  one  {Heterophyes 


DISTOMATOSIS-TREMATODE  OR  FLUKE  INFECTION,'^      549 

heterophyes)  is  known  to  occur  in  other  animals  (cats,  dogs  and  a 
fox). 

The  Parasites. — Intestinal  distomatosis  in  man  may  be  caused  by  the 
following  flukes: 

Fasciolopsis  Buslcii  (Lankester,  1857). — This  is  the  largest  and  perhaps 
the  most  important  of  the  intestinal  flukes  of  man;  thus  far  it  is  known 
only  for  Asia  (India,  Assam,  Siam,  China,  Straits  Settlements,  Sumatra), 
but  Moore  and  Terril  (1905)  have  reported  one  imported  case  in  the  United 
States.  It  measures  27  to  37  mm.  (or  even  75  mm.,  after  Busk)  long  by  5.5 
to  12  or  14  mm.  broad,  and  1.5  to  2  mm.  thick.  While  not  unlike  the  com- 
mon liver-fluke  (Fasciola  hepatica)  in  superficial  appearance,  it  can  be 
easily  distinguished  from  that  form  by  its  very  large  acetabulum  and  by 
its  simple  intestine.  The  eggs  measure  120  to  130  by  77  to  80/^ 
with  very  delicate  operculum.  The  life-history  and  source  of  infection  are 
unknown. 

Infection  with  this  parasite  is  reported  as  being  accompanied  by  in- 
digestion, nausea,  headache  and  severe  diarrhoea  with  bloody  stools. 
It  is  said  to  be  expelled  by  thymol  or  with  calomel. 

Fasciolopsis  Rathouisi  (Poirier,  1887). — This  trematode  has  been  re- 
ported but  once  (Asia)  and  in  this  case  it  does  not  seem  to  have  been 
definitely  established  whether  the  worm  was  in  the  intestine  or  in  the 
liver.  The  patient  is  said  to  have  had  "severe  body  pains."  The  parasite 
measures  25  mm.  long  by  16  mm.  broad;  eggs  ovoid,  150  by  80//. 
The  life-history  and  source  of  infection  are  unknown. 

Heterophyes  Heterophyes  (Siebold,  1852). — This  is  a  minute  trema- 
tode, 1  to  1.7  mm.  long  by  0.3  to  0.7  mm.  broad,  found  in  the  middle 
third  of  the  small  intestine  of  man,  dogs,  and  cats  in  Egypt  and  reported 
once  for  Japan.  Its  chief  anatomical  characteristic  is  the  presence  of  a 
sucker-like  disk  surrounding  the  genital  pore;  the  acetabulum  is  much 
larger  than  the  oral  sucker.  The  eggs  are  light  brown,  thick-shelled, 
oval,  20  to  30  by  15  to  17/x  with  distinct  operculum,  and  containing 
ciliated  miracidium  when  oviposited.  The  life-cycle  and  source  of 
infection  are  unknown.    It  seems  to  be  entirely  harmless  in  man  (Looss). 

Gastrodiscus  Hominis  (Lewis  and  McConnell,  1876). — This  fluke, 
originally  described  as  Amphistoma  hominis,  occurs  in  the  caecum  and 
colon  of  man  in  India  and  has  also  been  reported  for  East  Indian  immi- 
grants in  British  Guiana.  Braun  is  of  the  opinion  that  it  is  undoubtedly 
only  a  chance  parasite  in  man  and  that  its  normal  host  is  some  Indian 
mammal  Indications  are,  however,  not  lacking  that  it  is  a  more  common 
parasite  in  man  than  has  been  supposed.  It  measures  5  to  8  mm.  long  by 
3  to  4  mm.  broad  and  when  fresh  is  of  a  reddish  color;  the  body  is  divided 
into  an  anterior,  rather  slender  conical  portion  and  a  posterior  flattened, 
ventrally  concave  disk  with  small  ventral  acetabulum  at  the  posterior  end. 
The  eggs  measure  150  by  72/x  and  possess  an  operculum  at  the 
narrower  end;  the  miracidium  is  not  formed  before  oviposition.  The 
life-history  and  source  of  infection  are  not  known.  Its  medical  importance 
is  not  established. 

Cladorchis  Watsoni  (Conyngham,  1904)  Shipley,  1905. — This  is  an  8  to 
10  mm.  long  amphistome  reported  once  from  the  small  intestine  of  a  negro 
boy  from  Adamawa,  German  West  Africa. 


550  THE  ZOO-PARASiriC  DISEASES  OF  MAN 

VENAL   DISTOMATOSIS^BILHARZIOSIS^— BLOOD-FLUKE 
INFECTION. 

Geographical  Distribution. — Africa,  Asia,  Panama,  Cuba  and  Porto 
Rico  ;  probably  more  <i;cnerally  as  a  tropical  and  subtropical  disease. 
Occasional  cases,  chieiiy  imported,  are  recorded  for  the  temperate 
climates;   several  cases  have  been  recognized  in  the  United  States. 

Zoological  Distribution. — The  Asiatic  blood-fluke  is  reported  for 
cats  as  well  as  man.  An  infection  occurs  in  the  sooty  monkey,  which  may 
perhaps  be  identical  with  the  African  blood-fluke.  Generically  identical 
but  specifically  distinct  infections  occur  in  horses,  cattle  and  sheep. 

The  Parasites. — Bilharziosis  in  man  may  be  due  to  either  of  two  dis- 
tinct species  of  trematodes,  the  African  blood-fluke  and  the  Asiatic  blood- 
fluke. 

The  African  blood-fluke.  Schistosoma  hcematobium^  (Bilharz,  1852),  so 
far  as  records  are  published,  is  the  more  common  of  the  two;  it  occurs 
chiefly  in  Africa  and  adjacent  islands  but  extends  to  Persia,  Arabia,  India, 
Panama,  Cuba  and  Porto  Rico,  and  is  occasionally  found  elsewhere. 
The  male  is  4  to  15  mm.  long  by  1  mm.  broad;  the  sides  are  curved 
ventrally  to  form  the  gynjecophoric  canal;  the  worm  is  armed  with  nu- 
merous spinose  warts.  The  female  is  filiform,  15  to  20  mm.  long  and 
lives  in  the  gynaecophoric  canal  of  the  male.  The  eggs  are  oval,  135  to 
160;i  long  by  55  to  66/i  broad,  and  are  provided  with  a  terminal,^  or 
lateral,  subterminal  spine,  but  not  with  an  operculum. 

The  Asiatic  blood-fluke.  Schistosoma  ja'ponicum'^  (Katsurada,  1904) 
has  only  recently  been  discovered  (Japan,  China,  and  the  Philippines) 
and  its  frequency  and  distribution  are  not  yet  established.  The  male 
measures  7  to  12  mm.  long  by  0.53  mm.  to  0.8  mm.  broad;  it  is  not 
armed  with  spinose  warts;  gynsecophoric  canal  present.  The  female 
measures  8  to  12  mm.  long.  The  eggs  60  to  90  by  30  to  50//,  and 
are  not  provided  with  the  terminal  or  subterminal  spine  nor  with  an 
operculum. 

The  young  worms  live  in  the  veins  of  the  liver;  in  the  portal  vein  there 
are  but  few  young  pairs;  in  the  veins  of  the  intestine  and  bladder-wall, 
paired  flukes  are  numerous.  Oviposition  begins  while  the  parasites 
wander  from  the  portal  vem  to  the  pelvis,  and  eggs  are  deposited  in  various 
organs.  The  eggs  with  lateral  spine  are  especially  common  in  the  liver  and 
intestine.  The  ova  (80  by  30//  in  utero)  increase  in  size  as  they 
work  through  the  tissues  into  the  lumen  of  the  intestine  or  of  the  bladder; 

^Synonyms — Egyptian  hajmaturia;  endemic  hsematuria;  bilharzian  hsematur- 
ia;  bilharzia  disease.    See  especially  Looss,  1905,  Manson,  1903,  and  Milton,  1902. 

^Synonyms. — Dislomum  hoematobium  Bilharz,  1852;  Schistosoma  hcematobium 
(Bilharz)  Weinland,  1858;  Gyncecophorus  hcBmatobius  (Bilharz)  Diesing,  1858; 
Bilharzia  hoRmatobia  (Bilharz)  Cobbold,  1850;    Bilharzia  capensis  Harley,  1864. 

'The  position  of  the  spine  has  given  rise  to  considerable  discussion,  and  the 
view  has  been  advanced  that  the  lateral  spine  may  belong  to  a  species  of  fluke 
which  is  distinct  from  that  whicli  produces  the  terminal  spine.  Looss  (1905)  has 
however  recently  shown  that  eggs  with  lateral  spines  are  constantly  formed  at 
the  beginning  of  sexual  maturity  and  that  the  position  of  the  spine  is  dependent 
upon  the  orientation  of  the  egg  in  the  ootype. 

■'Synonyms. — Schistosomum  japonicum  Katsurada,  1904,  Aug,  13;  Schisto- 
soma cattoi  Blanchard,  1905, 


DISTOMATOSIS-TREMATODE  OR  FLUKE  INFECTIONS       551 

during  this  process  they  (or  at  least  in  *S'.  hcematobium)  develop  a  ciliated 
embryo  so  that  the  miracidium  is  present  when  the  egg  is  voided  in  the 
urine.  Upon  coming  into  water  this  embryo  escapes  from  the  egg-shell 
and  it  may  live  in  water  for  thirty  to  forty  hours. 

Source  of  Infection. — From  the  miracidium  in  water  to  the  time  that  the 
parasites  are  found  in  the  veins  of  the  liver,  the  life-history  is  unknown 
but  evidence  is  rapidly  accumulating  which  points  to  ah  infection  directly 
through  the  skin.  It  seems  possible,  therefore,  that  an  intermediate  host 
is  not  necessary  and  that  the  alternating  generations  of  the  worm  may 
develop  in  the  liver.  Analogy,  however,  seems  to  indicate  that  it  is  not 
yet  time  entirely  to  abandon  the  view,  supported  by  many  authors,  that 
infection  may  perhaps  take  place  through  the  drinking-water;  but  as 
observations  accumulate  this  opinion  does  not  seem  to  gain  in  strength. 
Some  authors  (Allen,  Brock,  Harley)  assume  direct  infection  through  the 
urethra  and  anus. 

Frequency. — Bilharziosis  is  much  more  common  in  males  than  in 
females  and  in  rural  districts  than  in  cities.  In  a  school  near  Cairo, 
Kautsby  Bey  found  98  cases  in  124  boys  examined,  or  nearly  80  per 
cent,  infected;  in  two  city  schools,  Engel  Bey  found  61  children,  or 
30.5  per  cent,  infected  in  200  examined  (Looss,  1905).  Postmortem 
statistics  indicate  that  it  is  present  in  quite  one-half  of  the  population 
of  Egypt  (Manson),  and  it  is  even  more  common  in  Uganda  (Low). 
Several  to  40  (Sonsino),  or  even  to  300  (Kartulis)  worms  may  be  found 
in  one  patient. 

Duration. — The  incubation  of  the  disease  is  about  four  to  five  months 
(Brock  et  al.),  and  it  is  said  to  last  usually  about  two  years  (Milton,  1902); 
cases  of  longer  duration  are  recorded  in  patients  who  have  passed  ova  for 
nine  (Sonsino)  or  fifteen  years  (Lortet)  after  leaving  the  infected 
area  and  some  authors  refer  to  cases  of  twenty  to  thirty  years  standing, 
although  evidence  is  not  presented  that  these  were  not  due  to  repeated 
infection. 

Symptoms — Course. — Bilharziosis  is  rarely  acute  (Griesinger) ;  it 
usually  stretches  over  years  and  if  death  occurs,  it  is,  as  a  rule,  from  some 
intercurrent  disease;  Buffer  isolated  the  colon  bacillus  in  the  kidney  of  all 
the  fatal  cases  he  observed  (Innes). 

Types. — There  are  two  chief  forms  of  the  malady  but  they  may  occur 
together.  If  the  ova  are  confined  chiefly  to  the  urogenital  system  the 
prominent  symptoms  are:  hsematuria,  pains  in  the  lumbar  region,  left 
iliac  fossa,  thigh,  or  vulva,  either  spontaneous  or  on  micturition;  cystitis, 
vesical  calculus,  urinary  fistulse,  vaginal  tumors  and  nephritis  may  de- 
velop. If  the  ova  are  confined  chiefly  to  the  rectum  the  most  prominent 
symptoms  are:  bloody  stools,  diarrhoea,  prolapse  of  the  rectum,  and 
papillif orm  growths ;  thus  far  the  Asiatic  parasite  has  been  reported  only 
in  connection  with  intestinal  bilharziosis. 

Hcematuria. — This  is  the  earliest  and  most  prominent  symptom.  In 
many  cases  the  patient  suffers  little  or  no  inconvenience.  The  simple 
hsematuria  occurs  chiefly  in  the  better  classes,  the  severer  forms  of 
bilharziosis  occurring  among  persons  who  are  subject  to  long  and  severe 
physical  labor  and  almost  exclusively  among  men.  At  the  end  of  micturi- 
tion a  few  drops  of  more  or  less  pure  blood  are  expelled  and  this  may  be 
the  only  symptom  observed;  frequently  this  is  not  noticed  at  the  time  but 


552 


THE  ZOO-PARASITIC  DISEASES  OF  MAN 


attention  is  directed  to  it  bv  blood  stains  on  the  shirt;  the  amount  of  blood 
lost  is  usually  small,  but  in  some  cases  more  extensive;  it  may  clot  in  the 
bladder  and  cause  acute  retention.  Later,  vague  pains  in  the  perineum, 
lumbar  region,  over  the  pubes,  and  a  burning  sensation  in  the  urethra 
during  micturition  are  exjierienced.  At  first  the  frequency  of  urination  is 
not  increased.  All  sym])toms  increase  tcmj)orarily  after  excesses  in  diet 
or  exercise,  or  during  straining  in  defecation.  The  sediment  of  the  urine 
contains  red  and  white  blood  cells,  epithelium,  mucus  and  blood-fluke 

eggs- 

The  simple  ha?maturia  may  be  followed  by  vesical  catarrh,  increased 

micturition  with  severe  pain  and  tenesmus,  later  by  pronounced  ci/sHHs. 

The  urine  gradually   loses  its  normal  condition  and  becomes  bloody, 

cloudy  and  oft'ensive;    loosened   tissue  from  the  bladder  may  clog  the 

urethra;    residual   urine  becomes  constant;    pyelonephritis  and  septic 

cystitis  may  result.     Relatively   soft  vesical  calculi  may  form  and  in 

Fig.  37. 


Bilharziosis  of  the  bladder.     Ur,  urethra;  PI,  flat,  hard,  encrusted  elevations;   note  the  cauli- 
flower-like growth  in  the  bladder.     (Looss.) 

infected  geographical  areas  cases  of  vesical  calculi  commonly  give  a 
history  of  hsematuria.  Calculi  may  also  form  in  the  kidneys  or  ureters  and 
cause  hydronephrosis.  Hypertrophy,  contraction  or  dilatation  of  the 
bladder  may  occur.  Pressure  on  the  bladder  causes  pain;  constipation 
is  reported  as  general,  and  defecation  causes  emission  of  a  few  drops  of 
blood  from  the  urethra.  In  some  cases  there  may  be  involvement  of  the 
prostate  or  of  the  vesiculfe  seminales,  causing  spermatorrhoea,  and  in 
the  latter  event  ova  are  found  in  the  seminal  discharge. 

Urinary  fistula  is  a  frequent  complication.  This  may  form  at  any  point 
near  the  genitalia  but  especially  in  the  perineum  near  the  scrotum ;  or  on 
the  posterior  surface  of  the  scrotum,  where  the  fistulse  are  usually  multiple, 
and  when  the  openings  are  numerous  (up  to  50  are  recorded)  some  of 
these  may  be  on  the  penis,  over  the  pubes,  near  the  anus,  on  the  legs,  etc. 


DISTOMATOSIS-TREMATODE  OR  FLUKE  INFECTIONS       553 


According  to  Milton,  all  simple  fistulse  spring  from  the  urethra;  most 
fistulse  take  origin  from  the  pubic  side  or  roof  of  the  urethra,  a  few  from 
the  perineal  side  or  floor;  most  floor  fistula;  are  formed  just  in  front  of  the 
bulb,  but  some  may  be  found  in  the  penile  urethra.  Urethral  stricture  is 
also  encountered,  especially  (Milton)  in  case  of  floor  fistulte;  the  latter 
form  from  periurethral  abscesses;  the  abscess  discharge  causes  urethritis 
and  a  thickening  of  the  wall;  the  urine  escapes  in  drops  and  part  of  it 
enters  the  fistulse.  The  urethra  may  become  solid  so  that  the  catheter  can- 
not be  passed. 

As  a  result  of  the  suffering  from  these  severer  infections,  the  patient 
becomes  anaemic,  debilitated  and  wasted,  and  may  succumb  to  some 
intercurrent  disease. 

When   bilharziosis   occurs  in  ^^^-  ^^■ 

women  it  is  usually  as  a  hsema- 
turia.  In  vaginal  bilharziosis 
there  is  subacute  vaginitis,  the 
mucosa  thickens  (especially  on 
the  posterior  surface  of  the 
vagina)  and  becomes  hard  and 
dry  and  with  longitudinal  and 
transverse  folds.  Polypoid 
growths  may  be  encountered, 
sometimes  filling  the  entire  vag- 
ina. The  lesions  may  occur  in  the 
vagina  without  appearing  in  the 
bladder;  bilharzia  papilloma 
may  be  confused  with  epithe- 
lioma. 

In  rectal  bilharziosis  the  mu- 
cous membrane  becomes  hyper- 
trophied,  excessively  vascular, 
and  of  rich,  red-velvet  appear- 
ance; small  or  larger,  simple  or 
branching,  soft,  pile-like  or  coral- 
like  growths  are  found  from  the 
sphincter  up  to  the  sigmoid  flex- 
ure. There  is  excessive  secre- 
tion of  mucus  and  the  patient 
feels  as  if  his  rectum  were  full 
and  as  if  he  wished  to  defecate. 
Little  is  passed,  mixed  with 
bloody  mucus  containing  fluke- 
eggs.  Repeated  straining  at 
stool  causes  prolapse  of  the  rec- 
tum; at  first  this  returns  of  itself 
but  as  time  advances  it  must  be 
helped  back;  finally  the  sphincter  weakens  and  the  rectum  remains 
prolapsed;    it  becomes  septic  and  may  cause  death. 

Prognosis. — In  case  of  light  infection,  the  patient  may  not  be  incon- 
venienced. In  simple  uncomplicated  cases,  prognosis  is  not  unfavorable 
but  the  possibility  of  new  infection  (since  a  careless  patient  is  always  a 


-  H 


Bilharziosis  of  the  rectvun.   H,  cavities  filled  with 
blood.     (Looss.) 


554  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

danger  to  himself  as  a  source  of  infection)  and  the  hability  to  septic  in- 
fection, make  bilharziosis  a  serious  disease  (Looss).  In  general,  the  prog- 
nosis is  practically  that  of  chronic  cystitis  depending  uj)on  an  irremediable 
but  not  in  itself  fatal  cause;  nuich  suffering  may  be  looked  for  and,  as  a 
consecjucnce,  anieniia  and  debility  (Alanson). 

Clinical  Diagnosis. — This  should  be  made  by  microscopic  examina- 
tion of  the  urine  and  iivvvs  to  find  the  eggs  of  the  parasites.  These  will  be 
found  especially  in  the  last  few  drops  forced  out  at  the  end  of  micturition; 
or  in  the  last  drops  of  urine  in  the  catheter.  In  old  cases,  however,  the 
eggs  may  not  be  present  in  the  urine;  if  necessary,  the  surface  of  the 
bladder  may  be  scratched  and  the  shreds  examined  for  eggs  or  the  poly- 
poid growths  in  the  rectum  may  be  removed  and  examined  (Manson). 

To  distinguish  concurrent  ati'ections  note:  Chyluria  (chyle  in  the  urine, 
a  large  clot  with  oil  granules  and  globules,  and  Filaria  will  be  found  in  the 
blood);  calcalus  (be  careful  not  to  mistake  the  hard,  sandy,  raised 
portions  of  the  bladder-wall  for  stones) ;  gonorrhoeal  cystitis  (history) ;  and 
enlarged  prostate.  Floor-fistulte  may  be  mistaken  for  stones  in  the 
urethra  but  the  sound  passes  through  and,  as  it  is  withdrawn,  pus  follows. 
In  the  rectum,  distinguish  bilharziosis  from  piles;  large  bilharzian  tumors 
may  resemble  epithelioma  or  sarcoma. 

Pathology. — It  is  generally  admitted  that  it  is  the  eggs  rather  than  the 
worms  that  are  of  importance.  These  ova  work  their  way  into  and 
through  the  tissues,  particularly  in  the  walls  of  the  bladder,  rectum,  and 
vagina;  they  may  also  be  found  in  the  liver,  lungs,  heart,  spleen,  pancreas, 
kidneys,  omentum,  peritoneum,  ligaments  of  the  uterus,  in  gall-stones,  and 
in  the  cutaneous  epithelium.  At  first  the  eggs  lie  in  the  blood  capillaries, 
but  leaving  these  they  collect  in  groups  in  the  tissue,  the  infiltrated  places 
appearing  as  yellowish  to  whitish  specks,  and  as  the  lesion  increases  it 
forms  a  papular  elevation  containing  eggs  and  minute  dilated  blood- 
vessels. These  thickenings  increase  in  size  and  may  coalesce  until  the 
entire  mucous  membrane  of  the  bladder  becomes  involved.  Round, 
slightly  projecting,  dense  patches  of  inflammatory  thickenings,  with  gran- 
ular surface  and  of  hard  consistency  are  seen,  especially  in  the  trigonum. 
The  ova  are  especially  numerous  in  the  submucosa,  less  numerous  in  the 
mucosa,  and  still  fewer  in  the  muscularis  and  subserous  connective  tissue. 
After  a  certain  age,  the  patches  begin  to  break  down,  and  even  slough, 
giving  rise  to  ulcers  and  crevices  on  their  surfaces,  which  tend  to  retain 
a  certain  amount  of  urine  to  set  up  decomposition  in  it  and  favor  deposi- 
tion of  its  salts.  In  some  cases  the  increase  in  the  mucous  membrane 
seems  to  be  out  of  all  proportion  to  the  development  of  fibrous  tissue  and, 
in  these  cases,  polypoid  excrescences  or  more  cockscomb-like  tumors, 
sometimes  ulcerated,  may  protrude  into  the  lumen  and  may  contain  the 
worms  as  well  as  their  ova.  The  bilharzia  growths  may  cause  retention 
of  urine,  resulting  in  dilatation  of  the  ureters  and  involvement  of  the 
kidneys.  The  muscularis  hypertrophies.  The  capacity  of  the  bladder 
is  decreased  and  its  mucosa  becomes  covered  with  a  bloody  mucus  con- 
taining numerous  eggs.     Carcinoma  may  develop. 

Lesions  similar  to  those  of  the  bladder  may  be  found  also  on  the  pros- 
tate, in  the  ureters  (especially  the  lower  third),  less  frequently  in  the 
pelvis  of  the  kidney.  The  ureters  may  present  constrictions  and  spindle- 
shaped  or  sacculated  dilatations.    Pyelitis,  hydronephrosis,  abscess,  etc., 


DISTOMATOSIS-TREMATODE  OR  FLUKE  INFECTIONS       555 

may  follow,  and  calculi  (more  important  in  the  early  stages  of  the  disease) 
may  form  in  the  bladder,  ureters  or  kidneys. 

The  vesiculae  seminaJes,  vagina  and  cervix  may  also  show  a  hyper- 
plasia with  a  bloody  discharge  containing  fluke  eggs. 

Rectal  bilharziosis  ranks  second  to  the  vesical  form  of  the  disease.  The 
bilharzian  growth  may  be  mistaken  for  piles  and  may  contain  the  adult 
worms  as  well  as  the  eggs. 

Blood. — Le  Dantec  (1904)  gives  the  leukocyte  count  as  follows:  Poly- 
nuclears  57  per  cent.,  mononuclears  35  per  cent.,  eosinophiles  8  percent. 

Death  is  due  to  exhaustion  from  pain  and  want  of  rest,  together  with 
debility  consequent  on  the  constant  hemorrhage,  aided  by  poisoning 
from  absorption  of  septic  matter  from  the  intestine,  or  to  pyonephrosis, 
pyaemia,  or  uraemia. 

Treatment. — No  radical  specific  medical  treatment  is  known  at  present, 
some  authors  even  claiming  that  such  attempts  are  undesirable  and  that 
efforts  must  be  confined  to  palliating  the  effects  of  the  presence  of  the 
parasites.  Good  results  are  claimed  by  some  authors  from  daily  doses  of 
male  fern  (1  gm. — 15  gr.,  t.  i.  d.),  santonin,  quinine  or  methylene  blue 
(3  gr.,  t.  i.  d.),  but  the  general  opinion  seems  to  be  that  treatment  must  be 
symptomatic  for  the  cystitis  and  dysentery,  and,  further  than  that,  opera- 
tive if  necessary.  Milton  warns  against  lithotomy  if  not  absolutely 
necessary,  but  he  had  good  results  from  lithotrity;  in  case  of  very  ex- 
tensive changes  in  the  bladder  he  uses  double  perineal  drainage,  by  Cock's 
puncture,  the  drainage  tubes  being  retained  eight  to  ten  days,  but  he 
says  that  the  results  cannot  be  foreseen,  as  the  growths  slough  and  the 
patient  is  likely  not  to  survive;  it  may,  however,  simply  be  a  question 
between  draining  and  allowing  the  patient  to  suffer. 

Hyperplasia  in  the  vagina  and  cervix  is  treated  by  excision  of  thickened 
and  infiltrated  mucous  membrane. 

Perineal  fistulse  are  treated  on  general  surgical  principles;  Milton  uses 
"free  and  wide  excision  of  the  fistula  and  its  surrounding  tissues"  and 
allows  the  wound  to  heal  by  granulation;  he  never  ties  a  catheter  in  the 
urethra. 

In  rectal  bilharziosis  the  irritation  is  allayed  by  local  sedatives  and 
astringent  applications,  as  enemata  of  starch  and  opium,  or  solution  of 
sulphate  of  copper.  The  rectal  tumors  are  removed  so  far  as  possible. 
In  case  of  high  tumors  Milton  destroys  them  by  swabbing  for  about  a 
minute  with  chloride  of  zinc  solution  1  to  10,  then  drying  out  the  excess 
with  cotton  followed  by  washing  with  copious  salt  solution. 

Operation  on  the  prolapsed  rectum,  avoiding  the  sphincter,  is  more  or 
less  successful  in  fresh  cases,  but  not  in  advanced  cases  of  long  standing. 
It  is  often  difficult  to  decide  whether  excision  of  the  prolapsed  portion  is 
justifiable. 

Stimulants  and  spices  should  be  avoided  in  the  diet.  Excesses  of  all 
kinds  should  be  avoided  and  during  exacerbations  rest  should  be  insisted 
upon. 

Prevention. — ^Until  the  life-cycle  and  source  of  infection  are  better 
understood  the  best  method  of  prevention  cannot  be  definitely  stated  but 
it  is  probably  one  of  the  following  and  for  the  present  both  should  be 
carried  out:  (1)  Guard  water  against  contamination  with  urine  from 
bilharzia  patients;  water  so  guarded  for  two  days  may  be  safely  used  for 


556  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

bathing  purposes  (Looss);  (2)  drink  only  filtered  or  boiled  water,  when 
in  an  infected  district. 


OPHTHALMIC  DISTOMATOSIS. 

Ophthalmic  distomatosis  has  been  reported  for  man  on  only  two 
occasions : — 

Monosiomulum  lentis  (Gescheidt,  1833)  is  a  trematode  of  uncertain 
systematic  position  which  has  been  reported  once,  in  Odessa,  in  the  crys- 
talline lens.     Possibly  it  is  an  erratic  liver-fluke. 

Agamodistomvm  ophfJialmohinm  (Diesing,  1850)  is  also  of  doubtful 
systematic  position  (possibly  an  erratic  liver-fluke).  It  is  reported  once, 
in  Dresden,  between  the  crystalline  lens  and  its  capsule. 


CHAPTER  XXV. 

TiENIASIS-CESTODE  INFECTION. 

By  CHARLES  WARDELL  STILES,  Ph.D.,  D.Sc. 

Terminology. — Tcenia  was  the  original  cestode  genus  (1758)  and  has 
served  as  the  great  collective  genus  of  the  tapeworms.  It  is  now  confined 
to  cestodes  of  the  type  of  Taenia  solium  but  the  term  tseniasis  may  be  con- 
veniently retained  to  denote  any  cestode  infection.  We  may  have  two 
kinds  of  tseniasis;  namely,  (a)  intestinal  infection  with  the  tapeworm 
stage,  or  (6)  somatic  infection  with  the  larval  stage, 

INTESTINAL  TJENIASIS— TAPEWORM^  INFECTION. 

The  day  is  passed  when  a  simple  diagnosis  of  "tapeworm"  is  sufficient, 
for  we  now  know  that  it  may  be  a  matter  of  importance,  both  to  the 
physician  and  the  patient,  to  establish  what  particular  kind  of  tapeworm 
is  present.  Upon  such  determination  may  rest  the  question  of  the  time 
of  treatment,  the  precautions  to  be  taken,  and  even — in  exceptional  cases — 
the  risks  to  be  run  and  the  chances  for  complete  recovery. 

So  far  as  is  established,  man  seems  to  be  the  normal  and  sole  host  for 
the  sexual  stage  of  at  least  two  of  the  large  tapeworms,  Tcenia  saginaia 
and  T.  solium.  Man,  together  with  the  dog,  probably  forms  the  normal 
host  for  a  third  large  tapeworm  {Dihothrioccphalus  latus).  In  common 
with  rats  and  mice,  man  seems  to  have  become  a  normal  host  for  the 
dwarf  tapeworm  {Hymenole'pis  nana)  although  it  is  not  absolutely  estab- 
lished that  the  worm  in  man  is  exactly  identical  with  that  of  the  rodents ; 
in  fact,  strong  indications  are  not  lacking  that  the  worm  (H.n.  fra- 
terna)  in  rats  and  mice  is  at  least  varietally,  perhaps  specifically,  dis- 
tinct from  the  worm  in  man. 

Occasionally,  though  rarely,  as  accidental  host,  man  harbors  the  double- 
pored  tapeworm  (Dipylidium  caninum)  of  dogs  and  cats,  the  flavopunctate 
tapeworm  (Hymenolepis  diminuta)  of  rats,  and  the  lanceolate  tape- 
worm {H.  lanceolata)  of  ducks  and  geese.  The  other  tapeworms  reported 
for  man  are:  Tmnia  confusa  (twice,  in  the  United  States),  T.  hominis 
(once,  in  Aschabad),  T.  africana  (two  specimens  from  East  Africa), 
JDavainea  madagascariensis  (occasionally  in  the  tropics),  D.  asiatica 
(once  in  Asiatic  Russia),  Dibothriocephalu^  cordatus  (Greenland),  Diplo- 
gonoporus  grandis  (twice,  in  Japan) ;  but  too  little  at  present  is  known  of 

^  For  keys  to  and  specific  diagnoses  and  full  synonymy  of  the  various  tape- 
worms of  man  see  Stiles,  1906,  pp.  1-104,  Figs.  1-160.  Bulletin  25,  Hygienic 
Laboratory,  U.  S.  Public  Health  and  Marine  Hospital  Service,  Washington. 

557 


558 


THE  ZOO-PARASITIC  DISEASES  OF  MAN 


the  occurrence  of  these  species  to  permit  a  definite  judgment  as  to  whether 
man  is  their  normal  or  simply  an  accidental  host,  except  perhaps  in  the 
case  of  Dib.  cordatus  for  which  man  seems  to  be  an  accidental  host.  In- 
teresting as  the  ten  last-named  infections  are  and  without  expressing  any 
adverse  opinion  as  to  their  importance  when  they  do  occur,  it  may  be 
said  that  from  a  clinical  i)oint  of  view  our  present  knowledge  of  the  adult 
tapeworms  in  man  is  based  chiefly  upon  three  large  species  {Dihoihrio- 
cephalus  lalus,  Tcriiia  sulium,  T.  .scujinata),  and  one  small  sjjecics,  {llymen- 
olepLs  nana).  Of  these  the  average  practitioner  in  Australia,  England  and 
North  America  will  come  in  contact  especially  \\  ilh  the  fat  tapeworm 
{T.  saginaia);  he  will  doubtless  meet  infections  with  the  dwarf  tapeworm 
{llijmcnolcpis  nana)  but  will  usually  fail  to  recognize  them,  although  in 
some  parts  of  the  United  States  he  will  probably  have  five  or  more  cases 
of  this  parasite  to  one  of  the  fat  tapeworm;  it  is  the  exception  that  the 
pork-measle  or  armed  tapeworm  (T.  solium)  is  found;  while  probably 
not  one  physician  in  a  hundred,  in  Australia,  England  and  North 
America,  has  seen  an  infection  with  the  broad  tapeworm  {Dihothrio- 
cephalus  laius),  and  if  he  does  see  such,  it  may  be  chiefly  imported  cases 
among  Russians,  Swedes,  Finns,  Germans  or  in  persons  who  have  visited 
the  more  infected  European  or  Asiatic  localities. 

All  four  of  these  species  present  certain  points  which  should  be  borne 
in  mind.  The  pork-measle  tapeworm,  though  not  common,  is  by  far  the 
most  dangerous.  The  dwarf  tapeworm  is  the  most  common  in  some 
localities,  though  its  frequency  in  others  is  not  established;  although 
it  is  very  small  it  may  occur  in  large  numbers  and  produce  severe  symp- 


FiG.  39. 


Fig  .  40. 


Egg  of  beef-measle  tapeworm  {Tcenia  saginata) 
with  thick  egg  shell  (embryophore),  containing 
the  six-hooked  embryo  (onchosphere),  enlarged, 
(Leuckart.) 


Gravid  segment  of  beef-measle  tapeworm 
{Twnia  saginata),  showing  lateral  branches 
of  the  uterus,  enlarged.     (Stiles.) 

toms.  The  fat  tapeworm  is  the  most  common  of  the  larger  forms;  it 
may  produce  severe  symptoms,  ir  sometimes  difficult  to  expel,  but  is  not 
dangerous  as  compared  with  T.  solium.  The  broad  tapeworm  may  be 
associated  with  a  more  or  less  severe  anaemia. 

The  Fat  Tapeworm. — Ta^jiia  saginata  Goeze,  1782. — Geographical 
Distribution. — Practically  cosmopolitan, 


TJENIASIS—CESTODE  INFECTION 


559 


Zoological  Distribution. — The  adult  is  known  only  for  man.  The 
larva  {Cysticercus  hovifs)  is  found  in  cattle;  it  is  also  reported  by  several 
authors  for  man  but  doubts  arise  regarding  the  determinations;  experi- 
ments to  grow  it  in  apes,  dogs,  goats,  hogs,  rabbits,  and  sheep  have  been 
negative  but  it  is  reported  that  Heller  succeeded  in  infecting  a  sheep  and 
that  Zenker  and  Heller  were  able  to  infect  young  goats. 

The  Parasite. — The  fat  or  unarmed  tapeworm,  Tcenia  {Twniarhyn- 
chusY  saginata,^  is  one  of  the  largest  known  cestodes,  attaining  a  length 
of  about  4  to  8  or  10  meters;  the  head  is  without  hooks;  there  may  be 
more  than  a  thousand  segments  present;  only  two  ovaries  are  found  in 
each  mature  segment;  the  uterus  in  the  gravid  segments  has  15  to 
35  slender  dichotomous  lateral  branches  each  side  of,  and  shorter 
than,  the  median  stem;  genital  pores  lateral  (marginal),  irregularly 
alternate;   terminal  segments  attain  16  to  25  mm.  long  by  4  to  7  mm. 


Fig.  41. 


Section  of  a  beef  tongue  heavily  infested  with  beef  measles,  natural  size.     (Stiles.) 

broad;    eggs  with  thick,  dark,  radially  ;striated  embryophore  ("inner 
shell,"  or  "shell"  in  most  medical  works)  30  to  40  by  20  to  30/i. 

Source  of  Infection. — This  parasite  is  obtained  through  eating  beef, 
especially  the  tongue  and  the  muscles  of  mastication,  infected  with 

^In  zoological  writings,  a  capitalized  name  inserted  in  parentheses  between 
the  generic  and  the  specific  names  denotes  the  subgenus.  The  present  genus, 
Tcenia,  for  instance,  may  be  divided  into  the  subgenera:  Tcenia,  type  T.  solium; 
Tceniarhynchus,  type  T.  saginata;  and  Multiceps  Gceze,  1782,  (Coenurus  1808)  type 
T.  coenurus.  Subgenera  are  used  in  zoology  for  several  purposes:  Their  chief 
use  is  to  enable  the  classification  of  species  into  groups  to  which  generic  rank  is 
not  given;  another  use  of  subgenera  is  to  foreshadow  probable  changes  in  the 
classification.  When  a  genus  is  divided  into  subgenera,  it  is  not  necessary  to 
cite  the  subgeneric  name  when  referring  to  the  species.  Thus,  Tcenia  saginata 
is  as  valid  a  citation  as  Taenia  {Tceniarhynchus)  saginata. 

^Synonyms. — Tcenia  solium  Linnaeus,  1758  pro  parte;  T.  mediocanellata  hom- 
inis,  seu  T.  mediocanellata  seu  T.  zittaviensis  Kiichenmeister,  1852;  T.  inermis 
Moquin-Tandon,  1860. 


560  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

Cysticerciis  bovis.^  Cattle  become  infected  by  swallowing  the  embryo 
(onchosphere),  encased  in  its  embiyophore,  in  their  food  or  in  water  con- 
taminated directly  or  indirectly  with  infected  human  fjvces. 

Frequency. — This  is  by  all  means  the  most  common  of  the  large  tape- 
worms of  man  in  Noith  America  and  Europe  (except  in  certain  regions 
where  Dihoihrioceplialus  latus  abounds)  but  it  will  doubtless  gradually 
decrease  in  frequency  because  of  the  meat  inspection  and  cold  storage  of 
beef.  It  is  reported  as  exceedingly  common  in  certain  localities  of  Africa 
and  Asia.  It  is  more  common  in  females  than  in  males  and  while  it  may  be 
present  in  patients  of  almost  any  age  it  is  more  common  in  people  between 
twenty  and  forty.  Usually  only  one  specimen  is  present  in  a  patient  but 
infections  with  from  1  to  59  worms  are  reported. 

Duration. — Beyond  the  fact  that  persons  may  harbor  this  worm  for 
a  number  of  years,  the  exact  longevity  of  this  species  is  not  established; 
considering  tlie  method  by  which  the  segments  are  formed,  the  age  of  the 
worm  seems  to  be,  theoretically,  potentially  almost  indefinite. 

Special  Medical  Features.— The  fat  tapeworm  is  not  only  more  com- 
mon than  Twina  solium,  but  the  general  consensus  of  opinion  seems  to  be 
that  it  is  more  difficult  to  expel,  despite  the  absence  of  hooks  from  the 
head.  While  clinical  reports  seem  to  show  that  auiemia  is  more  likely  to 
result  from  T.  saginaia  than  from  T.  solium,  and  less  likely  than  from 
Dibothrioccphalus  latus,  the  fat  tapeworm  is  really  of  much  less  import- 
ance than  T.  solium,  for  it  does  not  combine  with  it  the  danger  of  cysti- 
cercosis  (p.  574)  which  we  may  find  associated  with  infection  with  T. 
solium.  Hence,  if  treatment  is  not  convenient  at  the  time  of  diagnosis  (as 
in  case  of  pregnancy  or  because  of  important  business  engagements)  this 
can  be  postponed  until  a  more  convenient  time  without  any  special 
danger  to  the  patient. 

Differential  Diagnosis. — It  is  unwise  for  the  physician  to  trust  to  dis- 
tinguishing Taenia  sar/inafa  from  T.  solium  on  the  microscopic  exami- 
nation of  the  eggs  found  in  the  faeces.  The  author  has  examined  the 
adult  worms  which  various  persons  have  positively  determined  by  this 
method  as  being  T.  solium  and  in  every  case  thus  far  the  parasite  has 
proved  to  be  T.  saginata.  It  is  also  unwise  to  rely  only  upon  the  form  of 
the  segments.  A  safer  plan  is  to  press  the  discharged  segments  between 
two  pieces  of  glass,  hold  the  preparation  to  the  light,  and  count  the  lateral 
branches  of  the  uterus.  If  the  head  is  found,  determine  the  presence 
(T.  solium)  or  absence  {T.  saginata)  of  hooks. 

Prevention. — Proper  disposal  of  human  faeces  should  prevent  the  infec- 
tion of  cattle ;  a  proper  system  of  meat  inspection^  prevents  the  infection 
of  man;  the  cysticerci  in  beef  die  within  three  weeks  after  the  death  of  the 
steer,  so  that' beef  which  has  been  killed  for  twenty-one  days  will  not 
transmit  this  parasite ;  thorough  cooking  or  thorough  salting  of  the  meat 
also  kills  the  parasite. 

Taenia  (Ts3iiiarhynchus)  africana  Linstow,  1900,  is  a  species  closely 
allied  to  T.  saginata;  only  two  specimens  have  been  found — in  the  negro 
in  German  East  Africa.  The  parasite  attains  1.4  meters  in  length;  scolex 
unarmed;     segments    about    600    in    number,    always    broader    than 

^Synonyms. — Cysticercus  tcenice  saginatoe  Leuckart;   C.  bovis  Cobbold,  1866; 
C.  tcenifB  mediocanellatoe  Knoch,  1868;   C.  inermis  of  various  Germans  and  others. 
='See  Stiles,  1898,  pp.  77-83.     Bulletin  19,  U-  S.  Bureau  of  Animal  Industry. 


TMNIASIS—CESTODE  INFECTION 


561 


long,  attalaing  7  mm.  in  length  by  12  to  15  mm.  in  breadth;  uterus  with 
15  to  24  simple  (not  dichotomous)  branches  each  side  of,  and  longer  than, 
the  median  stem;  embryophore  31  to  39  by  33.8//.  The  life-cycle 
and  source  of  infection  are  unknown  but  the  zebu  has  fallen  under 
suspicion  as  possibly  representing  the  intermediate  host. 

Taenia  (T8eniarh5nichus)  hominis  Linstow,  1902  was  found  once,  in 
Aschabad.  in  a  girl.    The  parasite  measured  70  mm.  long  by  1.11  to  1.97 


Fig.  42. 


Gravid  segment  of  pork-measle  tapeworn  ( Taenia  solium),  showing  the  lateral  branches  of  the 
uterus,  enlarged.     (Stiles.) 

mm.  broad.  The  scolex  possesses  a  rudimentary  rostellum  without  hooks; 
suckers  directed  postero-anteriorly;  caudad  of  suckers  a  circular  ridge  is 
present.  The  genital  organs  were  not  developed,  but  von  Linstow  con- 
siders that  the  indications  are  that  this  worm  may  attain  as  great  size 
as  T.  saginata. 

The  Pork-Measly  Tapeworm.— Tcema  w^mm.— Geographical  Dis- 
tribution.— Practically  cosmopolitan,  following  the  hog. 

Zoological  Distribution. — Adult  known  only  for  man;  experiments  to 
grow  it  in  a  monkey  (Macacus  cynomolgus)  and  in  dogs,  guinea-pigs,  hogs 
and  rabbits  have  been  negative.  The  larva  {Cysticercus  cellulosce^)  is 
found,  especially,  in  hogs;  it  is  said  that  it  may,  occasionally,  occur  in 
sheep,  and  it  will  develop  in  young  dogs. 

The  Parasite. — The  armed  or  pork-measle  tapeworm,  Tcsnia  (Tcema) 
solium^  (Linnaeus,  1758)  is  slightly  smaller  than  the  fat  tapeworm;  it  does 
not  usually  measure  over  2  to  3.5,  6,  or  8  meters  in  length;  the  head  is 
armed  with  a  rostellum  bearing  a  double  row  of  hooks,  of  larger  and 
smaller  size,  22  to  32  in  number;  genital  pores  lateral  (marginal), 
irregularly    alternate;    mature    segments    contain    3    ovaries,    due    to 

1  Synonyms. — T.  cellulosce  Gmelin,  1790;  C.  celluloscc  (Gmelin)  Rudolphi, 
1808. 

2  Synonyms. — Tcenia  solium  Linna?us,  1758  (after  elimination  of  T.  saginata  and 
T.  hydatigena). 


562  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

the  fact  that  the  ovarv  on  the  pore-side  of  the  segment  is  divided; 
the  segments  may  attain  10  to  12  mm.  in  length,  by  5  to  G  mm.  in  breadth; 
SOO  to  900  segments  may  be  present;  in  gravid  segments,  the  median 
uterine  stem  possesses  7  to  15  Uiteral  dichotomous  branches  each  side; 
"eggs"  (embryophore)  very  similar  to  those  of  T.  saginata,  31  to  36// 
in  diameter. 

Source  of  Infection. — This  parasite  is  obtained  by  eating  under-cooked, 
or  undcr-picklcd,  or  under-cured  ])ork  or  wikl-boar  meat.  The  hogs  be- 
come infected  by  eating  human  ffcces  containing  the  egg  with  its  enclosed 
embryo,  or  from  food  or  drink  contaminated  with  these  eggs.  To  build  a 
privy  over  the  pig-pen,  as  one  repeatedly  sees  in  rural  districts,  means  the 
formation  of  an  endless  chain  in  the  biology  of  this  worm. 

Frequency.  — As  has  been  shown  by  Leidy,  Osier,  and  the  writer,  this  is 
certainly  a  rare  parasite  in  the  United  States  and  Canada,  despite  the 
statements  of  several  authors  (possibly  due  to  Weinland)  to  the  contrary. 
Of  300  tapeworms  from  man  examined  by  the  author  from  1891  to  1895, 
297  were  T.  saginata,  and  none  T.  solium.  Of  28  tapeworms  re- 
cently (1905)  examined  by  him  in  two  New  England  Museums,  23 
were  T.  saginata  (several  were  labelled  T.  solium),  4  were  Dibothrio- 
cephalus  latus,  and  1  was  too  poor  to  determine.  From  1891  to  1905, 
the  only  authentic  specimen  of  T.  solium  sent  to  the  writer  came  from  Ger- 
many. Osier  reports  76  cases  of  the  cysticercus  in  hogs  out  of  1,000  ex- 
amined in  Montreal;  and  the  writer  has  seen  several  American  cases  of 
cysticercosis  in  hogs  and  man  due  to  this  species;  so  that  there  can  be  no 
doubt  regarding  its  occurrence  in  this  country.  Perfectly  authentic  cases 
of  T.  solium  in  man  have  been  recognized  in  the  United  States.  However 
the  average  T.  solium  mentioned  in  American  literature  is  undoubtedly 
T.  sagiiuita.  T.  solium  is  said  to  be  rather  common  in  Panama.  The 
infrequency  of  the  pork  tapeworm  in  America  is  due  probably  to  (a) 
national  culinary  habits,  {h)  the  curing  methods,  and  (c)  the  federal  meat 
inspection.  In  Europe,  T.  solium  is  decreasing  in  frequency,  because  of 
the  meat  inspection.  It  is  not  found  among  orthodox  Jews,  or  among 
other  people  who  do  not  eat  pork.  It  is  especially  likely  to  be  found  in 
people  (as  of  Saxon  and  East  Prussian  origin,  but  not  of  West  and  South 
German  origin)  who  eat  raw  or  rare  pork.  It  may  be  found  in  patients  of 
almost  any  age,  but  appears  to  be  more  common  in  people  between 
twenty  and  forty  years. 

Duration. — The  longevity  of  the  individual  parasite  is  not  definitely 
established,  but  it  can  doubtless  live  for  years  (ten  to  fifteen  or  more). 

Special  Medical  Features. — While  less  likely,  according  to  clinical  re- 
ports, to  result  in  anaemia  than  is  either  Tcenia  saginata  or  Dibothrio- 
ce'phalus  latus,  the  fact  must  constantly  be  held  in  mind  that  Taenia  solium 
is  dangerous  especially  because  of  the  possibility  of  its  producing  cysticer- 
cosis (see  p.  574).  On  account  of  this  danger,  it  is  much  more  important 
to  treat  promptly  the  infection  with  T.  solium  than  the  infection  with  any 
other  tapeworm.  Further,  not  only  is  a  patient  with  T.  solium  a  constant 
danger  to  himself,  but  also  to  other  members  of  his  family,  and  especially 
to  any  one  occupying  the  same  bed  with  him.  Accordingly,  a  patient 
with  T.  solium  should  never  sleep  in  bed  with  another  person,  not  only 
between  the  time  of  diagnosis  and  treatment,  but  also  until  a  definite 
cure    is   thoroughly    established.     He   should   also   be   warned   to   be 


TMNIASIS—CESTODE  INFECTION 


563 


unusually  cautious  about  his  personal  habits,  relative  to  washing  his 
hands  and  cleaning  his  finger-nails. 

Fig.  43. 


Fig.  44. 


Gravid  segment  of  T.  confusa,  to  show  the 
Uterus.   X  6.     (Guyer  ) 


Onchosphere  sur- 
rounded by  em- 
bryophore,  from 
uterus.  X  660. 
(Guyer.) 

Prevention. —Faeces  from  infected 
patients  should  be  so  disposed  of  that 
they  can  not  infect  hogs;  hogs  heavily 
infected  (severe  hog-measles,  acute 
cestode  tuberculosis)  should  be  des- 
troyed, but  if  tho  infection  is  very  light 
no  vahd  hygienic  objection  can  be 
raised  against  eating  the  meat  in  case 
it  is  thoroughly  cooked;  cold-storage  is 
not  so  effective  against  this  parasite  as 
it  is  against  Cysticercus  hovis,  for  C. 
cell'ulosce  has  been  found  to  be  alive 
twenty-nine  days  after  its  host  was 
slaughtered. 

Taenia  (Tsenia)  teniaeformis  (Bloch, 
1780)  is  a  tapeworm  which  cats  con- 
tract from  eating  mice  containing 
Cysticerciis  faseiolaris.  Krabbe  thinks 
its  occasional  presence  in  man  is  pos- 
sible, because  in  Jutland  hashed  raw 
mice  are  occasionally  eaten  as  a  remedy 
for  retention  of  urine.  No  authentic 
case  of  such  infection  seems  to  be  re- 
ported as  yet. 

Taenia  (Taenia)  pisiformis  (Bloch 
1780),  is  a  tapeworm  which  dogs  con- 
tract by  eating  rabbits  infected  with 
Cysticercus  pisiformis.  Vital  (1874)  re- 
ports this  tapeworm  in  man,  but  legiti- 
mate doubts  may  arise  regarding  the 
correctness  of  the  zoological  determi- 
nation, especially  in  view  of  the  fact 
that  Galli-Valerio  (1898)  was  unable 
to  infect  himself  with  this  species  exper- 
imentally by  swallowing  the  larval  stage. 


564  THE  ZOO-PARASITIC  DISEASES  OF  MAN' 

Taenia  (Subg.?)  confusa  \Yard,  1S96  has  been  found  in  Lincoln, 
Nebraska.  It  attains  5  to  S  meters  in  length;  head  unknown;  segments 
may  attain  27  to  35  mm.  long  bv  3.5  to  5  mm.  broad,  greatest  breadth  8  to 
10  mm.;  ovaries  2,  distinctly  reniform;  uterus  with  14  to  18  short,  thick, 
dichotomous  lateral  branches  each  side  of  median  stem;   eggs  39  by  30/t. 

Thus  far  little  is, known  regarding  the  history  and  clinical  significance  of 
this  American  tapeworm,  which  should  be  looked  for  especially  in  the 
Northwest. 

The  Dwarf  Tapeworm.  — Ilymenolepis  nana. — Geographical  Distribu- 
tion.— In  North  America  this  parasite  has  been  found  from  Pennsylvania 
to  Texas,  but  its  distribution  is  probably  much  more  extensive.  It  is  also 
reported  for  South  America,  Europe,  Asia,  Africa,  and  is  probably  more 
or  less  cosmopolitan. 

Zoological  Distribution. — Several  authors  (Grassi,  Lutz,  Ransom,  and 
others)  consider  H ijmenolcpis  nana  fratcrna^  Stiles,  190G,  of  rats  and  mice 
identical"  with  //.  nana  of  man,  but  other  authors  (Moniez,  Braun, 
Looss)  are  inclined  to  doubt  this  identity.  Grassi  and  Looss  were  unable 
to  transmit  the  parasite  of  man  to  rats. 

The  Parasite. — Hymenolepis  nana  ^(Siebold,  1852)  is  the  smallest 
tapeworm  known  for  man.  It  measures  5  to  45  mm.  long  by  0.5  to  0.9 
mm.  in  maximum  breadth,  and  is  composed  of  100  to  200  small  segments. 
The  rostellum  is  armed;  there  are  3  testicles  to  each  segment,  and  the 
genital  pores  are  unilateral.  The  eggs  have  2  distinct  membranes: 
outer  membrane  30  to  60/i  in  diameter;  inner  membrane  16  to  34/f, 
presenting  at  each  pole  a  more  or  less  conspicuous  mammillate  projection 
provided  with  filamentous  appendages.  The  adults  are  found  especially 
in  the  upper  two-thirds  or  three-fourths  of  the  ileum. 

Source  of  Infection. — Hymenolepis  nana  fraferna  develops  in  rats  with- 
out any  intermediate  host;  the  eggs  escape  in  the  faeces,  and  when 
swallowed,  the  onchosphere  (embryo)  bores  into  the  villi  of  the  intestine, 
where  it  develops  within  a  few  days  into  a  larva  (cercocystis) ;  the  latter 
reaches  the  lumen  of  the  intestine  and  develops  into  the  adult  strobila. 
If  the  form  in  rats  is  identical  with  H.  nana,  man  probably  receives  his 
infection  from  food  soiled  by  the  excrements  of  rats  and  mice.  The 
large  number  of  specimens  sometimes  found  in  man  would  at  least  indi- 
cate that  H.  nana  probably  develops  in  the  manner  described  for  the 
form  that  occurs  in  rats;  auto-infection  seems  highly  probable. 

Frequency. — This  parasite^  is  unquestionably  much  more  common 
than  is  generally  supposed,  and  indications  are  not  lacking  that,  in  certain 

^H.  murina  (Dujardin,  1845). 

2  From  the  hygienic  point  of  view  this  assumption  must  be  made  until  the 
zoological  points  in  question  are  definitely  settled;  applied  zoology  is  of  course 
dependent  upon  theoretical  zoology,  but  in  doubtful  cases  we  must  be  more  con- 
servative in  applied  than  in  abstract  science.  The  WTiter  considers  the  form 
from  rodents  entitled  to  at  least  subspecific  rank. 

^Synonyms. — (?)  Tcenia  Tnwnna  Dujardin,  1845  (not  T  murina  Gmelin,  1790; 
Cysticercus  fasciolaris  Rudolphi);  T.  nana  Siebold,  1852  (not  VanBeneden,  1858) ; 
Hymenolepis  nana  (Siebold)  Blanchard,  1891;  H.  murina  (Dujardin)  Blanchard 
1891;    "Hymenolepsis"  nana  of  Osier,  1895,  and  other  authors  (misprint) 

*_For  a  complete  discussion,  in  English,  of  the  three  species  of  Hymenolepis 
which  occur  in  man,  together  with  summary  of  cases,  see  Ransom,  1904,  pp. 
1-138,  figs.  1-130.  Bulletin  18,  Hygienic  Laboratory,  U.  S.  Public  Health  and 
Marine  Hospital  Service,  Washington. 


TMNIASIS—CESTODE  INFECTION 


665 


parts  of  the  world,  at  least,  it  is  the  most  common  tapeworm  of  man. 
The  author  found  it  in  4  cases  (2.5  per  cent.)  of  about  160  persons 
examined  between  Richmond,  Va.,  and  Florida;  his  assistants  found  it 
in  6  cases  (4.8  per  cent.)  of  123  children  in  a  Washington  orphanage. 
Calandruccio  estimates  that  in  Sicily  10  per  cent,  of  the  children  are 
infected.  In  Germany,  the  parasite  does  not  appear  to  be  common,  so 
far  as  can  be  judged  from  existing  statistics.  It  has  been  found  in  patients 
from  under  five  to  over  fifty  years  of  age  but  is  more  common  in  children 


Fig.  45. 


Fig.  46. 


Egg  of  H ymenolepis  nana  as 
seen  in  fresh  faeces,  enlarged. 
( Ransom ,  from  Stiles. ) 

from  five  to  ten  years  old,  and  in  boys  than  in  girls. 
Crowded  conditions,  as  in  dormitories  of  orphan 
asylums,  seem  to  be  favorable  to  the  spread  of  the 
parasite,  which  is,  further,  more  common  in  poorer 
than  in  well-to-do  families.  From  one  or  two 
specimens  to  several  thousand  worms  may  be 
found  in  a  patient. 

Duration. — The  length  of  life  of  the  individual 
parasite  is  not  definitely  established,  but  infections 
have  been  reported  as  lasting  from  two  months  to 
two  and  one-half  years. 

Special  Medical  Significance. — Although  this 
is  a  small  tapeworm  it  seems  a  serious  error  to 
assume  that  it  is  of  no  significance.  Light  infec- 
tions do  not  appear,  per  se,  to  be  of  much  symp- 
tomatic importance,  but  they  may  lead  to  heavy 
Head  and  strobila  of  dwarf  infections  productive  of  pronounccd  symptoms. 

tapeworm,        (Hymenolepis  ggg        539^      rpj^g    Jo^g^l    Icsious    produced   by  the 
nana),  enlarged.  (Leuckart.)  ^  .,  ,       ,         t    1  ,  1    -i\,r-  •    • 

parasite  seem  to  be  slight,  and  iVlmgazzim  sug- 
gests that  the  symptoms  are  due  to  a  toxin  eliminated  by  the  worm. 

Treatment. — Male  fern  is  the  only  remedy  which  has  thus  far  been 
useful  in  expelling  this  worm,  while  cusso,  kamala,  santonin,  thymol,  and 
pomegranate  have  failed  in  the  cases  in  w^hich  these  drugs  were  tried. 

Prevention. — On  the  assumption  that  H.  nana  in  man  is  specifically 
identical  with  the  small  tapeworm  of  rats  and  mice,  the  most  important 
point  in  prevention  lies  in  protecting  food  from  these  rodents.  If  a 
person  is  found  to  be  infected,  he  should  occupy  a  separate  bed  until  fully 
cured. 


566 


THE  ZOO-PARASITIC  DISEASES  OF  MAN 


Hymenolepis  diminuta'  (Rudolphi,  1S19),  the  flavopunctate  tape- 
worm of  rats,  occasionally  occurs  in  man.  It  measures  10  to  60  mm. 
long  by  2.5  to  4  ram.  in  maximum  breadth,  and  is  composed  of  800  to 
1,300  segments.  The  head  is  unarmed;  3  testicles  are  present  in  each 
segment,  and  the  genital  pores  are  unilateral.  The  eggs  are  round  to 
oval;  the  outer  membrane  (56  to  80/i)  may  be  radially  striated; 
the  inner  membrane  measures  24  to  40  by  20  to  30/«.  The  larval 
stage  lives  in  insects,  such  as  the  larva  and  adult  of  meal  moths,  ear- 


FiG.  47. 


Fi<3.  48. 


Gravid  segment  of  H.  diminuta,  enlarged.     (Grassi.) 


Egg  of//,  diminuta  from  man, 
greatly  enlarged.  (Bizzozero.) 


wigs  and  in  adult  beetles.  Of  the  12  cases  thus  far  reported  for  man, 
3^  are  recorded  for  the  United  States,  2  for  South  America,  and 
7  for  Europe. 

Hymenolepis  lanceolata^  (Bloch,  1782),  the  lanceolate  tapeworm  of 
ducks  and  geese,  has  been  reported  once  (in  Germany)  for  man.  This 
worm  is  supposed  to  pass  its  larval  stage  in  small  crustaceans  belonging 
to  the  family  Cydojndcc. 

Davainea  madagascariensis  (Davaine,  1869)  is  known  only  for  man, 
and  has  been  reported  9  or  10  times  (Comoro  Islands,  Mauritius, 
Siam,  Nossi-Be,  British  Guiana),  chiefly  in  children.  It  measures  25  to 
30  cm.  long  and  is  composed  of  500  to  600  segments  which  attain  2  mm. 
long  by  1.4  mm.  broad;  head  with  large  round  suckers,  rostellum  with 
90  hooks;  genital  pores  unilateral;  calcareous  corpuscles  present;  about 
50  testicles  present;  eggs  with  2  clear  shells,  the  outer  possessing  2 
mammillate  projections;  eggs  collect  in  300  to  400  egg-balls.  The 
intermediate  host  is  unknown  but  Blanchard  has  suggested  that  possibly 
the  cockroach  (Blatta  orieyitalis)  plays  this  role. 

Davainea  asiatica  (Linstow,  1901)  was  found  once  in  Aschabad, 
Asiatic  Russia.  The  scolex  is  unknown,  but  the  anatomy  of  the  fragment 
indicates  that  the  worm  is  a  Davainea;  it  measures  298  mm.  long  by  0.16 
to  0.99  mm.  broad  and  possesses  about  750  segments;  calcareous  cor- 
puscles absent;    genital  pores  unilateral;    ventral  canals  very  large;    all 

^Synonyms. — Tcenia  diminuta  Rudolphi,  1819;  Hymenolepis  flavopunctata 
Weinland,  1858;  Hymenolepis  diminuta  (Rudolphi,  1819)  Blanchard,  1891; 
"Hymenolepsis"  flavopunctata  of  Osier,  1895,  and  other  authors  (misprint). 

^Two  additional  cases,  recently  recognized  in  Arkansas  and  in  Nebraska,  are 
knowTi  to  the  writer. 

^Synonym.s. — T  lanceolata  Bloch,  1872;  Hymenolepis  (Dilepis)  lanceolata 
(Blocb,  1782)  Weinland,  1858. 


T^NIASIS—CESTODE  INFECTION 


567 


eggs 


Fig.  49. 


genital  organs  are  developed  at  70  mm.  from  anterior  end.    The 
collect  in  68  to  70  egg-balls. 

Dipylidium  caninum^  (Linnaeus,  1758),  the  double-pored  dog-tape- 
worm, has  been  reported  for  man  (chiefly  children),  about  25  times, 
at  least  2  of  the  cases  being  recorded  in  American  literature.  It 
measures  15  to  30  cm.  in  length  by  1.5  to  3  mm.  in  maximum  breadth. 
The  head  is  armed  with  hooks  and  there  are  2  sets  of  genital  organs  to 
each  segment.  It  is  a  very  common  parasite  in  dogs  and  cats,  and  the 
larval  stage  lives  in  dog  lice  {Trichodectes  canis),  the  dog  flea  {Cieno- 
cephalus  canis)  and  the  human  flea  {Pulex  irritant). 

The  Broad  Tapeworm.^ — DibothriocepJialus  latus. — Geographical  Dis- 
tribution.— The  general  rule  may  be  laid  down  that  this  parasite  is  more 
common  in  the  vicinity  of  large  bodies  of  water  (as  in  lake  regions)  than 
in  regions  of  other  topography.  It  is  reported  as 
especially  common  in  Europe  for  the  Russian  Baltic 
provinces,  Finland,  Sweden,  Denmark,  North  East 
Prussia,  Switzerland,  and  Northern  Italy,  but  it 
occurs  also  elsewhere,  as  in  Belgium,  Holland,  Ire- 
land, Northern  France,  etc.  It  is  common  in  Japan 
and  Turkestan,  and  is  reported  for  Iceland,  N'gami 
Lakes  (Africa),  Madagascar,  South  Africa,  and  the 
United  States.  It  bids  fair  to  become  almost  cosmo- 
politan, following  the  fresh  water  fish  diet. 

Zoological  Distribution. — The  adult  worm  occurs 
in  man,  cats,  dogs,  and  foxes  (rare).  The  larval  stage 
(a  "plerocercoid")  attains  a  length  of  30  mm.  and 
is  found  in  the  muscles  and  various  organs  of  fresh-water  fish,  particu- 
larly in  the  pike,  ling  or  burbot,  perch,  and  several  members  of  the 
salmon  family. 

Fig  50. 


Egg  of  Dipylidium  can- 
inum.  Note  the  six 
hooks  in  the  embryo, 
greatly  enlarged. 
(Stiles.) 


Gravid  segment  of  D.  latus,  showing  the  rosette  uterus  in  the  median  line.    X  6.  (Leuckart.) 


The  Parasite. — Dibothriocephalus  latus^  (Linnaeus,  1758)  attains  2  to 
9  or  10  meters  in  length  by  20  mm.  in  maximum  breadth;  it  is  usually 
grayish-yellow  to  brown  in  color,  and  composed  of  3,000  to  4,200  segments. 


^Synonyms. — Taenia  canina  Linnseus,  1758;  T.  moniliformis  Pallas,  1781;  T. 
cucumerina  Bloch,  1782;  T.  elKptica  Batsch,  1786;  T.  (Dipylidium)  cucumerina 
of  Leuckart,  1863.  ' 

2 Synonyms. — Taenia  lata  Linnaeus,  1758;  T.  vulgaris  Linnaeus,  1758;  Both- 
riocephalus  latus  (Linnaeus)  Bremser,  1819;  Dibothrium  latum  (Linnaeus)  Diesing, 
1850;  Bothriocephalus  cristatus  Dsivaine,  1873;  Dibothriocephalus  latus  (Linnseiis) 
Luehe,  1899. 


5C8  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

which  are  usually  broader  than  lonp;,  especially  in  the  anterior  two-thirds 
of  the  strobila;  posterior  segments  become  quadrate  or  even  longer  than 
broad,  and  are  especially  characterized  by  the  rosette  spot  (uterus)  in  the 
centre;  genital  pores  ventromedian;  eggs  68  to  71  by  45/i,  with  distinct 
operculum;  laid  during  segmentation. 

Source  of  Infection. — This  tapeworm  is  contracted  by  eating  raw  or 
under-done  fish,  see  p.  567. 

Frequency. — About   .30    cases    of    infection    with   this   parasite  have 
been  recognized  for  the  United  States,  chiefly  among  foreigners.    In  some 
P  ,  .  parts  of  Eurojie  it  is  reported  as  the  most  common 

tapeworm  of  man,  the  frequency  varying  from  0.8 
to  10,  20  and,  locally,  even  to  more  than  .50  percent, 
of  the  poi)ulation.  In  Turkestan  and  Japan  it  is 
the  most  common  tapeworm  of  man.  Very  prob- 
ably it  will  become  more  commonly  known  in  the 
United  States,  for  now  that  special  attention  has 
been  recently  directed  to  it  in  several  American 
medical  journals,  it  will  be  moi'e  frequently  recog- 
nized and  further  it  is  highly  probable  that  immi- 
Egg  of  D.iatus.  X400.  grants  will  infect  the  fish  of  some  of  our  lake 
(Looss.)  regions.    It  is  observed  more  commonly  in  adults 

but  may  develop  in  persons  of  any  age. 
Duration. — The  growth,  after  infection,  is  very  rapid.  According  to 
Braun,  the  average  daily  increase  for  the  first  five  weeks  is  31  to  32 
segments,  involving  8  to  9  cm.  increase  in  length;  Zschokke  found  the 
average  daily  increase  in  length  to  be  5.2  to  8.2  cm.;  eggs  may  appear  in 
fseces  twenty-four  days  after  infection.  Cases  have  been  recorded  of 
fourteen  years  duration  (Mosler). 

Special  Medical  Significance. — The  special  medical  significance  of 
infection  with  the  broad  tapeworm  is  the  tendency  to  development  of 
a  severe  anremia  (Reyher,  1886,  etc.)  resembling  pernicious  anaemia. 
Retinal  hemorrhages  have  been  reported  in  50  per  cent,  of  certain  cases 
studied.  This  anaemia  is  attributed  by  most  authors  to  a  toxin,  supposed 
to  be  eliminated  by  the  parasite,  and  a  lethality  as  high  as  16  per  cent, 
has  been  reported  by  one  author.  Schauman  (1894)  found  the  red  cor- 
puscles reduced  to  an  average  of  1,311,000  (in  males)  and  1,273,000  (in 
females)  in  38  out  of  72  cases;  he  also  found  elevated  temperature  (99° 
to  104°  F.)  in  81  per  cent,  of  his  cases;  the  pulse  is  usually  full,  often 
accelerated  to  90  or  120. 

Clinical  Diagnosis. — There  should  be  little  or  no  difficulty  in  diagnosing 
cases  of  this  infection.  As  the  uterus  has  a  special  uterine  pore,  eggs  are 
constantly  discharged  from  gravid  segments  and  may  be  found  in  the 
fseces  by  microscopic  examination.  The  segments  show  a  tendency  to 
be  passed  in  small  chains  and  ought  not  to  be  confused  with  those  of  the 
other  tapeworms  found  in  man. 

Prevention. — Faeces  of  persons  harboring  this  worm  should  be  cared 
for  in  such  a  way  that  the  eggs  contained  therein  do  not  gain  access  to 
fresh-water  streams  or  lakes.  Thorough  cooking  of  fish  will  protect  man 
from  infection. 

Ward  (1906)  has  recently  reported,  but  not  yet  described,  a  new 
bothriocephalid  tapeworm  as  occurring  in  the  United  States. 


TJENIASIS—CESTODE  INFECTION  509 

Dibothriocephalus  COrdatUS^  (Leuekart,  18G3)  is  reported  in  Green- 
land for  man,  dogs,  bearded  sea],  and  walrus.  Its  reported  introduction 
into  the  vicinity  of  Dorpat  and  Berlin  (Prussia)  is  based  upon  an  error  of 
zoological  determination.  It  measures  80  to  115  cm.  long  with  a  maxi- 
mum breadth  of  7  to  8  mm.  and  is  composed  of  about  GOO  segments; 
uterus  with  6  to  8  lateral  loops  each  side;  the  head  is  heart-shaped;  neck 
absent;  eggs  75  to  80  by  50/i.     It  is  probably  contracted  by  eating  fish. 

Diplogonoporus  grandis  (Blanchard,  1894)  has  been  found  twice  in 
Japan.  It  may  attain  10  meters  in  length,  by  25  mm.  in  maximum 
breadth.     It  is  similar  to  Dibothriocephalus,  but  with  fig.  52. 

2  complete  sets  of  genital  organs  to  each  segment.  The 
eggs  are  brownish,  rather  opaque,  63  by  48  to  50//.. 
The  source  has  not  been  demonstrated  but  infection 
probably  takes  place  through  eating  fish. 

Ashford,  King  and  Gutierrez  (1904,  p.  92)  report 
1  case  of  this  infection  in  Porto  Rico  but  as  the  deter- 
mination was  made  solely  upon  the  eggs  in  the  stools 
while  the  adult  parasite  was  not  seen,  legitimate  doubts 
may  arise  regarding  the  correctness  of  the  zoological     ,  .  _ 

■,''•.■  An  egg  oiD.  grandis 

determmation.  _  ^  _  taken   from   the 

Symptoms. — Irregular  appetite  with  occasional  pains        uterus.  x44  0. 
extending  from  the  region  of  the  stomach  to  the  back;        (ijima   &   Kuri- 
intestinal  disturbance   indicated    by    diarrhoea,    colic,        moto.) 
and  constipation;    anaemia;    poorly  nourished  condition,  weakness,  and 
inclination  to  faint.^ 

General  Symptoms  of  Intestinal  Tasniasis.— In  connection  with  the 
various  species  of  tapeworm  found  in  man,  reference  has  been  made  to  the 
special  medical  significance  of  each  form.  In  regard  to  the  general 
clinical  picture  presented  by  patients  harboring  tapeworms,  one  noted 
clinician  has  remarked  that  its  chief  characteristic  is  its  lack  of  anything 
characteristic.  That  a  person  may  harbor  a  tapeworm,  especially  one  of 
the  smaller  species,  and  be  unaware  of  the  fact,  cannot  be  doubted;  and 
this  fact  has  led  more  than  one  person  to  minimize  the  importance  of 
cestode  infection.  On  the  other  hand,  that  tapeworm  infection  may  result 
in  severe  symptoms  is  equally  well  established,  for  in  numerous  cases  such 
symptoms  have  disappeared  with  the  expulsion  of  the  parasite;  and  this 
fact  has  led  some  observers  to  exaggerate  its  importance.  We  shall 
probably  follow  a  justified  mean  between  these  extremes  if  we  consider 
that  the  severity  of  the  symptoms  varies  with  the  species  of  tapeworm 
present,  with  the  number  of  the  parasites,  and  with  the  age  and  general 
physical  and  nervous  condition  of  the  infected  person.  The  injury  is 
attributed  to  the  following  factors  in  particular :  mechanical  obstruction, 
injury  or  irritation  to  the  intestinal  mucosa,  loss  of  food  which  goes  to  the 
parasite  instead  of  to  the  host,  and  toxins  produced  by  the  worms. 

The  appetite  varies;  it  may  be  decreased,  increased  to  a  point  of  in- 
satiability or  the  two  conditions  may  alternate;  Hirsch  reports  loss  of 
appetite  in  6  per  cent,  of  cases,  bulimia   in   10   per  cent.,  capricious 

1  Synonym. — BothriocepJmlus  cordatus  Leuekart,  1863. 

2  For  an  account  of  this  worm,  in  English,  see  Stiles  and  Taylor,  1902, pp.  43-47 
figs.  22-28.     Bulletin  29,  U.  S.  Bureau  Animal  Industry. 


670  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

appetite  in  other  cases/  Seeger  records  irregular  appetite  or  bulimia  in 
31  per  cent,  (selected  cases). 

Salivation  is  often  mentioned;  Hirsch  records  it  for  6  per  cent.  Eruc- 
tation finds  frequent  mention;  Hirsch  reports  it  for  5  per  cent.  Nausea 
is  common;  Hirsch  re])orts  it  in  13  per  cent.;  Seeger  reports  frequent 
nausea,  with  vomiting  or  feeling  of  faintness  in  49  per  cent.  Vomiting 
may  occur,  and  in  some  instances  the  tapeworm  or  portions  of  it  have  been 
vomited;  this  is  of  course  })articularly  dangerous  if  the  worm  is  Toenia 
solium;  Hirsch  reports  matitudinal  vomiting  in  1  per  cent.,  frequent  vomit- 
ing in  12  per  cent. 

Abdominal  pains  are  very  commonly  complained  of:  they  may  be  of  the 
nature  of  colic  or  of  gastralgia;  they  are  referred  to  different  parts  of  the 
abdomen,  are  of  varying  severity,  sometimes  intermittent;  there  may  be 
borborygmi,  a  sense  of  distortion  or  twisting  in  the  bowels,  or  a  sensation 
of  a  ball  or  weight  rolling  around  in  the  abdomen  following  the  movements 
of  the  body.  In  experimental  infection  on  myself  the  most  pronounced 
and  common  symptom  -vvas  that  peculiar  sensation  one  often  has  upon 
the  sudden  descent  of  an  elevator;  this  occurred  particularly  while 
walking.  Huber,  in  experiments  upon  himself,  experienced  a  gnawing 
sensation  in  the  epigastrium.  The  colic-like  pains  may  increase  after 
certain  foods  (herring,  onion,  garlic,  and  sour  foods)  or  decrease  after 
milk,  eggs,  and  oily  foods  (Hemmeter,  1902).  Seeger  reports  abdominal 
pains  of  various  sorts  in  42  per  cent.,  and  peculiar  sensations  of  move- 
ments in  the  abdomen  in  16  per  cent.,  acute  colic,  17  per  cent.;  Hirsch 
reports  abdominal  pains  as  common,  colic  in  14  per  cent.  Digestive 
troubles  are  reported  by  nearly  all  authors.  Constipation  (5  per  cent., 
Hirsch),  diarrhoea  (6  per  cent.,  Hirsch)  or  irregularity  of  bowels  (3  per 
cent.,  Hirsch)  may  obtain.  Seeger  reports  digestive  troubles  and  irregu- 
larity of  bowels  in  33  per  cent. 

Anremia  is  most  likely  to  occur  in  infections  with  Dibothriocephalus 
latus,  less  likely  with  Taenia  saginata  and  is  said  by  some  authors  not  to 
occur  with  TcBjiia  solium.  Hirsch  reports  ansemia  in  1  per  cent.,  chlor- 
osis, 1  per  cent.,  paleness,  4  per  cent.,  icterus,  2  per  cent. 

Unequal  pupils  are  very  commonly  recorded;  disorders  in  vision,  as 
narrowing  of  visual  field,  amaurosis,  monocular  polyopia,  are  on  record. 
Ringing  or  humming  in  the  ears,  disturbances  in  hearing,  and  deafness 
are  mentioned.  Headache  is  more  or  less  common  (14  per  cent.,  Hirsch) ; 
Seeger  reports  periodical  and  habitual  headache,  usually  unilateral  (19 
per  cent.)  and  vague  pains  in  different  parts  of  body  (11  per  cent.)  Itch- 
ing and  dryness  of  the  nose  and  epistaxis  are  more  or  less  common. 
According  to  Davaine,  anal  pruritis,  like  nasal  pruritis,  may  be  attri- 
buted to  a  sympathetic  influence  but  is  usually  due  to  irritation  of  the 

iThe  statistics  quoted  from  Cobbold  (lS83a),  Hirsch  (1879),  and  Seeger  (1852), 
are  based  upon  infections  with  large  tapeworms  and  to  a  certain  extent  represent 
selected  cases.  Ransom  (1904)  has  published  a  very  instructive  compilation  of 
the  symptoms  reported  for  49  cases  of  infection  with  the  dwarf  tapeworm; 
the  reader  is  referred  to  Ransom's  paper  for  details  since  so  many  complex 
factors  enter  into  consideration  that  to  quote  these  details,  not  all  taken  from 
one  observer,  in  comparison  with  the  statistics  quoted  for  the  large  tapeworms, 
would  require  a  lengthy  discussion  extending  beyond  the  limits  prescribed  for  this 
article.  In  general  it  may  be  said  that  the  same  sjonptoms  recorded  for  the  large 
tapeworms  may  occur  also  in  connection  with  the  dwarf  tapeworm. 


T^NIASIS—CESTODE  INFECTION  571 

lining  of  the  lower  part  of  the  intestine  produced  by  contact  and  move- 
ment of  detached  segments;  nasal  pruritis  (12  per  cent.,  Hirsch)  is  less 
frequent  than  anal  pruritis  (19  per  cent.,  Hirsch)  but  it  is  rare  (Davaine) 
that  a  patient  has  neither. 

Emaciation  is  common  when  the  infection  is  of  long  standing  and  may 
be  accompanied  by  bloating  and  distension  of  the  abdomen.  There  may 
be  gradual  loss  of  strength  (4  per  cent.,  Hirsch),  a  general  and  continued 
weariness  (4  per  cent.,  Hirsch),  or  weakness,  especially  in  the  knees  (2  per 
cent.  Hirsch) ;  cramps  and  pains  in  the  limbs  may  be  severe  enough  to 
interfere  with  the  usual  occupation  (Davaine).  Disturbed  sleep  is  com- 
mon; complete  insomnia  or  abnormal  sleepiness  may  be  present  in  about 
1  per  cent.  (Hirsch) ;  insomnia  may  be  persistent.  Vertigo,  which  many 
authors  mention,  Seeger  records  in  15  per  cent.,  Hirsch  in  16  per  cent. 
Epileptiform  attacks  {epilepsia  tceniosa)  are  mentioned  by  a  numVjcr  of 
authors;  the  symptom  is  rare,  1  per  cent.  (Hirsch),  and  may  occur  in 
patients  as  young  as  three  years  (Comby) ;  the  attacks  do  not  attain  the 
severity  of  true  epilepsy;  the  aura  is  of  long  duration,  the  convulsions 
may  last  ten  to  fifteen  minutes  and  the  stage  of  coma  is  equally  long;  all 
stages  are  more  prolonged  than  in  ordinary  epilepsy  (Comby)  and  there 
is  a  tendency  to  periodicity  (Martha,  1892). 

Among  other  symptoms  reported  are:  chorea,  2.3  per  cent 
(Cobbold);  severe  manifestations  of  convulsive  nature,  2  per  cent 
(Hirsch);  convulsive  fits  (Cobbold,  1  in  130);  loss  of  memory;  momen- 
tary loss  of  speech;  failure  and  derangement  of  speech,  1  per  cent 
(Seeger)  and  of  special  senses,  15  per  cent.  (Seeger) ;  cough;  weaken- 
ing of  mental  faculties;  loss  of  consciousness,  2  per  cent.  (Hirsch) 
hysteria;  paralysis;  tremors;  pyrosis,  8  per  cent.  (Hirsch);  cardiac 
palpitation,  6  per  cent.  (Hirsch);  urticaria  chronica  (Heffter,  1855a) 
herpes  (Bigelow,  1848a);  pleuritis-like  conditions  (Beauchamp,  1876a); 
etc. 

Treatment.^ — In  considering  the  advisability  and  the  time  of  treatment 
emphasis  may  again  be  laid  upon  the  point  that  if  Tcenia  solium  is  pres- 
ent, especially  in  patients  with  a  tendency  to  vomit,  no  unnecessary  time 
should  be  lost  in  expelling  the  worm;  in  case  of  infection  with  any  of  the 
other  species  mentioned,  prompt  treatment  is  advisable  on  general  prin- 
ciples but  a  postponement  for  a  few  days  or  even  a  few  weeks  or  months  to 
suit  the  convenience  of  the  patient  or  physician,  is  of  less  serious 
moment.  During  such  period,  however,  the  patient  should  have  a  care 
not  to  defecate  in  any  place  where  the  eggs  in  his  discharge  can  gain  access 
to  the  intermediate  host. 

Special  precautions  are  to  be  taken,  or  the  treatment  is  to  be  indefinitely 
postponed,  according  to  circumstances,  in  cases  of  pregnancy,  or  in 
patients  especially  debilitated  from  other  cause  than  taeniasis,  and  in 
convalescence,  tuberculosis,  and  cancer. 

Having  decided  upon  treatment,  three  points  in  particular  are  to  be 
held  in  mind:  (1)  the  clearer  the  bowels  are  the  better  the  chances  for 
expelling  the  parasites;  (2)  the  older  the  drugs  the  less  are  the  chances 
for  success ;  (3)  the  tapeworm  is  an  animal  with  a  highly  organized  ner- 
vous system.  Corresponding  to  these  important  facts,  there  are  three 
periods  in  treatment: 

^  See  also  remarks  under  the  various  species  discussed. 


572  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

1.  Preparatory  Treatment. —  Place  the  patient  on  a  light  diet  for  two 
or  three  days,  avoiding  bread  and  vegetables  and  such  food  as  is  likely  to 
increase  the  fnecal  material;  allow  chiefly  liquid  diet,  milk,  broths,  eggs, 
etc.  jSIany  physicians  {prefer,  not  without  good  reason,  to  withhold  food 
absolutely  for  twenty-four  hours  immediately  preceding  the  administra- 
tion of  the  anthelmintic.  At  the  same  time  give  a  mild  laxative,  such  as  a 
few  doses  of  sulphate  of  soda,  or  a  teaspoonful  of  compound  licorice 
powder  in  water  in  the  mornings,  and  take  every  precaution  to  empty  the 
bowels  thoroughly,  as  by  a  saline  purgative  the  night  before  the  anthel- 
mintic treatment,  and  encmata  the  night  before  and  the  morning  of  treat- 
ment. The  object  of  this  is  twofold:  the  smaller  amount  of  contents  in 
the  small  intestines  the  less  the  tapeworm  is  protected  from  the  drug; 
and  if  the  worm  meets  with  an  obstruction  as  it  descends,  it  may  have  a 
chance  to  recover  its  hold  and  thus  remain  in  the  intestines.  Some  auth- 
ors advise  a  salad  of  dried  herring,  garlic,  and  onions  the  night  before 
treatment. 

2.  Anthelmintic  Period. — Early  in  the  morning,  following  the  period 
of  preparation,  coffee  may  be  allowed  but  no  solid  food.  Then  take  any 
one  of  the  standard  tseniafuges,  provided  it  is  fresh.  For  the  comfort  of 
the  patient  it  is  well  for  him  to  remain  in  bed  or  on  a  couch  during  this 
period,  as  various  disagreeable  symptoms  (syncope,  vertigo,  vomiting) 
may  otherwise  arise. 

Of  the  numerous  tapew^orm  remedies,  certain  are  recognized  as  more 
or  less  standard  but  it  ^vould  be  difficult  to  obtain  a  great  majority  vote 
for  any  one  of  them  to  the  exclusion  of  the  others.  The  following  are 
among  those  which  are  most  popular: 

Male  fern-}  This  is  perhaps  the  most  commonly  used  drug  in  this 
country  and  parts  of  Europe  for  the  expulsion  of  Toenia  and  Dibothrio- 
cephalus.  In  Europe  larger  doses  are  administered  than  in  America. 
Its  oleoresin  or  ethereal  extract  is  usually  given  and  should  be  fresh.  The 
dose  is  2  to  8  grams  (^  to  2  drams)  either  in  a  simple  syrup 
or  in  gram  gelatine  capsules,  which  may  be  coated  with  keratin  in 
order  to  prevent  their  solution  in  the  stomach  and  thus  have  the  drug 
reach  the  worm  in  more  concentrated  form;  the  capsules  are  taken  at 
intervals  of  about  fifteen  minutes.  In  an  overdose,  male  fern  is  a  distinct 
poison  and  it  is  reported  that  24  grams  (6  drams)  have  caused 
death.  Some  authors  advise  that  the  dose  should  never  exceed  10  grams 
(2^  drams),  w'hile  others  maintain  that  doses  higher  than  8  grams 
(2  drams)  are  both  unnecessary  and  not  devoid  of  danger.  Authors 
also  advise  against  its  administration  two  days  in  succession  and 
on  an  absolutely  empty  stomach.  Some  authors  advise  its  administra- 
tion in  pills.  The  last  dose  should  be  followed  in  thirty  to  sixty  minutes 
by  a  full  dose  of  salts  (as  magnesium  sulphate)  or  calomel  and  salts, 
rather  than  with  oil  which  increases  its  absorption. 

Cusso  {or  Kosso,  or  Kousso) . — This  drug  is  used  most  frequently  in  cer- 
tain parts  of  Africa  and  is  highly  recommended  by  several  prominent 
authors.    It  must  be  quite  fresh.    Heller  prefers  it,  and  Tyson  (1903) 

^For  the  properties  and  chracteristics  of  this  and  other  drugs  mentioned,  the 
reader  is  referred  to  the  pharmacopoeia  and  works  on  therapeutics  and  materia 
medica,  as  a  detailed  discussion  of  these  points  cannot  be  given  in  this  short 
article. 


T^NIASIS—CESTODE  INFECTION  573 

says  that  in  his  hands  cusso  "has  been  decidedly  the  most  efficient" 
remedy.  It  should  never  be  given  in  case  of  pregnancy.  Dose  20^ 
grams  (5  drams)  for  Taenia  solium,  30  grams  (7.5  drams)  for  T.  sarjinata. 
There  are  several  "best"  methods  of  administering  it.  One  is  to  make 
an  infusion  in  240  Cc  (8  ounces)  of  water;  a  more  pleasant  method  is  to 
give  5  grams  (75  grains)  in  a  glass  of  white  wine  every  half  hour  until 
four  doses  are  taken;  or  it  may  be  mixed  with  honey,  enclosed  in  cap- 
sules, compressed  into  tablets,  or  combined  with  male  fern. 

Generally  this  requires  no  purgative  but  if  no  movement  of  the  bowels 
has  taken  place  after  six  hours,  castor  oil,  compound  jalap  powder,  or 
elaterium  is  given. 

Kamala. — Kamala  is  administered  in  doses  of  4  to  8  grams  (1  to  2 
drams),  in  syrup  or  cinnamon  water,  sweetened  coffee  or  tea,  or 
the  fluid  extract  (2  to  4  Cc. — |  to  1  dram)  is  given.  It  is  a  purgative  and 
may  cause  nausea,  vomiting,  and  griping. 

Bark  of  Fresh  Pomegranate  Root. — This  is  given  third  place  by  Tyson. 
Hemmeter  advises  50  grams  (If  ounces),  macerated  for  twenty-four  hours 
in  500  Cc.  (16  ounces)  of  water;  then  evaporate  down  to  250  Cc.  (8  ounces) 
and  add  syrup  of  orange  peel,  30  grams  (1  ounce);  to  be  taken  in  two 
parts.  It  often  causes  nausea,  giddiness  or  faintness.  The  fluid  extract, 
2  to  8  Cc.  (i  to  2  drams)  is  a  more  convenient  dose. 

Pelletierine,  an  alkaloid  prepared  from  pomegranate,  is  especially  pop- 
ular in  France.  It  is  given  in  doses  of  0.3  to  1.3  grams  (5  to  20  grains). 
Tanret's  preparation  is  the  most  popular  but  none  except  fresh  im- 
portations should  be  used.  The  efficacy  of  the  tannate  is  said  to  be 
increased  and  its  toxic  action  diminished  by  preceding  it  with  a  few 
grains  of  tannic  acid. 

Pomegranate  preparations  should  be  followed  within  an  hour  by  a 
brisk  cathartic.  Some  authors  give  half  an  ounce  of  magnesium  sulphate 
twenty  minutes  before  and  the  same  dose  twenty  minutes  after  the  pel- 
letierine. 

Decorticated  Pum'pkin  Seed. — This  is  an  old  and  rather  popular  rem- 
edy, which  has  been  known  to  expel  Tcenia  saginata  when  the  foregoing 
drugs  have  repeatedly  failed;  it  is  the  safest  and  a  good  drug  for  children. 
Tyson,  however,  places  it  below  the  foregoing  in  efficiency.  It  is  given 
in  various  ways: 

(a)  30  to  120  grams  (1  to  4  ounces)  of  the  seed  are  crushed  and  given 
in  a  strained  emulsion  followed  by  a  brisk  purgative. 

(&)  The  seeds  are  made  into  an  electuary,  "which  is  almost  as  pleasant 
as  sugar  candy,  and  often  about  as  effectual"  (Tyson,  1903). 

(c)  Seeds  are  carried  in  the  pocket  and  eaten  at  short  intervals  for  two 
or  three  days  till  the  worm  passes. 

Some  authors  advise  that  pumpkin  seed  be  preceded  by  castor  oil  or 
by  effervescent  magnesium  citrate,  this  to  be  repeated  two  hours  after 
the  anthelmintic  if  the  tapeworm  has  not  been  expelled. 

Santonin  is  advised  by  some  authors,  but  the  writer,  in  experiments 
upon  himself  (with  Tcenia  saginata)  found  it  useless.  Thymol  has 
been  recommended  by  various  authors,  but  in  laboratory  experiments 

1  Some  authors  advise  only  one-fourth  to  one-half  this  amount,  but  ■^Titers  who 
are  higli  in  the  praise  of  cusso  give  large  doses. 


574  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

upon  clogs,  the  writer  has  failed  to  obtain  positive  results  (infection 
with  Dipylidium  ca7iinu7n) .  Naphthalin  has  its  admirers  (dose  0.1  to  0.6 
gram — 2  to  10  grains — followed  in  an  hour  by  a  cathartic).  Cocoanut 
has  been  gaining  in  repute;  the  entire  milk  and  meat  of  one  cocoanut  is 
taken,  followed  by  a  purge. 

Chloroform,  oil  of  turpentine  (with  equal  or  twice  the  quantity  of  cas- 
tor oil),  zinc  filings  in  syrup,  oil  of  pine  needles,  and  various  other  drugs 
have  their  advocates.  As  one  of  the  curiosities  in  helminthology,  men- 
tion may  be  made  of  the  existence  of  a  patent  tapeworm  trap  which  the 
patient  is  directed  to  swallow;  the  tapeworm  is  suj^posed  to  put  its  head 
into  the  trap  which  is  then  induced  to  pass  from  the  bowels! 

3.  Expulsion. — The  patient  should  be  instructed  to  use  a  vessel  con- 
taining 'Warm  water  while  passing  the  worm  and  under  no  circumstances 
to  pass  it  into  a  water  closet,  a  privy,  or  a  cold  chamber.  If  the  worm 
comes  in  contract  with  a  cold  object,  while  a  ])ortion  of  its  body  is  still  in 
the  warm  intestines,  it  may  contract  so  suddenly  and  violently  as  to 
break;  the  head  may  thus  remain  in  the  bowels.  The  patient  should  be 
further  instructed  not  to  pull  on  the  worm,  should  this  be  coming  slowly, 
but  rather  to  use  injections  of  warm  water.  If  the  physician  is  pre- 
sent during  the  passage  of  the  worm,  the  parasife  is  sometimes  given 
an  injection  of  morphine.  Finally  the  patient  should  submit  the  entire 
stool  to  the  physician  for  examination.  Search  is  made  for  the 
head,  to  determine  whether  the  treatment  has  been  entirely  successful. 
Should  the  head  not  be  found,  it  is  still  possible  that  it  has  been  passed,  so 
that  it  is  unnecessary  to  repeat  treatment  until  (after  several  months) 
segments  or  eggs  again  appear  in  the  stools. 

Treatment  of  Children. — The  treatment  of  children  is  of  course  at- 
tended with  greater  difficulty  than  the  treatment  of  adults.  Comby  ad- 
vises cusso  10  grams  (2.5  drams),  or  decoction  of  fresh  pomegranate 
bark,  15  to  20  grams  (4  to  5  drams),  or  ethereal  extract  of  male  fern,  4  to  6 
grams  (1  to  1.5  drams),  or  pumpkin  seed  in  emulsion  50  to  60  grams  (1.66 
to  2  ounces).  Comby  gives  ethereal  extract  of  male  fern,  4  grams 
(1  dram)+essence  of  turpentine  1  gram  (15  minims)+syrup  of  orange 
flower  30  grams  (1  ounce) +peppermint  water  70  Cc.  (2.33  ounces); 
taken  at  one  dose  by  child  five  to  ten  years  old  and  followed  in  half  an 
hour  by  15  to  20  grams  (4  to  5  drams)  of  castor  oil  (see,  however, 
p.  562).  French  prefers,  for  children,  drugs  in  the  following  order: 
pumpkin  seed  mush,  cocoanut,  black  oxide  of  copper,  pelletierine. 


SOMATIC   T-ffiNIASIS. 

Somatic  tseniasis,  due  to  infection  with  the  larval  stage  of  tapeworms, 
may  be  of  three  kinds  (in  order  of  their  importance):  hydatid  disease, 
due  to  infection  with  the  larval  Echinococcus  granulosus;  cysticercosis, 
due  to  infection  with  the  larvai  Tmnia  solium,  known  as  Cysticercus  cellu- 
losos;  and  infection  with  bothriocephalid  larvae,  classified  as  Sparga- 
num  mansoni  and  S.  prolijerui.i. 

Cysticercosis  or  Infection  with  Larval  Taenia  Solium— Geograph- 
ical and  Zoological  Distribution. — See  p.  561. 


T^NIASIS—CESTODE  INFECTION  575 

The  Larval  Parasite. — In  the  early  days  of  helminthology,  what  we 
now  know  to  be  the  larval  stage  of  Toenia  solium  was  supposed  to  repre- 
sent a  distinct  species  of  animal,  to  which  the  name  Cysticercus  celluiosoB 
was  given.  This  larva  is  an  elliptical,  translucid,  bladder-like  structure, 
6  to  12  mm.  long  by  5  to  10  mm.  broad,  with  a  white  spot  at  its 
equator,  due  to  the  invaginated  head.  While  it  usually  agrees  with  the 
same  organism  as  found  in  hogs,  it  may  (particularly  when  located  in  the 
subarachnoidal  spaces)  grow  to  a  larger  size  and  assume  an  irregularly 
branched  form,  described  as  Cysticercus  raceviosus.  The  parasite  in- 
habits the  subcutaneous  connective  tissue,  muscles,  brain,  spinal  canal, 
eye,  heart,  lymphatic  glands,  tongue,  liver,  bones,  lungs,  kidney,  mam- 
mary gland,  or  prepuce,  producing  symptoms  which  vary  according  to  the 
location  and  number  of  parasites  present.  In  some  cases,  especially  in 
very  light  infections,  no  symptoms  may  be  observed  and  the  infection  is 
discovered  at  autopsy.  In  other  instances,  particularly  in  case  of  location 
in  the  brain  or  eye,  the  infection  is  of  more  importance  and  in  case  of 
cerebral  infection  it  may  result  fatally.  If  the  parasite  is  in  the  eye,  it  is 
more  Hkely  to  be  discovered  by  the  ophthalmologist  than  by  the  practicing 
physician,  so  that  in  an  article  of  this  kind  reference  to  the  infection  will 
suffice.  In  case  of  cerebral  infection  the  symptoms  are  varied  according 
to  the  exact  location;  in  case  of  continued  pain  in  the  head,  visual  dis- 
orders, mental  disorders,  with  depression  and  confusion  or  dizziness,  un- 
ilateral paralysis,  epileptiform,  subacute,  cumulative  spasms,  especially 
in  patients  over  forty  years  of  age,  and  showing  concurrent  adult  Twnia 
solium  in  the  intestine,  or  recent  history  of  such  intestinal  infection,  the 
possibility  or  even  probability  of  infection  with  the  larval  stage  should  be 
borne  in  mind. 

It  takes  about  three  months  for  the  parasite  to  develop  from  the  six- 
hooked  embryo  (onchosphere)  to  the  bladderw^orm  stage,  which  may  live 
in  man  as  long  as  twenty  years.  A  patient  may  harbor  from  one  to  several 
thousand  bladderworms,  the  heavy  infections  probably  representing  cases 
in  which  an  entire  segment  of  the  tapeworm  has  gained  access  to  the 
stomach  through  the  pylorus. 

There  is  no  medical  treatment;  Feletti  (1894a,)  however,  claims  good 
results  with  male  fern,  1  to  3  grams  (15  to  45  grains)  for  several  days. 
Surgical  interference  maybe  resorted  to  if  the  parasite  can  be  located.  A 
number  of  cases  of  extractions  of  bladderworms  from  the  eye  are 
recorded. 

Cysticercosis  is  decreasing  hand  in  hand  with  the  decrease  of  the  adult 
worm;  the  latter  is  decreasing  as  a  result  of  meat  inspection  and  better 
curing  and  cooking  of  pork. 

Cysticercus  hovis,  the  larval  stage  of  T.  saginata,  is  alleged  to  have 
occurred  in  man,  but  as  C.  cellulosce  may  lose  its  hooks  and  thus  resemble 
the  larval  stage  of  T.  saginata,  doubts  arise  regarding  the  correctness  of 
the  determinations. 

Cysticercus  acanthotrias  Weinland,  1858,  characterized  by  the  presence 
of  three  rows  of  hooks  on  the  head,  and  taken  as  the  type  of  a  special  genus 
Acanthotrias,  is  now  interpreted  as  simply  an  anomaly  of  C.  celluloses. 

Tcenia  hydatigena  (Batsch,  1786),  is  a  tapeworm  very  closely  aUied  to 
Toenia  solium,  wath  which  it  was  for  years  confused.  The  mature  worm 
lives  in  dogs;  the  larval  stage,  known  as  Cysticercus  temdcollis,  is  found 


576 


THE  ZOO-PARASITIC  DISEASES  OF  MAN 


in  cattle,  sheep,  liogs,  etc.,  and  is  reported  for  certain  monkeys;  the  cysti- 
cercus  has  also  been  reported  for  man  but  the  correctness  of  the  zoological 
determination  has  been  called  into  question. 

Echinococcosis:  Echinococcus  Disease;  Hydatid  Disease. — Geo- 
graphical Distribution. — This  infection  is  practically  cosmopolitan,  but 
is  i'i)und  es])ecially  in  Iceland,  certain  ])arts  of  Germany,  and  in  Aus- 
tralia. INIany  of  the  cases  rejiorted  for  the  United  States  have  occurred 
in  immigrants  who  were  doubtless  infected  before  they  came  here,  but 
we  also  have  the  ])arasite  as  ]>art  of  our  American  fauna. 

Zoological  Distribution. — The  adult  tapeworm  occurs  in  the  upper 
half  of  the  small  intestine,  but  never  close  to  the  stomach,  of  dogs,  wolves, 
jackals,  Canis  dingn,  and  it  can  develop  in  cats.    The  larval  stage  occurs 
in  quite  a  number  of  domesticated  animals,  as  sheep,  cattle,  hogs,  and 
^  also  in  certain  wild  animals,  be- 

ing reported  in  all  from  twenty- 
seven  species  of  mammals.  From 
the  public  health  point  of  view 
it  is  especially  the  dog,  sheep, 
cattle,  and  swine  which  come 
into  consideration.  Man  is  prob- 
ably an  accidental  though  not 
a  rare  host. 

The  Parasite. — It  is  at  present 
an  open  question  upon  which 
there  may  be  a  legitimate  differ- 
ence of  opinion,  whether  one, 
two,  or  three  distinct  species  or 
varieties  of  echinococcus  should 
be  recognized.  Most  zoologists 
admit  only  one  species,  com- 
monly known  as  Taenia  echino- 
coccus (Zeder,  1803)  Siebold, 
1853,  but  the  writer  agrees  with 
Weinland  that  it  is  well  to  place 
this  in  a  distinct  genus;  if  this 
is  done  the  correct  name  of  the 
species  is  Echinococcus  granu- 
losus'- (Batsch,  1786)  Zeder,  1803. 
This  is  one  of  the  smallest  tapeworms  known.  It  is  composed  of  a  head 
with  28  to  50  hooks,  a  short  neck,  and  3  or  4  segments ;  the  first  segment  is 
immature,  the  second  is  mature,  the  last  segment  is  gravid  and  it  composes 
about  ^  (2.  mm.)  of  the  total  length  (2.5  to  5  mm.)  of  the  worm.  The 
larval  stage  of  this  worm  is  the  largest  larval  cestode  known,  and  is  the 
Eckinococcus"^  or  Echinococcus  hydatid  of  medical  and  zoological  authors. 


Hooks  of  hydatid  tapeworm :  a,  from  a  hydatid; 
h,  three  weeks  after  feeding  to  a  dog;  c,  from 
an  adult;  d,  combined  figures  of  a-c,  showing 
the  gradual  changes  in  form.  X600.  (Leuckart. ) 


*  Generic  Synonyms. — Echinococcus  Rudolphi,  1802;  Acephalocystis  Lsennec, 
1804. 

Specific  Synonyms. — Adult:  Tcenia  nana  van  Beneden,  1861,  (not  Siebold, 
1853);  Tania  echinococcus  (Zeder,  1803)  Siebold,  1853;  Echinococctjer  echin- 
ococcus (Zeder)  Weinland,  1861. 

^  E  polymorphus  Diesing,  1850;  E.  unilocularis  Huber,  1896;  E.  cysticus  Huber, 
1891. 


T^NIASIS—CESTODE  INFECTION 


577 


This  may  assume  a  number  of  different  variations  in  growth,  as  will  be 
described  below. 

One  of  the  peculiar  extreme  forms,  the  multilocular  echinococcus,  is 
recognized  by  some  authors  as  a  distinct  parasite  but  most  writers  deny 


Fig.  54. 


Diagram  of  an  Echinococcus  hydatid:  cu,  tliick  external  cuticle;  pa,  parenchym  (germinal) 
layer;  c,  d,  e,  development  of  the  heads  according  to  Leuckart;  f ,  g,  h,  i,k,  development 
of  the  heads  according  to  Moniez;  I,  fully  developed  brood  capsule  with  heads;  to,  the 
brood  capsule  has  ruptured,  and  the  heads  hang  in  the  lumen  of  the  hydatid;  n,  liberated  head 
floating  in  the  hydatid;  o,  p,  q,  r,  s,  mode  of  formation  of  secondary  exogenous  daughter-cyst; 
t,  daughter-cyst,  with  one  endogenous  and  one  exogenous  granddaughter-cyst  u,  v,  x,  formation 
of  exogenous  cyst,  after  Kuhn  and  Davaine;  y,  z,  formation  of  endogenous  daughter-cysts, 
after  Naunyn  and  Leuckart;  y,  at  the  expense  of  a  head;  z,  from  a  brood  capsule:  evag.,  con- 
stricted portion  of  the  mother-cyst.     (R.  Blanchard  slightly  modified.) 

its  right  to  distinct  rank.  It  would  seem  to  the  writer  that  the  present 
evidence,  based  largely  upon  geographical  distribution  and  the  larva,  more 
than  the  adult  stage,  entitles  it  to  rank  as  a  sub-species,  possibly  as  a  species. 
If  recognized  as  of  sub-specific  rank  the  correct  name  is  Echinococcus  granu- 
losus multilocularis-^  if  recognized  as  a  distinct  species  the  correct  name  is 

*  Synonyms. — Echinoccoccus  multilocularis;     E.   alveolaris;    E.   muUilocularis 
exulcerans  Huber,  1896;   E.  osteoklastes  Huber,  1896. 
37 


578  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

Echinococcus  multilocularis.  The  finer  points  of  distinction  between  the 
adult  of  this  form  and  the  typical  form  call  for  further  investigation;  the 
larval  form  or  multilocular  echinococcus  is  the  "Gallcrtkrebs,"  "alveo- 
lar colloid,"  or  "colloid  cancer,"  usually  found  in  the  liver  and  reported, 
in  man,  especially  for  Kussia,  Bavaria,  Switzerland,  Wtirtemberg,  Aus- 
tria, the  Alps,  and  Baden. 

Von  Ledenfeld  (18SG)  states  that  an  echinococcus  tapeworm  occurs  in 
the  dingo  in  Australia  and  may  attain  10  to  30  mm.  in  length.  The  writer 
has  not  examined  these  worms,  but  unless  confusion  has  here  occurred 
with  some  other  sj^ecies,  he  would  incline  to  the  view  that  this  parasite 
represented  a  distinct  species. 

Life-Cycle  of  the  Parasite  and  Source  of  Infection. — The  gravid,  ter- 
minal segment  of  the  tapeworm  is  discharged  in  the  faeces  of  the  dog,  and 
the  egg,  which  is  said  not  to  be  very  resistant,  gains  access  to  the  inter- 
mediate host  (sheep,  cattle,  hogs,  man,  etc.)  through  contaminated  food 
or  drinking  water,  or  in  the  case  of  man,  possibly  also  from  hands  soiled 
while  petting  dogs.  Upon  arriving  in  the  stomach,  the  oncosphere  (six- 
hooked  embryo)  escapes  from  the  shell  and,  by  means  of  its  hooks,  bores 
its  way  to  various  parts  of  the  body,  especially  to  the  liver.  Here  it  comes 
to  rest  and  increasing  gradually  in  size  it  presents  a  thick  outer  cuticle  and 
an  inner  parenchymatic  layer  surrounding  a  cavity  containing  fluid.  An 
outer  connective-tissue  cyst  is  furnished  by  the  host.  This  simple  form 
is  known  as  an  Accphalocystis  Ljennec,  1804.  Brood  capsules  arise 
from  the  parenchymatic  layer  and  hang  into  the  cavity;  heads  form  in 
these  brood  capsules.  If  this  stage  is  fed  to  dogs  each  head  develops  into 
a  tapeworm.  The  growth  of  the  hydatid  need  not  stop  at  the  stage  last 
mentioned  but  daughter-cysts  and  even  granddaughter-cysts  may  form 
and  fall  into  the  cavity  of  the  mother-cyst;  this  variation  represents  the 
endogenous  echinococcus,^  and  is  the  more  common  variation  as  it  occurs 
in  man;  it  may  attain  10  to  15  kilograms  (22  to  33  pounds)  in  weight; 
the  daughter-cysts  may  be  numerous,  "twenty-five  to  fifty"  or  up  to 
"thousands."  In  still  other  cases  the  daughter-cysts  pass  outside  of  the 
mother-cyst  into  the  surrounding  tissue,  thus  giving  rise  to  the  exogenous 
echinococcus,^  a  rather  infrequent  variation  in  man,  but  more  common 
in  ruminants,  pigs  and  the  horse.  It  occurs  in  the  omentum,  peritoneum, 
kidneys,  mammary  gland,  and  brain,  exceptionally  in  the  liver,  but  it  never 
attains  the  enormous  size  sometimes  seen  in  the  endogenous  variation. 

Frequency. — We  are  hardly  able  at  present  to  give  even  approximate 
statistics  covering  the  frequency  of  echinococcus  infection  in  the  United 
States.  The  writer  recalls  one  abattoir  (in  Kansas  City),  where  this 
infection  in  hogs  was  estimated  several  years  ago  at  1  per  cent.  This 
would  indicate  that  in  certain  rural  localities,  indigenous  cases  have 
probably  occurred  in  man  which  have  escaped  attention.  Several  years 
ago  a  former  assistant  (H.  O.  Somer)  of  the  Avriter  collated  100  cases 
in  man  for  the  United  States  and  12  cases  for  Canada,  but  as  33  of  the 
United  States  cases  were  reported  for  New  York  alone,  these  statistics 

^E.  altricipariens  Kuchenmeister,  1855;  E.  hominis  (Zeder,  1800)  Rudolphi. 
1810.  Echinococcus  endogena  (Kuhn,  1830);    E.  hydatidosus  Leuckart,  1863. 

"^Echinococcus  granulosus  (Batsch,  1786)  Rudolphi,  1805;  E.  veterinorum 
Rudolphi,  1810;  E.  exogena  (Kuhn,  1830);  E.  scolecipariens  Kiichenmeister, 
1855f 


TJENIARIS—CESTODE  INFECTION  579 

must  surely  cover  only  a  percentage  of  the  cases  which  have  actually 
occurred;  they  further  show  quite  a  percentage  as  having  been  found 
in  foreigners,  and  as  probably  many,  if  not  most  of  these  latter 
brought  their  infection  with  them  to  this  country,  the  figures  can  hardly 
be  taken  as  representing  American  conditions.  We  may  expect  more 
cases  in  rural  and  village  districts  in  which  the  "country  slaughterhouse" 
flourishes.  In  Manitoba,  the  infection  has  been  common  among  the  Ice- 
landers. Of  the  English-speaking  countries,  Australia  has  presented  the 
highest  figures;  the  province  of  Victoria,  for  instance,  is  said  to  have  3  per 
1,000  mortality  from  hydatids  and  1  case  of  echinococcus  for  every  175 
hospital  patients,  while  1.61  to  2.73  per  cent.  mortaUty  is  said  to  occur  in 
South  Australia.  The  estimate  of  400  deaths  per  year  for  England  is  very 
difficult  to  accept,  especially  in  view  of  the  comparatively  few  articles  on 
this  disease  in  the  current  English  medical  journals,  but  Huber  quotes 
Murchison  as  reporting  about  1.5  per  cent,  infection  in  his  postmortem 
examinations.  In  certain  parts  of  Continental  Europe,  echinococcus  dis- 
ease is  not  uncommon;  thus  Madelung  reports  for  Rostock  1  case  per 
1,056  inhabitants;  from  1861  to  1883,  Rostock  also  showed  25  post- 
mortem cases  in  1,026  autopsies,  or  2.43  per  cent.;  and  the  slaughter- 
house statistics  for  entire  Germany  give  an  average  of  10.39  percent,  for 
cattle,  9.83  per  cent,  for  sheep,  and  6.47  per  cent,  for  hogs. 

Iceland  is  recognized  as  the  classical  echinococcus  land,  but  some  of  the 
estimates  published  must  be  taken  with  reserve.  The  more  conservative 
statistics  give  the  infection  as  from  1  in  43  to  1  in  63  of  the  inhabi- 
tants and  Krabbe  reports  it  for  25  per  cent,  of  the  dogs. 

Hydatids  seem  to  be  more  common  in  females  than  in  males,  but  some 
statistics  give  them  as  more  common  in  males,  and  according  to  Meisser, 
they  occur  more  commonly  in  patients  from  twenty-one  to  thirty  years  of 
age  (about  30.8  per  cent,  of  the  cases  collected),  than  from  thirty-one  to 
forty  years  (about  24.6  per  cent.),  forty-one  to  fifty  years  (about  15.2  per 
cent.),  eleven  to  twenty  years  (about  13.2  per  cent.),  fifty7one  to  sixty  years 
(6.2  per  cent.),  0  to  ten  years  (4.8  per  cent.),  sixty-one  to  seventy  years 
(2.8  per  cent.),  and  seventy-one  to  eighty  years  (1.4  per  cent.). 

The  parasite  is  most  commonly  located  in  the  liver.  Thus,  of  1,806 
organ-infections,  the  following  organs  were  the  most  frequently  affected: 
liver  (1,011),  lung  (147)  and  kidney  (126);  the  parasite  can,  however, 
develop  in  any  portion  of  the  body. 

Duration. — The  growth  of  the  echinococcus  is  very  slow;  according  to 
Leuckart's  experiments  on  swine,  it  takes  five  months  for  the  cyst  to 
reach  a  diameter  of  15  to  20  mm.  If  scolices  are  fed  to  dogs,  the 
development  of  the  adult  worm  is  also  slow;  about  ten  to  twelve  weeks 
may  be  required  for  the  worm  to  reach  the  gravid  stage. 

How  long  an  hydatid  cyst  might  live  in  man  is  an  open  question;  it  has 
been  stated  that  50  per  cent,  of  the  infections  are  fatal  within  five  years, 
but  as  many  cases  are  doubtless  not  diagnosed,  statistics  on  this  point  are 
naturally  always  open  to  some  question.  Authority  exists  for  cases  in  man 
of  two  to  eight  years  duration  and  even  longer 

Symptoms. — ^The  symptoms  of  echinococcus  disease  are  practically 
those  of  a  slowly  growing  tumor,  which  may  attain  10  to  20  kilograms 
(22  to  44  pounds)  in  weight  and  which  causes  different  symptoms 
according  to  its  location.    In  some  cases  the  worm  may  die,  the  parasite 


5S0  THE  ZOO-PARASITIC  DISEASES  OF  MA^ 

then  collapses  and  the  cyst  becomes  gelatinous  and  thick;  the  heads,  or 
at  least  the  hooks,  may  be  found  in  tlie  altered,  thick,  opaque  contents. 
In  some  cases  the  cyst  may  suj)purate.  The  hydatids  are  occasionally 
discharged  through  various  channels  (bile-ducts,  lungs,  in  urine,  etc.). 
Urticaria  may  develop  upon  the  ru])ture  or  puncture  of  the  cyst  admitting 
the  echinococcus  fluid  into  the  body  cavity,  but  it  is  said  to  occur  also  in 
case  of  ap|)arently  uninjured  cysts. 

Diagnosis. — In  many,  but  not  all  cases,  the  so-called  hydatid  thrill  or 
fremitus  is  felt  on  percussion,  resembling  the  quivering  of  jelly.  Deeply 
seated  echinococci  give  an  elastic  feeling,  superficial  parasites  a  fluctua- 
tion. Positive  diagnosis  may  be  made  microscoj)ically  by  finding  the 
hooks  or  heatls  in  case  of  discharge,  or  in  the  aspirated  fluid;  and  ])re- 
sumptive  diagnosis  may  be  made  by  finding  sugar  in  the  aspirated  fluid. 
The  multilocular  echinococcus  is  usually  in  the  liver  and  accompanied  by 
a  chronic  icterus. 

Treatment. — Numerous  methods  of  medicinal  treatment  have  been 
proposed  for  hydatitl  disease,  all  having  one  attribute  in  common,  namely, 
apparent  uselessness.  Echinococcus  infection  is  a  surgical  disease  and  in 
our  present  knowledge  of  the  malady  only  surgical  interference  is  capable 
of  curing  it.  For  the  technique  of  operation,  the  reader  is  referred  to 
works  on  surgery.  Several  authors  refer  to  "boldly  incising  the  cyst, "  but 
attention  may  be  directed  to  the  fact  that  by  o]:)ening  the  external  cyst 
(namely  the  surrounding  cyst  which  is  furnished  by  the  host)  very  cau- 
tiously, the  inner  cyst  (namely  the  parasite  itself)  can  be  taken  out  entire; 
to  do  this  the  external  cyst  should  be  raised  at  a  convenient  point  leaving 
a  small  space  between  it  and  the  inner  cyst.  To  gain  experience  in  this 
operation  it  is  well  to  practice  on  several  echinococcus  livers  of  hogs  or 
other  animals  from  a  slaughter  house;  judging  from  the  observations  of 
the  writer  on  the  killing  floors  of  our  large  abattoirs,  such  experimental 
material  is  not  difficult  to  obtain.  Strictly  aseptic  tapping  has  been  fol- 
lowed by  recovery.  In  the  event  of  suppuration  the  condition  is  treated 
as  one  of  abscess. 

Prevention. — Since  this  disease  is  transmitted  from  dogs  to  man,  and 
since  dogs  obtain  their  infection  more  particularly  from  eating  the  in- 
fected organs  of  slaughtered  sheep,  cattle,  and  hogs,  it  is  clear  that  any 
plan  of  prevention  should  follow  two  lines:  First  and  most  important, 
dogs  should  be  kept  away  from  slaughter  houses  in  order  to  prevent 
them  from  eating  the  organs  rejected  on  account  of  hydatid  infection; 
the  rule  that  no  dog  which  enters  a  slaughter  house  or  its  refuse  yard 
should  ever  be  allowed  to  leave  would,  if  carried  out,  save  many  lives  and 
much  valuable  live  stock,  but  it  is  difficult  of  practical  application. 
Secondly,  whatever  our  affection  may  be  for  "Old  Dog  Tray,"  we 
should  recall  that  he  is  a  dog  and  not  a  human  being;  in  his  place  he  is 
useful,  but  out  of  his  place  he  may  be  a  very  dangerous  friend. 

So  far  as  can  be  judged  from  the  federal  meat  inspection,  hydatid 
disease  is  much  more  common  than  is  generally  supposed.  As  stated 
above,  the  writer  recalls  one  abattoir  where  the  infection  among  the  hogs 
was  estimated  at  1  per  cent. ;  with  this  percentage  it  seems  positive  that 
in  some  sections  of  the  country  the  parasite  has  developed  to  such  an 
extent  that  local  boards  of  health  should  institute  measures  for  its  control 
by  placing  the  local  slaughter  houses  under  sanitary  supervision. 


TJUNIASIS—CESTODE  INFECTION  581 

Sparganum  Mansoni  (Cobbold,  18S2)  is  a  larval  hothriocephalide 
tapeworm  reported  10  times^  in  the  Japanese.  It  measures  8  to  36  cm.  in 
length  by  0.1  to  12  mm.  in  breadth,  and  0.5  to  1.75  mm.  in  thickness; 
it  is  flat  and  unsegmented  and  as  yet  no  stage  with  genital  organs  has  been 
found.  It  occurs  in  the  subperitoneal  connective  tissue  and  body  cavity 
of  man  in  Amoy  and  Japan.  Sonsino  reports  it  for  the  jackal  in  Egypt. 
Daniels  found  this  or  a  similar  parasite  in  British  Guiana.  Of  the  Jap- 
anese cases,  7  of  the  patients  were  males,  2  were  females,  1  unstated. 
By  age:  1  case  occurred  in  a  patient  nine  years  old,  3  cases  between 
eleven  and  twenty,  3  between  twenty-one  and  thirty,  1  between  thirty- 
one  and  forty,  1  between  forty-one  and  fifty,  1  unstated. 

The  parasite  was  lodged  in  the  region  of  the  eye  in  3  cases;  it 
escaped  from  the  urethra  in  4  cases;  was  in  the  connective  tissi^e  of 
abdominal  region  in  1  case  and  in  the  pleural  cavity  in  1  case.  A 
single  parasite  was  reported  in  9  cases,  12  parasites  in  1  case. 

Looss  (1905)  suggests  that  the  escape  of  the  worm  through  the  urethra 
indicates  that  the  definite  host  is  an  aquatic  animal  and  he  thinks  the 
regular  intermediate  host  may  possibly  be  one  of  the  large  ruminants. 

Surgical  treatment  should  be  used  in  superficial  swellings,  while  in 
urethral  cases  the  worm  should  be  extracted  while  the  patient  is  in  a 
warm  bath,  the  parasite  being  slowly  drawn  out  or  wound  around  a  stick 
under  water.  It  might  perhaps  be  well  to  give  the  parasite  a  hypoder- 
mic injection  of  morphine  shortly  before  pulling  it  out. 

Sparganum  proliferum^  (Ijima,  1905)  is  a  peculiar  larval  Japanese 
cestode  reported  but  once.  It  occurred  in  the  subcutaneous  tissue, 
especially  of  the  leg,  and  produced  acne-like  swelling  and  a  condition 
somewhat  similar  to  elephantiasis.  The  worms  measure  1  to  12  mm. 
long  by  2.5  mm.  in  breadth,  and  possess  the  peculiarity  of  reproducing 
by  budding.     Adults  and  life  history  are  unknown. 

1  For  compilation  of  cases  to  date,  see  Stiles  and  Tayler,  1902,  pp.  47-56,  figs. 
30-36. 

2  Synonyms. — Plerocercoides  prolifer  Ijima,  1905;  Plerocercus  prolifer  Ijima, 
1905. 


CHAPTER  XXVI. 

ROUNDWORM  INFECTION— NEMATHELMINTHES. 

By  CHARLES  WARDELL  STILES,  Ph.  D.  D.  Sc. 

The  roundworms  are  divided  into  three  orders  (see  key,  p.  531),  namely 
the  Nematoda,  the  Gordiacea  and  the  Acanthoccphali.  Of  these,  the 
nematodes  are  by  far  the  most  important,  while  the  horse-hair  worms 
and  the  thorn-headed  worms  are  of  secondary  importance  in  human 
medicine.  For  practical  reasons  they  will  be  arranged  in  this  article 
according  to  the  part  of  the  body  they  inhabit  instead  of  according  to 
their  zoological  arrangement.  Systematically  the  nematodes  parasitic  in 
man  are  classified  as  follows  : 

Family  Anguillulidge :    genera  Anguillula,  p.  624;  Anguillulina,  p.  602; 

Leptodera,  p.  624;  Rhabditis,  p.  611. 
"         Angiostomidse :    genus  Strongyloides,  p.  595. 
"         Gnathostomidse :    genus  Gnathostoma,  p.  611. 
''         Filariidse:  genera  Filaria,  p.  613;  Dracunculus,  p.  611; 

Agamofilaria,  p.  623. 
"         Trichinellidffi:    genera  Trichinella,  p.  605;    Trichuris,  p.  603. 
"         Strongylidae :    genem  Metastrongylus,  p.  610;  Trichostrongylus,  p.  602; 
Uncinaria,  p.  583 ;   Agchylostoma,  p.  584; 
Necator,  p.  583;  Dioctophyme,  p.  624; 
Physaloptera,  p.  602. 
"        Ascaridse:    genera  Ascaris,  p.  597;   Toxocara,  p.  597;  Oxyuris,  p.  600. 

INTESTINAL  ROUNDWORMS. 

Uncinariasis^  or  Hookworm  Disease.— Geographical  Distribution. — 

Uncinariasis  encircles  the  globe  in  the  tropical  and  subtropical  belt, 
diminishing  in  frequency  in  the  temperate  climates,  but  occurring  locally 
in  mines  as  far  north  as  England,  Holland,  and  Germany  in  Europe;  in 
North  America  the  endemic  infection  stops  about  at  the  Potomac  River. 
Zoological  Distribution. — Generically  identical,  but  specifically  distinct 
infections  occur  in  dogs,  cats,  foxes,  and  various  other  animals.  The 
infection  of  cats,  which  was  supposed  to  be  specifically  identical  with  the 
Old  World  hookworm  of  man,  has  proved  to  be  distinct  and  the  infection 
of  the  chimpanzee,  supposed  to  be  identical  with  the  New  World  hook- 
worm of  man,  is  also  probably  distinct. 

^Synonyms. — Anchylostomiasis;  ankylostomiasis;  brick-makers'  anaemia; 
dirt  eating  (in  part);  dochmiosis;  Egyptian  chlorosis;  geophagia  (in  part), 
malarial  anaemia  (in  part);  malnutrition  (in  part);  miners'  anaemia;  miners' 
cachexia;  negro  consumption;  St.  Gothard  tunnel  disease;  tropical  chlorosis; 
tunnel  anaemia;   tunnel  disease. 

6S2 


RO  UNDWORM  INFECTION— NEMA  TIIELMINTHES 


583 


The  Parasites. — Hookworm  disease  in  man  is  known  to  be  due  to  two 
distinct  species  of  parasites  belonging  to  the  subfamily  Uncinariinse/ 
namely,  the  Old  World  hookworm  and  the  New  World  hookworm. 

The  New  World  hookworm,  Necator  americanus^  (Stiles,  1902)  or 


Fig.  58. 


Fia.  67. 


JuiSffll. 


Fig.  55.    Fia.  56 


tcm.t. 


«R 


Fig.  55. — New  World  male  hookworm.     Natural  size.     (Stiles.) 

Fig.  56. — New  World  female  hookworm.     Natural  size.     (Stiles.) 

Fig.  57. — The  same,  enlarged  to  show  the  position  of  the  anus  (a)  and  the  vulva  («).     (Stiles.) 

Fig.  58. — Dorsal  view  of  anterior  end  of  New  World  hookworm:  b.c,  buccal  cavity;  c.  p.,  cer- 
vical papillse;  d.w.<.,  dorsal  median  tooth,  projecting  prominently  into  the  buccal  cavity; 
d.sm.l.,  small  dorsal  semilunar  lip;  c,  oesophagus;  m.m.  margin  of  mouth,  the  prominent 
oval  opening 'seen  upon  high  focus;  p.  p.  papillae;  v.  sm.  I.,  large  ventral  semilunar  lips  homol- 
ogous with  the  ventral  hooks  of  A.  duodenale      Greatly  enlarged.     (Stiles.) 

1  As  this  group  of  worms  is  more  carefully  studied,  it  becomes  apparent  that  the 
old  genus  Uncinaria  {ty-pe  vulpis  =criniformis)  must  be  divided  into  at  least  four 
smaller  groups:  Uncinaria  (type  vulpis),  Agchylostoma  (type  duodenale) ,  Neca- 
tor (type  americanus),  Bunostomum  (type  trigonocephalum),  and  probably  into 
several  additional  units.  Opinion  will  probably  differ  for  some  time  to  come  as 
to  whether  these  units  represent  genera  or  subgenera,  but  evidence  is  accumula- 
ting to  the  effect  that  they  should  be  given  generic  rank.  Changes  in  the  generic 
nomenclature  in  consequence  of  such  division,  are  of  course  unavoidable,  in  the 
same  way  that  a  new  terminology  had  to  be  used  when  (1860)  trichinosis  was 
differentiated  from  typhoid  fever.  No  changes,  however,  in  the  specific 
nomenclature  of  the  two  forms  {americanus  and  duodenale)  found  in  man 
can  be  foreseen. 

■* Synonyms. — Uncinaria  americana  Stiles,  1902;  Ankylostomum  ameri- 
canum  (Stiles)  Linstow,  1903  (exclusive  of  form  in  the  chimpanzee) ;  Unci- 
naria (Necator)  americana  (Stiles) ;  Necator  americanus  (Stiles) ;  Uncinaria 
hominis  Ashford,  King  and  Gutierrez,  1904,  in  part. 


584 


THE  ZOO-PARASITIC  DISEASES  OF  MAN 


Fig.  59. 


Uncinaria  americana  Stiles,  1902,  is  the  common  hookworm  of  the 
American  continent  and  adjacent  islands  but  it  has  been  introduced 
into  Italy,  and  doubtless  also  into  Spain.  It  has  been  reported  recently 
also  for  Africa,  China,  and  Guam.  This  cylindrical  worm  is  7  to 
11  mm.  long  and  jiossesses  a  dorsal  and  a  ventral  j^air  of  lips  at  the  mouth, 
a  prominent  dorsomedian  buccal  tooth,  and  four  buccal  lancets ;  in  the 
male,  the  dorsal  ray  of  the  bursa  divides  at  the  base  and  each  branch 
possesses  two  tips.  In  the  female  the  vulva  is  in  the  anterior  half  of  the 
body.  The  eggs  are  thin-shelled,  G4  to  72^  long  by  36  to  40;^  broad; 
they  are  oval  with  somewhat  bluntly  rounded  poles. 

The  Old  World  hookworm,  Agchylos- 
ioma  duodcnalc^  Dubini,  1843,  or  Unci- 
naria duodenalis  (Dubini,  1843)  Railliet, 
1885,  is  the  common  hookworm  for 
Europe,  Asia,  Africa,  and  Australia,  but 
it  has  also  been  introduced  to  some  ex- 
tent into  the  Americas.  This  parasite 
measures  8  to  18  mm.  in  length  and 
possesses  in  its  mouth  2  pairs  of  strong, 
curved,  ventral  teeth  and  1  pair  of  knob- 
like dorsal  teeth;  the  dorsomedian  tooth 
of  the  buccal  capsule  is  nil  or  practically 
so;  a  pair  of  ventral  lancets  is  present  in 
the  buccal  cavity.  In  the  male,  the  dorsal 
ray  of  the  bursa  is  divided  two-thirds  its 
length  from  the  base  and  each  branch  is 
subdivided  into  three  tips.  In  the 
female,  the  vulva  is  in  the  caudal  half  of 
the  body.  The  eggs  measure  52  to  61 /x 
long  by  32  to  38 /x  broad;  they  are  oval 
Avith  very  bluntly  rounded  poles. 

Both  parasites  inhabit  the  small  intes- 
tine, especially  the  jejunum  and  ileum 
but  also  duodenum  and  occasionally  the 
stomach. 

Source  of  Infection, — The  eggs  are  oviposited  in  the  intestine  of  the 
patient;  they  do  not  develop  until  after  they  escape  with  the  faeces;  then 
they  develop  within  twenty-four  hours  or  more,  according  to  co,nditions 
of  heat,  moisture  and  amount  of  oxygen,  a  rhabditiform  embryo  which 
undergoes  ecdysis  (shedding  of  skin)  after  about  forty-eight  to  seventy- 
two  hours;  a  second  ecdysis  which  occurs  within  about  five  to  nine  days 
changes  the  worm  to  the  infecting  stage — the  so-called  "encysted  larva"; 
from  this  point  the  worm  takes  no  more  food  until  it  reaches  man.  In- 
fection takes  place  in  two  different  ways:  (1)  It  has  been  experi- 
mentally demonstrated,  first  by  Looss,  that  the  hookworm  larva?  may 
pass  through  the  skin,  reach  the  circulatory  system,  pass  with  the  blood 


Four  eggs  of  the  New  World  hook- 
worm, in  the  1,  2,  and  4-cell  stages. 
The  egg  showing  3  cells  is  a  lateral 
view  of  a  4-cell  stage.  These  eggs 
are  found  in  the  faeces  of  patients 
and  give  a  positive  diagnosis  of  in- 
fection.   Greatly  enlarged.    (Stiles.) 


*  Synonyms. — Agchylostoma  duodenale  Dubini,  1843;  Ancylostoma  duodenale 
(Dubini)  Creplin,  1845;  Dochmius  duodenalis  (Dubini)  Leuckart,  1876;  Anchi- 
lostoma  duodenale  (Dubini)  Bozzolo,  1879;  Uncinaria  duodenalis  (Dubini)  Rail- 
liet, 1885;  Ankylostoma  duodenale  (Dubini);  Ankylostomuyn  duodenale  (Dubini); 
Uncinaria  hominis  Ashford,  King,  and  Gutierrez,  1904,  in  part. 


RO  UNDWORM  INFECTION— NEMA  TIIELMINTIIES 


585 


through  the  heart  to  the  hings,  from  the  lungs  to  the  air  passages,  up  to 
the  larynx,  down  the  oesophagus  to  the  stomach  and  then  to  the  small 
intestine.  Looss's  theory  of  skin  infection  first  met  with  oj)position, 
incredulity,  or  reserve  from  various  sides,  but  it  now  stands  on  the  firm 
foundation  of  experimental  proof  and  has  been  accef)ted  not  only  by 
helminthologists  who  first  preserved  a  noncommittal  position  toward  it,  but 

Fig.  00. 


V.p. 


Or.  oes. 


-  c.  g. 

\ 


7 —  d.  p. 


Dorsal  view  of  the  Old  World  hookworm:    c.  3.  opening  of  cephalic  gland;  v.  I.  ventral  lancet; 
d.  p.  V.  p.  dorsal  and  ventral  papillae:  note  also  the  four  teeth.     Greatly  enlarged.     (Looss.) 

also  by  men  who  at  first  directly  opposed  it.  Strange  and  incredible  as 
the  view  is,  it  is  now  not  only  established  as  a  possible  method  of  infection 
but  evidence  is  rapidly  accumulating  to  the  effect  that  it  is  a  common,  if 
not  the  most  common,  method  by  which  hookworms  gain  access  to  the 
system.     (2)  A  second  method  of  infection  is  through  the  mouth,  either 

Fig.  61. 


Six  stages  in  the  embryonic  development  of  Old  World  hookworm; 
fresh  faces.      X  336.      (Looss.) 


e  f 

a-c.  are  the  stages  found  in 


with  contaminated  food  or  water  or  from  earth  containing  the  hookworm 
larvae  and  clinging  to  the  hand.  Since  Looss'  skin  infection  theory  has 
been  proved,  the  idea  of  infection  through  the  mouth  has  lost  many  sup- 
porters, and  numerous  arguments  are  submitted  to  prove  that  it  is  of 
exceptional  occurrence.  That  the  time  may  perhaps  come  when  the  skin 
infection  will  be  generally  accepted  as  the  most  important  method,  may 


586  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

be  readily  admitted,  but  it  does  not  seem  to  the  writer  that  the  time  is  now 
here  when  we  would  be  justified  in  looking  upon  infection  by  the  mouth  as  a 
curiosity  or  as  a  method  which  can  be  practically  ignored.  The  skin- 
infection,  as  demonstrated  by  Looss,  is  a  most  brilliant  proof  of  the 
correctness  of  an  old-fashioned  popular  view  which  obtained  regarding 
infection  with  certain  parasites,  a  view  which  was  practically  abandoned 
as  being  too  complicated  and  improbable,  when  the  mouth  offered  such  a 
simple,  probable,  and,  in  some  cases,  demonstrated  entrance  for  intestinal 
worms.  And  it  would  be  wise  for  us  now  not  to  be  carried  away  with  these 
new  brilliant  discoveries  and  this  demonstration  of  the  correctness  of  an 
old-fashioned  idea  to  such  an  extent  that  we  fall  into  error  of  forgetting 
that  worms  can  and  do  enter  the  system  by  the  mouth  and  that,  given  the 
proper  conditions,  there  is  no  reason  at  present  evident  why  the  hook- 
worm should  not  be  taken  into  the  body  in  this  way. 

The  view  advanced  by  several  authors  that  the  free  embryos  may  de- 
velop into  free  adults,  the  progeny  of  which  become  parasitic,  is  not  in 
harmony  with  what  is  otherwise  known  of  this  group  of  worms. 

Frequency. — Uncinariasis  is  a  malady  the  spread  of  which  is  incon- 
sistent with  a  proper  sewage  system,  cold  weather  or  dry  conditions. 
Accordingly,  in  general  terms,  it  is  more  common  in  moist  localities  than 
in  dry,  more  common  in  warm  countries  than  in  cold  and  more  common 
in  rural  districts  than  in  cities.  Although  it  is  one  of  the  worst  scourges 
of  the  tropics,  even  here  its  frequency  may  be  decreased  by  a  proper 
disposal  of  faeces,  for  fortunately  the  specific  infections  in  man  are  not 
known  for  other  animals. 

It  is  more  common  among  people  who  come  into  direct  contact  with 
damp  earth,  as  farmers,  miners,  tunnel-diggers  and  people  who  go  bare- 
footed, than  it  is  among  persons  of  other  occupations  and  those  who  wear 
shoes. 

Most  authors  report  that  it  is  more  common  among  men  than  among 
women  and  children,  but  this  view  is  not  in  harmony  with  the  writer's 
experience,  for  he  has  found  it  more  common  and  more  severe  in  children 
and  in  women  than  in  adult  males.  It  is  not  difficult  to  harmonize  these 
divergent  statements.  Physicians  reporting  for  mining  districts  Avould,  in 
general,  find  more  cases  among  the  miners,  namely  among  men,  for  the 
infection  here  occurs  chiefly  "underground,"  while  the  homes  in  many 
mining  districts  are  provided  with  sewage  or  with  proper  privies  and  the 
miners'  families  are  thus  more  or  less  protected  from  infection.  Further, 
most  authors  have  reported  upon  cases  which  came  to  them  for  diagnosis 
and  treatment,  while  in  the  investigations  of  the  writer  he  went  to  the 
families  in  order  to  find  the  cases;  hence  the  conditions  covered  by  his 
repo  ts  represent  more  exactly  the  natural  conditions  in  the  rural  districts 
visited.  Again,  in  rural  districts  containing  more  children  and  women 
than  adult  males,  as  found  in  the  localities  in  question,  under  conditions 
favorable  to  infection  there  would  naturally  be  more  cases  among  the  chil- 
dren and  women;  furthermore  the  children  and  women  were  following 
a  life  more  conducive  to  infection,  namely  staying  near  the  house,  in  the 
area  of  concentrated  infection,  more  than  were  the  men,  and  infection 
would  therefore  be  expected  to  be  more  common  among  the  former. 

Ashford,  King,  and  Gutierrez  (1904)  in  their  splendid  "Report  on 
Anemia  in  Porto  Rico"  found  more  cases  (1,027  of  5,490)  between  the 


ROUNDWORM  INFECTION— NEMATHELMINTHES  587 

ages  of  five  and  nine  years  than  at  any  other  five-year  period;  of  the  same 
5,490  patients,  3,259  or  59.34  per  cent,  were  males,  and  2,231  or  40.66  per 
cent,  were  females.  The  percentages  relative  to  sex  will  naturally  vary 
according  to  customs  and  proportion  of  sexes  in  different  countries. 

In  the  districts  which  were  visited  by  the  writer,  uncinariasis  was  pre- 
eminently a  disease  of  the  piney  wood  and  sand  localities,  occurring  less  in 
clay  regions.  However  this  distribution  was  not  confirmed  by  Ashford, 
King,  and  Gutierrez  in  Porto  Rico.  Some  of  the  physicians  in  the  South 
have  confirmed  the  author's  findings  in  this  respect  while  others  have  ob- 
tained different  results.  The  explanation  of  the  different  findings  is  not 
clear  at  present.  There  is  evidently  some  factor  in  the  case  which  has 
thus  far  escaped  attention  and  which  will  doubtless  harmonize  the  diver- 
gent reports.  Possibly  Nicholson  and  Rankin  (1904)  have  given  the 
correct  clue  when  they  state  that  it  is  not  so  much  a  question  of  the  sandy 
nature  of  the  soil  as  it  is  a  question  of  fiiie  soil  which  by  its  ability  to  hold 
moisture  offers  the  most  favorable  conditions  for  development.  Further, 
the  trees  would  naturally  protect  the  young  worms,  to  some  extent, 
against  the  drying  effects  of  the  sun.  A  certain  seasonal  periodicity  is 
shown  in  so  far  that  infection  decreases  in  cold  and  very  dry  seasons,  but 
increases  in  warm  and  moist  seasons.  Uncinariasis  is  more  common  and 
more  severe  among  the  poor  than  among  the  well-to-do,  and  more  common 
among  people  who  live  under  conditions  of  filth  than  among  those  who 
live  under  better  hygienic  conditions. 

As  for  statistics,  some  physicians  in  Southern  Florida  estimate  that  90  per 
cent,  of  the  rural  population  in  that  district  harbor  the  parasite  to  a  greater 
or  lesser  degree,  and  Ashford,  King,  and  Gutierrez  estimate  that  about  90 
per  cent,  of  the  rural  population  of  Porto  Rico  are  infected.  In  some 
German  mines,  30  to  80  per  cent,  of  the  miners  have  been  found  infected. 
So  far  as  known  the  infection  is  rare  in  American  mines. 

Symptoms. — Cases  may  be  divided  into  light,  medium,  and  se'ye?'^  infec- 
tions. Under  the  light  infections  may  be  included  those  patients  who  show 
eggs  in  the  faeces  upon  microscopic  examination,  but  who  do  not  ex- 
hibit any  or  sufficiently  marked  symptoms  to  attract  special  attention. 
These  cases  are  numerous  and  are  important  in  that  they  are  capable  of 
keeping  a  region  infected  and  thus  giving  rise  to  severe  cases;  hence  from 
a  prophylactic  standpoint,  they  should  always  be  treated  when  found. 
Under  medium  cases  may  be  included  those  persons  who  show  a  definite 
ansemia,  while  other  symptoms,  mentioned  below,  develop  to  an  extent 
which  attract  sufficient  attention  to  bring  the  patient  under  medical  treat-^ 
ment;  a  physician  in  the  infected  district  should  immediately  suspect  un- 
cinariasis, but  the  Northern  physician  might  not  be  so  promptly  led  to 
this  diagnosis.  Under  severe  cases  may  be  classified  the  typical  dirt- 
eaters  who  present  a  clinical  picture  which  even  the  laity  in  the  South 
recognize  on  sight.  A  fourth  class,  very  severe  cases,  may  be  recognized 
if  desired,  to  include  those  patients  in  whom  death  may  occur  at  any 
moment. 

It  is  needless  to  say  that  these  four  phases  grade  imperceptibly  from  the 
lightest  to  the  most  severe.  The  division  suggested  is  a  compromise  be- 
tween the  classification  proposed  by  the  writer  in  1902  and  that  used  by 
Ashford,  King,  and  Gutierrez  (1904)  and  is  here  adopted  from  a  practical 
standpoint  in  prophylaxis  in  order  to  lay  stress  upon  that  large  number 


588  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

of  cases  in  which  eggs  may  be  present  but  nu  special  syinptoiiis  noticed; 
these  cases  must  be  constantly  kept  in  mind  in  any  scheme  for  eradica- 
tion of  the  disease,  and  are  likely  to  be  overlooked  or  ignored  unless  special 
attention  is  directed  to  them.  Thus,  of  16  medical  students  examined 
by  the  writer  in  one  of  the  Southern  medical  colleges,  4  showed  infec- 
tion but  only  1  of  these  exhibited  even  slight  symptoms;  and  Nicholson 
and  Rankin  (1904)  have  recently  shown  that  there  are  numerous  cases  of 
infection  in  North  Carolina  which  were  not  even  suspected  until  the 
microscopic  examination  Mas  made.  If  these  light  cases  were  submit- 
ted to  physical  examination  for  enlistment  in  the  army  or  navy,  probably 
most  of  the  men  -would  be  accepted  as  sound,  unless  some  other  defect 
were  found. 

General  Development. — If  infection  occurs  before  ])uberty  it  is 
likely  to  retard  devel()j)ment  both  ]>hysical  and  mental.  A  boy  or  girl  of 
twelve  to  fourteen  years  may  appear  to  be  eight  to  ten  and  one  of  eighteen 
to  twenty-two  may  not  appear  to  be  over  twelve  to  sixteen. 

Skin. — The  skin  may  be  waxy  wdiite  to  dirty  yellow,  tallow  or  tan,  the 
color  being  a  general  superficial,  but  not  in  all  cases  exact,  indication  of 
the  degree  of  antemia.  It  becomes  dry  and  parchment-like,  perspiration 
being  more  or  less  completely  suppressed.  Petechise  may  be  observed  in 
older  cases.  Pruritis  may  be  noticed  more  or  less  frequently.  Atrophy 
of  the  skin  is  seen  in  chronic  cases. 

Ground  Itch. — As  Bently  (1902a)  pointed  out,  it  is  very  common  to  find 
a  history  of  ground  itch  in  hookworm  districts.  Of  4,741  Porto  Rican 
patients  questioned  by  Ashford,  King,  and  Gutierrez  on  this  point,  4,654 
or  over  98  per  cent,  gave  a  history  of  "mazamorro,"  as  the  dermatitis 
is  called  by  the  natives.  "New  Sump  bunches"  is  the  corresponding 
condition  in  the  Cornwall  miners  as  reported  by  Boycott  and  Haldane. 
Claude  Smith  and  other  observers  in  our  Southern  States  report  a  similar 
condition  as  common.  The  present  evidence  is  that  this  rapidly  develop- 
ing condition  (characterized  by  a  few  itching  papules  to  a  severe  dermi- 
titis,  found  more  particularly  in  bare-footed  people,  between  the  toes 
especially  and  on  the  sides  and  top  of  the  foot,  and  in  some  cases  on  the 
buttocks  or  other  portions  of  the  body)  is  the  initial  symptom  of  uncinari- 
asis, due  to  the  penetration  of  the  larvse  into  the  skin,  and  doubtless  ac- 
companied in  many  cases  with  some  bacterial  infection.  The  writer  is 
not  aware  that  any  dermatologist  has  as  yet  made  any  special  study  of 
ground  itch  and  until  this  is  done  it  will  be  wise  to  leave  the  question 
open  as  to  whether  all  cases  of  this  affection  are  due  to  uncinariasis, 
especiaWy  since  Strongyloides  larvae,  also,  may  enter  the  skin.  Sufficient 
evidence  has  however  been  presented  by  the  supporters  of  the  ground 
itch  theory  to  compel  its  recognition  as  a  very  general  symptom  of  hook- 
worm disease. 

Hair. — While  the  hair  on  the  head  may  be  normally  developed,  there 
may  be  a  marked  scarcity  or  absence  of  hair  on  the  pubes,  in  the  armpits, 
and  on  other  parts  of  the  body,  in  patients  who  become  infected  before 
puberty. 

(Edema.  — (Edema  of  the  face,  feet,  ankles,  leg,  scrotum,  or  entire  body 
may  be  present.  According  to  the  Porto  Rican  (1904)  statistics  it  was 
most  frequently  found  in  patients  showing  a  haemoglobin  of  20  to  49 
per  cent. 


ROUNDWORM  INFECTION— NEMATHELMINTIIES  5S9 

Wounds  and  Ulcers. — In  a  number  of  cases,  it  is  noticed  that  even  slight 
lesions  of  the  skin  heal  slowly. 

Head. — The  face  may  show  an  anxious,  stupid  expression.  The  con- 
junctivae may  be  chalky-white.  The  puj)ils  have  a  decided  tendency  to 
dilatation;  the  patient  may  show  a  blank  stare;  night-blindness  is  re- 
ported in  a  number  of  cases.  The  visible  mucous  membranes  vary  from  a 
natural  color  to  a  white,  corresponding  more  or  less  to  the  degree  of 
anaemia.  The  tongue  may  show  two  purplish  smears,  one  on  each  sicJe  of 
the  median  lines;  pigmented  spots  and  a  partial  denudation  of  the  epi- 
thelium may  be  observed. 

Neck. — Cervical  pulsation,  especially  in  severe  cases,  is  very  evident, 
often  being  visible  from  six  to  twelve  feet  from  the  patient. 

Thorax. — In  emaciated  cases  the  ribs  are  of  course  very  prominent. 

Abdomen. — A  more  or  less  prominent  abdomen  is  rather  common, 
known  among  the  laity  as  "jDot-belly,"  "butter-milk  belly"  or  "shad- 
belly,"  and  ascites  may  develop. 

Digestive  System. — Appetite:  This  may  be  light  to  ravenous;  in  late 
stages  there  may  be  complete  anorexia.  There  is  further  a  marked  ten- 
dency to  the  development  of  abnormal  appetite  for  sour  articles  as  lemons 
or  pickles,  or  for  salt,  coffee,  and  buttermilk,  or  a  perverted  appetite  for 
resin,  charcoal,  chalk,  tobacco  ashes,  dried  mortar,  mud,  clay,  sand, 
gravel,  shells,  rotten  wood,  cloth,  garments  (the  writer  met  one  boy 
who  had  eaten  three  coats,  thread  by  thread,  within  one  year!),  paper, 
tobacco  pipes,  and  even  mice  and  young  rats.  Salivation  is  frequent. 
Flatulence  and  heartburn  are  common.  Nausea  is  frequently  reported. 
Vomiting  may  occur.  Pain  and  tenderness  in  the  epigastrium  are  men- 
tioned by  nearly  all  observers;  Ashford,  King,  and  Gutierrez  (1904)  give 
it  as  "the  most  constant,  most  suggestive,  and  most  clearly  marked  of  all 
the  symptoms  of  the  digestive  tract."  It  may  be  brought  into  promi- 
nence by  pressing  on  the  right  hypochondrium.  Constipation  is  common, 
but  diarrhoea  may  be  present.  The  statements  by  authors  relative  to  the 
faeces  are  very  contradictory.  Ashford,  King,  and  Gutierrez  found  blood 
macroscopically  in  only  6  cases  and  blood  and  mucus  in  5  cases,  out  of 
over  22,000  faecal  examinations,  statistics  which  are  far  below  the  condi- 
tions observed  in  the  Southern  Atlantic  States  by  the  writer.  Leich- 
tenstern  has  suggested  that  the  blood  is  more  likely  to  appear  during  the 
period  of.  copulation  of  the  worms.  Whatever  the  conditions  are  which 
have  determined  the  divergent  observations,  evidence  shows  that  in  some 
cases  blood  may  be  absent,  in  other  cases  present,  either  macroscopic- 
ally  or  microscopically,  in  the  stools. 

Circulatory  System. — Heart:  The  apex  beat  is  pronounced  in  the 
slight  grades  of  the  disease;  in  moderate  grades  it  is  often  displaced 
downward  and  to  the  left;  in  marked  grades,  a  notable  phenomenon  is 
the  great  reduction  in  the  force  of  the  apex  beat,  which  is  replaced  by  a 
wavy,  indefinite  pulsation  in  the  epigastrium,  or  a  tumultuous  heaving 
of  the  whole  pericardium  and  in  these  cases  cyanosis,  chiefly  in  the  lips,  is 
likely  to  be  noticed;  a  presystolic  thrill  is  not  infrequent  in  moderate 
cases,  more  common  in  marked  cases;  in  moderate  cases,  hypertrophy, 
especially  of  the  left  ventricle,  causes  an  enlargement  of  the  heart  area, 
the  murmurs  are  best  heard  in  the  third  intercostal  space;  in  moderate 
cases,  hsemic  murmurs  are  almost  always  present  (Ashford,  King,  and 


590  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

Gutierrez).  Palpitation  occurs  early  and  is  very  prominent  and  con- 
stant. Dyspnoea  is  very  common,  especially  in  the  later  stages.  The 
pulse  varies  from  SO  to  132,  without  any  necessary  relation  to  the  tem- 
perature; in  the  later  stages  it  becomes  dicrotic,  then  weak  and  com- 
pressible, finally  thready,  irregular  and  intermittent. 

Blood. — The  anannia  is  the  most  pronounced  symptom  and  has 
been  taken  as  basis  for  a  number  of  the  vernacular  names  of  the  disease 
(miner's  ant^mia,  brick-maker's  anjvmia,  etc.);  it  is  natural  that 
recent  authors  have  conducted  special  studies  on  the  blood.  Ashfo'-d, 
King,  and  Gutierrez  (1904)  especially  have  made  a  faithful  study  of 
the  blood  contlitions.  In  one  series  of  540  jjcrsons,  compared  as  to  race, 
they  found  the  average  ha'moglobin  at  over  45  per  cent,  in  whites,  over 
44  per  cent,  in  mulattoes,  and  over  49  per  cent,  in  negroes.  In  a  series  of 
577  persons  compared,  in  reference  to  sex,  the  males  showed  an  average 
of  41  per  cent,  hc-emoglobin,  females  48  per  cent.  As  extremes,  8  per  cent, 
and  101  per  cent,  are  reported,  while  special  selected  cases  ranged  from 
9  to  65  per  cent.,  with  an  average  of  24.38  per  cent.  Of  one  series  of  579 
cases,  the  haemoglobin  upon  later  examination  during  treatment  showed 
an  increase  in  371  cases  from  1  to  71  percent.,  average  21.34  per  cent.;  45 
cases  lost  from  1  to  16  per  cent.,  average  5.04  per  cent.;  7 cases  neither 
gained  nor  lost;  a  weekly  increase  of  20  to  30  per  cent,  was  not  rare. 
During  the  disease,  the  htemoglobin  falls  before  the  red  cell  count  and 
may  reach  as  low  as  30  per  cent,  before  much  change  in  the  reds  is  no- 
ticed; under  treatment  the  reds  usually  increase  more  rapidly  than  the 
hfemoglobin. 

The  red  cells  vary  from  754,000  to  normal  according  to  conditions ;  of 
61  special  cases,  the  average  was  2,406,416;  as  the  disease  pro- 
gresses, the  cells  become  polychromatophilic  and  show  poikilocytosis; 
under  treatment  the  red  cells  increase  very  rapidly,  reaching  or  exceeding 
normal  sometime  before  the  haemoglobin.  In  42  treated  cases  with 
a  final  average  of  100  per  cent,  haemoglobin,  the  red  cells  averaged 
5,624,197.  Leukocytosis  was  not  met  with  in  Porto  Rico;  the  majority 
of  cases  showed  5,000  to  10,000  leukocytes,  and  in  chronic  cases  of  long 
standing  leukopenia  was  often  found;  the  average  white  count  of  61 
cases  was  8,009  on  admission;  during  treatment  42  cases  increased 
to  9,041  whites,  16  cases  to  7,533  whites,  and  3  fatal  cases  in- 
creased to  14,133.  The  eosinophil es  present  special  interest:  very 
severe  chronic  cases  with  poor  resisting  power  and  exhausted  blood- 
making  organs  have  little  or  no  eosinophilia;  a  rise  in  eosinophiles  is  of 
good  prognostic  import;  if  very  severe  cases,  presenting  little  or  no 
eosinophilia,  show  a  fall  in  the  eosinophile  count,  the  prognosis  is  not 
generally  good;  in  general,  good  resistance  to  the  toxin  of  hookworms  is 
expressed  by  eosinophilia;  the  "special"  cases  gave  an  average  of  10.8 
per  cent,  before  treatment,  and  13.2  per  cent,  after  treatment.  In  29 
cases,  before  treatment,  the  differential  leukocyte  count  averaged  as 
follows:  eosinophiles,  17.1  per  cent.;  polymorphonuclears,  54.5  per  cent.; 
small  lymphocytes,  16.3  per  cent.;  large  lymphocytes,  8.6  percent.;  other 
leukoc\ies,  3.5  per  cent. 

Respiratory  System. — The  respiratory  symptoms  are  not  character- 
istic. Patients  may  complain  of  difficulty  in  breathing,  especially  after 
exertion. 


ROUNDWORM  INFECTION— N EM ATHELMINTHES  591 

Temperature. — This  may  be  normal,  subnormal,  or  reach  100°  to  102° 
F.  Fever  at  the  onset  is  said  to  be  a  fairly  constant  symptom  in  Porto 
Rico. 

Nervous  System. — ^The  effect  of  uncinariasis  upon  the  mental  condition 
is  marked;  the  infected  children,  of  school  age,  are  greatly  handicapped 
by  it  in  their  studies;  in  severe  cases,  there  is  a  noticeable  delay  in  answer- 
ing even  simple  questions  and  some  of  the  patients  are  more  or  less 
stupid.  Mental  lassitude,  headache  and  dizziness  are  frequently  noticed; 
the  patients  may  be  more  timid  and  emotional  than  normal;  the  patellar 
reflex  is  diminished  or  suppressed;  tingling  and  formication  are  common; 
either  insomnia  or  somnolence  may  be  marked;  dizziness  is  common, 
especially  upon  rising  suddenly  to  the  feet;  joint-pains  are  also  very 
frequent. 

Muscular  System. — ^The  muscles  are  soft  and  flabby,  and  the  patient  is 
naturally  weak;  he  tires  easily,  is  obliged  to  rest  after  slight  exertion  and 
a  feeling  of  lassitude  is  experienced  which,  in  absence  of  severe  symptoms, 
may  seem  unexplained ;  as  a  result,  persons  who  are  not  acquainted  with 
the  true  condition  attribute  it  in  the  less  evident  cases  to  laziness,  and 
there  is  no  doubt  but  that  much  of  the  alleged  laziness  in  infected  dis- 
tricts is  simply  the  natural  lassitude  connected  with  uncinariasis.  A 
person  with  a  haemoglobin  of  30  to  60  per  cent,  and  a  subnormal  blood 
count  as  a  result  of  hookworm  infection  cannot  be  expected  to  be  vigorous, 
any  more  than  a  person  with  this  condition  of  the  blood  as  a  result  of 
other  infection. 

Urinary  System. — The  urine  varies  from  1,010  to  1,015  in  specific  grav- 
ity, is  pale,  neutral  or  alkaline,  rarely  acid,  and  is  increased  in  amount. 

Genital  System. — In  case  of  infection  before  puberty,  delayed  develop- 
ment may  be  very  marked.  Menstruation  is  delayed  several  years  beyond 
the  normal  and  may  be  more  or  less  irregular,  or  absent,  especially  in 
summer.  Abortions  and  miscarriages  are  frequent.  Sterility  and  impo- 
tence are  common. 

Lethality. — The  writer  cannot  state  the  average  lethality  of  untreated 
cases  in  the  United  States,  but  Ashford,  King,  and  Gutierrez  (1904,  p.  88) 
after  a  most  careful  study  of  the  subject,  express  the  astounding — yet 
probably  correct — opinion  that  30  per  cent,  of  the  deaths  in  Porto  Rico 
are  due  to  uncinariasis!  The  Porto  Rico  Commission  treated  5,490 
cases,  with  the  following  results:  cured,  2,244  cases,  or  40.8  per  cent.; 
practically  cured,  377  cases,  or  6.8  per  cent.;  improved,  1,727  cases,  or 
31.4  per  cent.;  result  not  recorded,  522  cases;  never  returned,  224  cases, 
and  ceased  to  return,  283  cases,  total  18  per  cent. ;  unimproved,  86  cases; 
died,  27  cases,  or  0.5  per  cent.  Sandwith  (1894,  pp.  16-17)  states  that  of 
the  patients  nominally  under  his  care,  89.5  per  cent,  were  cured  or 
greatly  relieved,  2.5  per  cent,  were  not  relieved,  8  per  cent.  died. 

Pathology. — Aside  from  the  anaemic  conditions,  attention  may  be 
directed  to  the  intestinal  tract.  The  stomach  is  usually  dilated  and  exhib- 
its a  chronic  catarrh.  The  small  intestines,  especially  the  jejunum  and 
ileum,  show  a  diffuse  catarrh  of  variable  severity,  and  the  bites  made  by 
the  worms;  hemorrhages  may  be  present  or  absent;  there  may  be  large 
spots  of  hemorrhagic  infiltration  with  a  worm  hanging  from  its  centre; 
there  is  a  chronic  interstitial  inflammation;  Ashford,  King,  and  Gutierrez 
report  the  intestinal  wall  as  very  much  thinned  but  several  authors  report 


592  THE  ZOO-PARASITIC  DISEASES  OF  MAX 

it  as  very  much  thickened;    constrictions  have  been  reported  in  South 
American  hterature. 

The  parasites  injure  in  different  ways,  but  evidence  seems  to  be  accu- 
mulating in  support  of  the  view  that  it  is  their  toxic  effect  which  is  the 
most  serious.  Loeb  and  Allen  J.  Smith  have  shown  that  hookworms 
produce  a  substance  which  inhibits  the  coagulation  of  the  blood. 

Economic  Importance. — A  person  who  has  not  been  in  an  uncinariasis 
district  and  who  has  not  seen  the  extent  of  the  cases,  the  way  the  people 
live,  or  rather  exist,  how  they  attempt  to  work,  how  little  they  accomplisl 
compared  with  what  they  might  do  if  they  were  healthy,  how  the  mental 
faculties  arc  tlullctl,  how  backward  the  children  are,  how  exhausted  the 
laborers  become  and  what  a  change  takes  {)lace  in  them  during  and  after 
treatment,  may  find  it  difficult  to  grasp  the  full  economic  importance  of 
this  malady.  As  stated  by  the  writer  in  1902,  it  was  "exceedingly  difficult 
to  escape  the  conclusion  that  in  uncinariasis,  caused  by  Uncinaria 
amencana,  we  have  a  pathological  basis  as  one  of  the  most  important 
factors  in  the  inferior  mental,  physical  and  financial  condition  of  the 
poorer  classes  of  the  white  population  of  the  rural  sand  and  piney  wood 
districts  visited.  This  sounds  like  an  extreme  statement  but  it  is  based 
upon  extreme  facts."  Since  this  statement  was  published  many  southern 
physicians  have  either  stated  or  written  that  they  are  of  the  same  opin- 
ion. The  economic  importance  of  the  malady  in  Porto  Rico,  as  depicted 
by  the  Porto  Rican  Commission  must  be  accepted  as  not  being  exagger- 
ated; and  as  observations  in  the  United  States  multiply,  what  once  seemed 
an  extreme  opinion  is  now  rapidly  becoming  a  very  conservative  view. 

The  importance  of  the  disease  in  the  cotton  mills  is  not  to  be  under- 
estimated. The  typical  cotton  mill  "anaemic,"  of  whom  the  writer  has  seen 
a  number  in  different  parts  of  the  South,  is  a  diagram  of  medium 
uncinariasis.  From  a  purely  financial  point  of  view,  it  would  pay  the 
cotton  mills  to  compel  all  candidates  for  positions  to  submit  to  micro- 
scopic examination  for  diagnosis,  and,  if  infected,  also  to  treatment, 
before  they  are  given  employment.  Whether  the  American  coal  mines 
will  experience  a  repetition  of  the  sad  and  expensive  history  European 
mines  have  had  from  hookworm  disease,  will  depend  primarily  upon  the 
sanitary  regulations  they  enforce. 

Diagnosis. — In  severe  cases,  a  diagnosis  upon  symptoms  can  be  made 
with  a  very  high  probability  of  correctness  by  anyone  who  is  familiar 
with  the  disease.  A  positive  diagnosis  may  be  made  in  either  of  two  ways: 
(1)  Examine  the  fpeces  microscopically  to  find  the  eggs^;  or  (2)  give  an 
anthelmintic  experimentally  and  examine  the  stools  for  the  adult  worms. 

Blotti7ig-paper  Test. — For  persons  who  have  no  microscope  a  very  simple 
test  may  be  made  with  filter-,  blotting-  or  ordinary  newspaper.  Fold  an 
ounce  or  so  of  faeces  in  the  paper  and  allow  it  to  stand  for  several  hours, 
then  unwrap  and  examine  for  a  blood  stain. 

^Recently,  Bass,  (1906)  has  suggested  a  new  method  for  concentrating  the 
eggs.  He  shakes  thoroughly  a  portion  of  ixcal  matter  in  a  test  tube,  or  similar 
receptacle,  filled  nearly  to  the  top  with  a  nine-tenths  saturated  solution  of  salt 
in  water.  As  the  specific  gravity  of  the  eggs  is  less  than  that  of  the  salt  water, 
they  float  to  the  top.  This  procedure  has  been  tested  by  the  writer  several 
times  and  the  observations  confirmed.  The  method  takes  more  time,  however, 
than  does  the  ordinary  examination  of  slides,  but  in  some  cases  may  be  morQ 
satisfactory. 


ROUNDWORM  INFECTION— NEMATIIELMINTHES  593 

Several  authors  who  have  criticized  this  test,  seein  not  to  have  under- 
stood why  it  was  suggested  and  have  objected  that  it  is  open  to  error. 
Certainly  it  is  open  to  error,  the  same  as  are  numerous  other  tests,  but  in 
not  a  few  cases  it  is  an  additional  link  in  the  evidence-chain,  exactly  as  the 
anaemia,  the  dirt-eating,  the  red  cell  count,  etc.,  and  for  the  "country 
physician"  who  probably  owns  no  microscope,  and  who  is  perhaps  fifty 
miles  away  from  any  one  who  does,  it  forms  an  additional  clue.  The 
writer  has  found  it  useful  u})on  a  number  of  occasions,  even  when  a 
microscope  was  at  hand,  but  it  is  self-understood  that  a]  rough  test  of 
this  kind  is  not  to  be  given  much  weight  when  a  better  test  can  be  made, 
neither  is  a  negative  result  with  it  to  be  accepted  as  final. 

Treatment. — The  usual  drug  used  in  uncinariasis  is  either  thymol  or 
male  fern  and  recently  beta-naphthol  is  springing  into  popularity. 

Thymol. — ^As  the  parasites  are  more  or  less  protected  by  the  mucus  in  the 
intestine,  this  should  be  removed  by  administering  magnesium  or  sodium 
sulphate,  or  other  purge,  the  evening  before  the  anthelmintic  is  taken. 
Early  the  next  morning,  say  at  eight  o'clock,  give  (adult  dose)  2  grams 
(30  grains)  of  finely  powdered  thymol  in  capsules;  at  ten  o'clock,  re- 
peat this  dose;  at  noon,  administer  another  dose  of  salts.  The  size  of  the 
dose  should  be  modified  according  to  the  age  or  the  condition  of  the  pa- 
tient. Ashford,  King,  and  Gutierrez,  on  the  basis  of  an  experience  with 
12,330  doses,  state  that  in  general  0.5  gram  (7.5  grains)  may  be  given 
with  good  results  to  children  under  five  years;  1  gram  (15  grains) 
between  five  and  ten  years;  2  grams  (30  grains)  between  ten  and  fifteen 
years;  3  grams  (45  grains)  between  fifteen  and  twenty  years;  4  grams 
(60  grains)  between  twenty  and  sixty  years ;  2  or  3  grams  (30  to  45  grains) 
above  sixty  years;  and  in  common  with  other  clinicians  they  warn  that 
certain  conditions  as  great  debility,  very  old  age,  pregnancy,  advanced 
cardiac  or  other  organic  disease,  a  tendency  to  vomit,  anasarca,  chronic 
diarrhoea  and  dysentery  are  unfavorable  to  the  administration  of  thymol. 
This  medication  is  carried  on  one  day  per  week  until  the  patient  is  cured. 

It  is  in  the  interest  of  safety  not  to  allow  or  give  by  mouth  any  alcohol, 
oil  or  other  solvents  of  thymol  on  the  day  of  treatment.  If  stimulants  are 
necessary,  they  may  be  given  hypodermically. 

Many  authors  warn  about  the  ill  effects  of  thymol.  The  Porto  Rican 
Commission,  after  administering  12,330  doses  seems  to  incline  to  the  view 
that  these  warnings  have  been  exaggerated  and  states  that,  "under  certain 
precautions,"  they  "came  to  know  that  thymol  was  an  exceedingly  in- 
oft'ensive  drug."  Still,  they  warn  of  certain  ill  effects  in  some  cases 
(especially  with  chronic  enterocolitis,  oedematous  patients,  etc.),  and  while 
they  state  that  they  had  no  deaths  directly  attributable  to  thymol,  it  might 
perhaps  be  legitimately  recalled  that  of  4,482  persons  treated  at  Utuado, 
224  patients,  or  nearly  5  per  cent.,  never  returned  to  the  clinic  after  their 
first  medication.  Whether  a  history  of  any  of  these  224  cases  would  have 
modified  the  conclusions  reached  is  not  altogether  clear,  but  so  far  as 
known  (even  with  the  unusually  efficient  check  on  deaths  occurring  on 
the  island)  none  of  these  patients  died. 

The  Porto  Rican  Commission  is  entirely  in  harmony  with  the  excep- 
tion taken  by  the  writer  to  the  apparently  prevailing  opinion  of  English 
writers  that  large  doses  of  thymol  must  necessarily  be  given.  If  a  patient 
jannot  stand  a  large  dose,  smaller  doses  will  expel  a  few  worms  and  thus 
38 


594  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

enable  him  gradually  to  reach  a  condition  in  which  the  dose  may  be 
increased. 

Of  4,630  Porto  Rican  patients  treated  with  thymol,  the  worms  were 
entirely  expelled  in  3,630  cases:  1  treatment  was  required  in  1,518  cases; 
2  treatments  in  1,166  cases;  3  treatments  in  518  cases;  4  treatments  in 
247  cases;  5  treatments  in  104  cases;  6,  in  47  cases;  7,  in  19  cases;  8,  in  6 
cases;  9,  in  3  cases;  10,  in  1  case;  and  11,  in  1  case.  The  number  of  doses 
varied,  of  course,  with  the  severity  of  the  case. 

Beta-napJitJiol. — Beiitlcy  (1904)  abandoned  thymol  two  years  ago  in 
favor  of  beta-naphthol.  This  he  has  now  used  in  several  thousand  cases 
with  excellent  results.  The  Porto  Rican  Connnission^  used  it  with  success 
in  several  cases.  The  drug  is  used  in  the  same  way  as  thymol,  but  with 
doses  one-half  as  large  (total  of  2  grams — 30  grains,  instead  of  4  grams 
— 60  grains). 

Extract  of  Male  Fern. — This  drug  has  been  used  successfully  in  thou- 
sands of  cases  of  hookworm  disease.  With  thymol  producing  less 
serious  effects  than  male  fern,  the  former  drug  should,  however,  be  shown 
preference.  If  it  fails,  male  fern  can  be  used.  The  dose  is  4  to  8  Cc. 
(about  1  to  2  fluid  drams)  followed  by  salts  or  calomel  and  salts. 

Eucalyptus  Oil  and  Chlorojorm. — In  severe  cases,  especially  when  the 
patients  are  weak,  Phillips  (1905)  favors  the  following  formula:  Euca- 
lyptus oil  2.  to  2.5  Cc,  chloroform  3.  to  3.5  Cc.  and  castor  oil  40.  Cc. 
This  is  divided  into  two  or  three  doses,  according  to  the  age  and  con- 
dition of  the  patient,  and  these  are  given  twenty  to  thirty  minutes 
apart,  beginning  early  in  the  morning,  fasting;  should  any  depression 
occur  after  the  first  dose,  the  later  doses  are  omitted.  Particular  stress 
is  laid  on  the  inclusion  of  chloroform  in  the  formula,  as  three  cases 
in  which  positive  diagnoses  had  been  made,  were  unaffected  when  chlo- 
roform water  was,  in  error,  substituted. 

The  writer  has  used  this  treatment  on  only  one  occasion  and  then 
unsuccessfully  (as  the  patient  was  severely  nauseated)  and  accordingly, 
is  not  in  a  position  to  form  a  valid  judgment  on  this  formula. 

Prevention. — Since  the  fseces  of  hookworm  patients  represent  the  po- 
tential infection  in  concentrated  form,  it  is  clear  that  a  proper  disposal  of 
the  discharges  is  the  great  factor  in  preventing  hookworm  disease.  Build 
proper  privies  and  insist  upon  their  being  used ;  in  mines,  adopt  the  pail 
system.  This  one  line  of  prevention,  if  carried  out,  is  sufficient  to  blot 
hookworm  disease  out  of  existence,  for  fortunately  w^e  do  not  have  to  deal 
with  any  specifically  identical  infections  in  any  of  the  domesticated 
animals. 

Numerous  other  preventive  measures  have  been  advanced,  but  while 
good  in  themselves,  they  fail  to  reach  the  source  of  the  evil.  The  propo- 
sition to  wear  shoes  and  thus  prevent  ground  itch  is  of  course  a  very 
good  one,  but  financial  considerations  inhibit  its  universal  adoption; 
if  the  infected  fseces  are  properly  disposed  of,  ground  itch  will  prac- 
tically disappear  even  if  shoes  are  not  worn.  The  proposition  to  drink 
boiled  or  filtered  water  is  an  excellent  one,  but  of  impracticable  general 

^According  to  their  most  recent  results  (1905),  it  is  not  quite  so  efficient  as 
thymol;  it  is  more  necessary  to  thoroughly  clean  the  intestine  before  using  it; 
its  systemic  effects  are  however  less  marked,  although  its  effects  on  diseased 
kidneys  seem  to  be  more  marked. 


RO  UNDWORM  INFECTION— NEMA  TIIELMINTHES 


595 


Fig.  62. 


(Es 


Nerv. 


application  among  the  poor;  but  if  the  fjieces  are  disposed  of,  the  danger 
of  infecting  the  water  is  removed.  To  keep  the  hands  clean  is  of  course 
an  excellent  plan,  but  unfortunately  one  of  limited  application.  The 
great  principle  is  to  prevent  the  dirt  from  becoming  "dirty";  clean  dirt 
is  not  dangerous. 

Strongyloidosis.* — Infection  with  Strongyloides  stercoral^. — €reo- 
graphical  Distribution. — The  distribution  of  this  infection  is  much  more 
general  than  was  formerly  supposed;  it  seems  to  be  especially  a  tropical 
and  subtropical  species,  but  as  such  probably 
encircles  the  earth.  American  cases  have  been 
found,  locally,  as  far  north  as  Baltimore  and  im- 
ported cases  even  further  north.  European 
cases  have  been  found  as  far  north  as  Belgium, 
England,  Germany,  and  Holland,  and  the  in- 
fection is  also  reported  for  Siberia.  In  Asia 
it  is  known  for  China,  India,  and  Japan.  In 
Africa  it  is  known  for  Egypt.  In  South  America 
it  extends  into  Brazil.  In  general  it  follows 
the  distribution  of  hookworms  in  man,  and  is 
very  common  in  Porto  Rico. 

Zoological  Distribution. — Strong  (1901)  re- 
ports this  parasite  for  monkeys  as  well  as  man, 
and  he  was  able  to  transmit  the  disease  to  mon- 
keys by  feeding  infected  human  excreta  to 
them. 

The  Parasite. — I.  (a)  The  parasitic  (intes- 
tinal) adults  are  parthenogenetic  females, 
measuring  2.2  to  3  mm.  long  by  34  to  70// 
broad,  with  an  oesophagus  about  one-fourth  as 
long  as  the  body;  a  double  uterus  is  present, 
each  horn  containing  a  moderate  number  (3  or 
6)  of  segmenting  eggs  (50  to  59  by  30  to  Mjj.) 
which  escape  through  the  vulva,  situated  in  the 
posterior  third  of  the  body.  These  eggs  are 
deposited  in  the  intestinal  lumen  of  the  host  or 
in  galleries  in  the  intestinal  mucosa  made  by 
the  females,  and  developed  into — 

(b)  Rhabditiform  embryos,  200  to  240  jjl  long 
by  12  /<  broad,  which  may  grow  to  450  to  600  p. 
long  by  16  to  20  [i  in  diameter  by  the  time  they 
are  discharged  with  the  faeces.  The  buccal 
Cavity  is  short,  relatively  broad,  and  without  thickened  chitinous  lining. 
These  embryos  then  develop  within  two  or  three  days  into — 

II.  (c)  Free-living  dioecious  adults.  The  males  measure  0.7  mm.  long; 
the  tail  is  curved  ventrally  to  form  a  hook;  spicules  curved,  38  /z  long. 
The  females  measure  1  mm.  long;  vulva  slightly  posterior  of  equator  of 
the  body.  Each  female  develops  30  to  40  eggs  which  may  or  may  not 
segment  in  the  uterus,  these  eggs  develop  forming  the — 


Gen. 


Larva  of  Strongyloides  atercor- 
alis  as  found  in  fresh  faeces; 
Nerv. ,  nervous  systems ;  (Es., 
oesophagus;  Int.,  intestines; 
Gai.,  genital  primordium; 
An.  anus.   X228.  (Looss.) 


1  Synonyms. — Anguilluliasis,  Rhabdonemiasis. 
and  Thayer  (1901). 


See  especially  Strong.  (1901) 


596  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

{(l)  Free  livinr/  ritahditiform  embryos,  which  measure  220^t  long;  when 
they  attain  550/j.  in  length,  they  moult  and  at  the  same  time  change  to — 

(e)  Filariforvi  cmbri/o.s,  possessing  an  elongate  cylindrical  oesophagus 
about  halt'  as  long  as  the  body.  This  is  the  infecting  stage,  which  enters 
man  by  the  mouth  or  through  the  skin,  reaches  tlie  duodenum  and  upper 
part  of  the  jejunum  anddevclopsdirectlyto(«)  the  part  henogenetic  females. 

llic  complete  life-cycle  (a-b-c-d-e-a)  is  thus  an  alternation  of  a  dioe- 
cious with  a  ])arthen()genetic  generation  (alloiogenesis)  and  is  the  cycle 
reported  more  commonly  in  tropical  and  subtropical  cases.  In  other 
cases,  notably  in  the  temperate  zone,  an  abridged  cycle  consisting  of 
a-b-e-a  may  occur;  in  other  words  there  is,  in  these  instances,  a  tendency 
to  a  more  completely  parasitic  life  by  the  omission  of  tiie  free-living  dioe- 
cious generation. 

Source  of  Infection. — Infection  takes  place  in  either  of  two  ways,  pas- 
sively by  means  of  contaminated  food  or  drinking  water  or  actively 
tlirough  tlie  skin. 

Frequency. — Extensive  statistics  of  a  satisfactory  nature  are  not  acces- 
sible. In  general,  the  infection  increases  in  frequency  from  cooler  to 
warmer  climates.  In  Washington,  D.  C,  several  cases  have  been  known 
(probably  none  contracted  within  the  city);  the  writer  believes  the 
infection  is  much  more  common  in  this  country  than  is  generally  supposed. 
Powell  found  it  in  75  per  cent,  of  the  cases  of  amemia  in  India  (Manson). 

Duration. — The  longevity  of  the  individual  worm  is  not  established. 
Cases  of  infection  are  known  of  several  years  standing,  due  perhaps  to 
reinfection.  Ward  (1903)  suggests  that  the  very  heavy  infections  occasion- 
ally reported  possibly  point  to  an  endless  chain  multiplication  by  means 
of  the  ablireviated  cycle  (a-b-e-a)  inside  the  intestine. 

Symptoms  and  Pathology. — Here  again,  as  in  so  many  other  cases  of 
parasitism,  the  literature  contains  extreme  statements,  that  the  parasite  is 
utterly  harmless  and  that  it  is  exceedingly  injurious.  A  number  of  authors, 
however,  see  in  this  parasite  a  worm  which  may  indeed  in  some  cases  be 
apparently  harmless,  but  which,  when  present  in  large  numbers,  may 
cause  "clinically,  an  intermittent  diarrhoea  with  intestinal  disturbances, 
and  pathologically,  a  catarrh  of  the  small  intestine"  (Strong). 

Clinical  Diagnosis. — The  only  possible  method  of  diagnosis  is  by  means 
of  microscopic  examination  of  the  f feces  for  the  rhabditiform  embryo  (h) 
(see  p.  595).  In  this  connection  see  also  p.  602.  In  violent  purging,  eggs, 
strung  together  end  on  end  and  surrounded  by  a  delicate  tube,  may 
appear  in  the  stools. 

Treatment.— Repeated  doses  of  thymol  (see  p.  593)  as  used  in  hook- 
worm infection  are  usually  advised  for  strongyloidosis  also,  but  owing 
to  the  fact  that  the  parasites  may  burrow,  treatment  is  not  always 
satisfactory. 

Ascariasis— Eelworm  Infection.— Geographical  Distribution. — Cos- 
mopolitan, more  in  rural  districts  than  in  cities. 

Zoological  Distribution.— In  many  medical  works  including  some 
recent  editions,  the  authors  maintain  that  the  common  eelworm  of  man 
occurs  in  certain  domesticated  animals,  such  as  the  pig,  horse,  cattle,  etc. 
This  view  is  not  in  harmony  with  the  present  zoological  classification 
which  recognizes  these  infections  as  generically  identical  but  specifically 
distinct. 


ROUNDWORM  INFECTION— NEMATHELMINTHES  597 

The  Parasite. — Ascaris  lumhricoides  Linnaeus,  1758,  i.s,  in  general 
terms,  about  as  large  as  an  ordinary  lead  pencil  but  tapering  toward 
both  ends;  the  male  measures  15  to  17,  even  25  em.  in  length  by  about 
3  mm.  in  diameter;  the  female  is  somewhat  larger,  20  to  40  cm.  in  length 
by  5  mm.  in  diameter,  and  is  oviparous.  The  worms  are  grayish  to  red- 
dish-yellow in  color;  the  anterior  end  is  provided 
with  three  lips.    The  egg  is  50  to  75  by  30  to  55/j!,  '  '  ' 

unsegmented  when  oviposited,  and  provided  with 
a  thick  mammillate  covering,  frequently  tinged 
yellow  when  found  in  the  fax-es.  The  parasites 
live  in  the  small  intestine.  Development  is 
direct,  without  intermediate  host. 

Toxocara  canis  (Werner,  1782),  the  canine  eel- 
worm,  is  an  exceedingly  common  intestinal  para- 
site of  dogs  and  cats,  and  8  cases  have  been 
reported  for  man,  the  worms  having  been  vomi- 
ted in  most  of  these  instances.  It  measures  40 
to  90  (male)  and  120  to  200  (female)  mm.  in  Egg  of  the  common  ascaris 
length  by  about  1  mm.  in  diameter,  and  is  easily  {Ascaris  iumbricoides}oi 
recognizable  from  its  arrow-shaped  head ;  the  eggs  ^^^  w'th°superfic Jho- 
are  nearly  globular,  68  to  72//,  with  a  thinner  shell  ^us.  Greatly  enlarged. 
than  that  of  A.  lumhricoides.  Development  is  (Stiles.) 
direct,  without  an  intermediate  host. 

{f  Ascaris)  maritima  Leuckart,  1876,  has  been  reported  for  man  but 
once  in  Greenland.  One  immature  specimen  wsiS  vomited  by  a  child 
and  was  doubtless  an  accidental  parasite,  possibly  swallowed  with  the 
entrails  of  some  food  animal. 

{f  Ascaris)  texana  Smith  and  Goeth,  1904,  has  been  described  as  a  new 
eelworm  for  man  in  Texas;  it  measured  58  to  60  mm.  in  length  and  is 
said  to  possess  intermediate  lips;  uterine  eggs  segmented,  60  by  40/i. 
Through  the  kindness  of  the  describer,  Allen  J.  Smith,  the  writer  was 
enabled  to  examine  the  original  specimens ;  the  structures  described  as 
intermediate  lips  do  not  correspond  to  the  intermediate  lips  so  far  as  he  is 
familiar  with  them  in  other  species  of  Ascaris,  but  as  the  material  was  poor 
the  writer  refrains  from  expressing  any  definite  opinion  regarding  this 
species,  which  is  still  sub  judice. 

Source  of  Infection. — ^The  egg  escapes  in  the  faeces  and  slowly  (in  one  to 
several  months,  according  to  conditions)  develops  an  embryo;  no  inter- 
mediate host  is  required,  at  least  for  Ascaris  lumhricoides  and  Toxocara 
canis;  but  when  the  developed  eggs  are  swallowed,  either  in  contam- 
inated food  or  water,  or  from  hands  soiled  with  dirt  containing 
the  eggs,  the  embryo  develops  directly  to  the  adult  stage.  Drinking 
water  and  fruits,  especially,  are  blamed  for  carrying  the  parasite  to 
man.  Some  years  ago  the  writer  bred  common  house-flies  in  a  dish  con- 
taining eggs  of  the  eelworm  of  hogs,  a  parasite  very  closely  allied  to  that 
of  man,  and  later  found  the  eggs  in  the  intestine  of  the  adult  flies.  It 
would  seem  therefore,  that  flies,  by  breeding  in  privies,  might  act  as  dis- 
seminators of  the  lumbricoid  worm  of  man. 

Frequency. — The  eelworm  is  one  of  the  most  common  parasites  of 
man;  it  may  occur  at  any  age,  from  about  eight  months  to  eighty-five 
years,  but  is  usually  more  frequent  in  childhood  (from  five  to  ten  years) 


598  THE  ZOO-PARASlTIC  DISEASES  OF  MAN 

and  youth  than  in  adult  age,  anil  more  conunon  in  women  than  in  men. 
Autopsy  statistics  for  Germany  pubHshed  by  Heller  and  jMuller,  give 
the  following  combined  results:  males,  220  cases  in  2,275  autopsies,  or 
9.67  per  cent.;  females,  194  cases  in  1,440  autopsies,  or  13.41  per  cent.; 
children,  101  cases  in  584  autopsies,  or  17.29  per  cent.  It  was  present  in 
0.49  per  cent,  of  3,457  persons  examined  under  direction  of  the  writer. 
In  Porto  Rico,  Guam,  and  the  Philippines,  it  is  excessively  common. 

Usually  only  from  2  to  G  individuals  are  present  in  one  patient,  but 
infections  with  30,  40,  100,  140,  and  300  to  GOO  worms  are  recorded,  while 
P'auconncau-Dufresne  (ISSOa)  re])orts  the  case  of  a  boy  of  twelve  years 
who  passed  (chiefly  by  vomiting)  more  than  5,000  worms  within  less  than 
three  years,  GOO  being  passed  on  one  day! 

In  general  terms,  Ascaris  lumhricoides  is  more  common  in  warmer  than 
in  temperate  and  colder  climates,  and  more  common  in  the  rural  districts 
than  in  the  cjties.  Authors  attribute  its  greater  frequency  in  rural  patients 
to  the  use  of  unfiltered  water,  but  other  factors  seem  to  be  of  more  impor- 
tance: in  cities  with  a  sewage  system  the  infectious  material  is  carried 
away,  while  in  country  districts  the  boxprivy  affords  greater  possibilities 
for  the  spread  of  infection. 

Duration. — The  worm  matures  and  oviposits  in  about  a  month  after 
infection,  but  definite  details  as  to  the  longevity  of  the  individual  parasites 
are  lacking. 

Symptoms. — Very  frequently  no  symptoms  are  noticed.  In  other  cases 
they  are  more  or  less  indefinite,  practically  all  of  the  symptoms  reported 
for  tseniasis  and  oxyuriasis  (see  pp.  5G9,  601)  being  recorded  for  ascaria- 
sis  also.  For  instance,  among  those  recorded  may  be  mentioned  the 
following:  irritation  of  the  skin,  urticaria,  pallid  appearance,  alternate 
pallor  and  redness  of  the  face,  jaundice,  dark  rings  around  the  eyes, 
unequal  or  dilated  pupils,  flashes  before  the  eyes,  mydriasis,  amblyopia, 
amaurosis,  strabismus,  disturbances  in  sight  and  hearing,  inflammation 
of  the  eye,  itching  of  and  picking  at  the  nose,  grinding  of  the  teeth,  bad 
taste  and  offensive  breath,  dry  cough,  hiccough,  aphonia,  anorexia,  irreg- 
ular or  capricious  appetite,  dirt-eating,  eructations,  sensibility  of  stomach 
on  pressure,  nausea,  vomiting,  gastrorrhagia,  vague  abdominal  pain, 
borborygmi,  colicy  pains,  cramps,  irregular  bowels,  diarrhoea,  constipa- 
tion, intestinal  obstruction,  meteorism,  itching  at  the  anus,  muscular 
pains,  progressive  emaciation,  headache,  vertigo,  fretfulness,  fainting- 
spells,  chorea,  convulsions,  epilepsy,  catalepsy,  ecstasy,  hysterical  con- 
ditions, eclampsia,  neuralgia,  paralysis,  psychoses,  tetanoid  states,  pseudo- 
meningitis,  palpitations  and  irregular  action  of  the  heart,  syncope,  etc. 

While  many  physicians  recognize  the  elements  of  danger  which 
smoulder  in  an  infection  with  ascaris,  others  sometimes  view  eelworms 
with  little  more  than  a  passing  curiosity.  Hundreds  of  cases  of  ascariasis, 
recognized  or  unrecognized,  may  pass  through  a  physician's  hands  without 
any  fatal  results  being  noticed.  Still,  the  occasional  danger  connected  with 
eelworms  is  deserving  of  attention.  If  a  light  infection  of  ascariasis  is 
present,  the  chances  are  very  great  that  nothing  serious  will  result  from 
it;  but  unfortunately  these  worms  have  a  habit  of  wandering,  especially 
in  febrile  conditions,  and  medical'  literature  shows  that  it  is  these  wander- 
ings, even  in  light  infections,  which  present  the  most  dangerous  aspect 
of  the  disease.    The  escape  of  erratic  eelworms  by  the  mouth  or  nose  is 


ROUNDWORM  INFECTION— NEMATHELMINTHES  599 

not  very  rare.  If  during  this  wandering  the  worm  happens  to  come  into 
contact  with  an  ulcer,  perforation  into  the  abdominal  cavity  or  the  lungs 
may  result;  or  the  worm  may  enter  the  Eustachian  tube  and  escape  by 
the  external  ear;  in  some  cases  it  enters  the  lachrymal  duct;  or  it  may 
turn  at  the  larynx  and  pass  a  greater  or  less  distance  down  the  trachea 
and  bronchi,  in  some  cases  causing  suffocation,  in  others  abscess  or 
gangrene  of  the  lungs;  about  40  cases  are  recorded  in  which  ascarids  have 
entered  the  air  passages.  About  90  cases  are  recorded  in  which  the  eel  worms 
have  wandered  into  the  bile  ducts,  9  cases  into  the  pancreatic  duct,  and 
some  20  cases  into  the  urinary  passages.  In  some  cases  the  worms  pass 
into  the  abdominal  cavity,  either  piercing  the  intestinal  wall  or  working 
their  way  through  an  ulcer.  Blanchard  has  compiled  81  cases  in  which  eel- 
worms  have  escaped  through  the  body- wall;  29  cases  through  the  umbilicus, 
30  through  the  groin,  10  at  unstated  points  of  the  abdomen,  2  by  the 
hypochondrium,  2  by  the  lumbar  region,  2  by  an  inguinal  abscess,  1  each  by 
the  sacral,  pubic,  perineal  region,  and  abscess  of  the  thigh,  inferior  por- 
tion of  thorax  and  linea  alba.  Davaine  points  out  that,  corresponding  to 
hernia,  ascarids  escape  by  the  umbilicus  more  frequently  in  children  than 
in  adults,  and  by  the  groin  more  frequently  in  adults  than  in  children. 

In  view  of  the  foregoing  brief  account  of  erratic  ascarids,  in  not  a  few 
cases  fatal,  it  is  seen  that  it  is  at  least  worth  while,  from  a  prophylactic 
standpoint,  to  treat  all  cases  of  ascaris  infection  which  are  found,  even 
independently  of  the  question  as  to  whether  any  moderate  or  serious 
local  or  perhaps  reflex  symptoms  are  traced  to  the  presence  of  the  worms 
in  the  patient  under  consideration..  That  heavy  ascarid  infections,  such 
as  are  found  in  unhygienic  tropical  countries,  may  be  of  considerable 
clinical  importance  is  evident. 

Manson  states  that  in  China  he  treated  his  young  patients  twice  a  year 
with  santonin  as  a  matter  of  routine. 

Diagnosis. — It  is  possible  to  make  a  diagnosis  independently  of  symp- 
toms, either  by  a  microscopic  examination  of  the  fgeces  to  find  the  char- 
acteristic eggs,  or  by  recognition  of  worms  passed  by  the  anus,  mouth, 
or  nose. 

Treatment. — Santonin  is  the  classical  drug  for  ascariasis.  It  is  given 
in  powder  or  troches,  dose  0.01  gram  per  day  {\  grain)  for  each  year  of 
the  child's  age,  0.06  to  0.3  gram  (1  to  5  grains)  for  an  adult.  It  is  best  given 
with  an  equal  or  greater  amount  of  calomel,  every  morning  two  or  three 
days  in  succession;  then  repeat  the  medication  every  three  or  four  days 
as  long  as  eggs  are  found  in  the  fseces  or  until  no  further  worms  are 
expelled.  In  treating  children  it  is  well  to  forewarn  the  mothers  of  the 
possible  effects  of  santonin  upon  the  patient. 

Among  other  drugs  used  for  the  expulsion  of  eelworms  may  be  men- 
tioned: oil  of  chenopodium,  0.13  to  0.666  Cc.  (2  to  10  minims)  on  a  lump 
of  sugar  or  in  emulsion,  before  meals  for  two  days,  followed  by  a  purge 
(calomel).  Fluid  extract  of  senna,  with  equal  parts  of  fluid  extract  of 
spigelia,  2  to  4  Cc.  (|  to  1  dram)  of  the  mixture,  three  times  daily  until 
purgation  occurs.    Thymol  (see  p.  593)  may  be  used. 

Serious  intestina;l  obstruction  by  ascarids  should  be  treated  as 
obstruction  from  any  other  cause. 

Ox3niriasis. — Pinworm  Infection. — Geographical  Distribution. — 
Cosmopolitan. 


600  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

Zoological  Distribution. — The  pinwonn  o^  man  is  not  known  to  occur 
in  any  other  animal;  gencrically  identical  but  specifically  distinct  infec- 
tions are,  however,  known  for  a  number  of  mammals. 

The  Parasite. — Oxyuris  (Oxyurias)  vermicularis^  (Linnseus,  1758), 
known  as  the  pinworm,  seatworm,  also  mawworm,  is  a  small,  white, 
roundworm  measuring  3  to  5  mm.  (male)  to  10  mm.  (female)  in  length, 
0.10  to  0.6  mm.  in  diameter;  the  male  has  but  one  spicule;  the  female  is 
proviiled  with  a  relatively  long,  sharply  pointed  tail;  the  vulva  is  in  the 
latter  half  of  the  anterior  third  of  the  body;  two  uteri  are  present  filled 
with  numerous  eggs,  in  which  an  embryo  is  developed 
before  oviposition;  these  eggs  are  50  to  52  by  16  to 
24/(,  with  thin  shell,  and  with  dorsal  surface  much 
more  convex  than  the  ventral.  The  earlier  stages 
of  the  parasite  live  in  the  small  intestine,  where  the 
worms  copulate.  The  males  are  not  long-lived.  The 
fertilized  females  wander  to  the  csecum,  and  later 
when  gravid  to  the  colon.  It  has  been  maintained 
t.   ,        r.,  „  that  the  normal  location  for  pin  worms  is  the  vermi- 

Embryo  of  the  common        „  ^•        •  i        i       i        i    i  • 

pinworm  {Oxyuris      I oHU  appendix;  it  cauiiot  be  doubtcd  that  pmworms 
vermicuiaTis)oi man,      do  enter  the  appendix,  for  Heller,  for  instance,  re- 
in the  eggshell,   as      ported  36  males  in  1  case;   19  males  and  19  females 
fiiuckLtT''  ^'''''"      ^"  another;  30  males  and  9  females  in  another;  46 
males  and   27    females   in  another;   but  it  hardly 
seems  proved  tliat  the  appendix  is  the  normal  habitat  for  these  para- 
sites.    The  statement  occasionally  found  in  medical  works  to  the  effect 
that  the  embryo  escapes  from  eggs  oviposited  in  the  rectum  and  develops 
there  into  an  adult  is  possibly  traceable  to  VLx  (1860);  but  this  view 
cannot  be  accepted. 

Source  of  Infection. — Pinworms  have  a  pronounced  tendency  to 
wander  out  of  the  anus,  and  when  the  female  is  crushed  by  scratching 
with  the  fingers  to  relieve  the  irritation,  a  person  naturally  infects  his 
fingers,  especially  under  the  finger-nails,  with  the  embryo-containing  eggs; 
from  the  fingers  to  the  mouth  or  nose  is  but  a  short  distance,  and  auto-in- 
fection thus  occurs.  Or  the  embryos  in  the  bedclothes  may  easily  soil 
the  hands  of  a  bed-fellow,  a  companion,  or  a  nurse,  and  thus  be  transmitted 
to  a  second  person.  Or  the  eggs  (free  in  the  fpeces  or  in  the  body  of  the 
discharged  female  worms)  may  be  transmitted  to  people  by  means  of  con- 
taminated food,  as  uncooked  fruit,  vegetables,  etc.  No  intermediate  host 
is  necessary.  Theoretically  it  seems  perfectly  possible  that  flies  may  oc- 
casionally, if  not  frequently,  play  an  accidental  role  in  the  dissemination 
of  the  eggs. 

Frequency. — ^This  parasite  is  one  of  the  most  common  of  the  intestinal 
worms,  varying  in  different  autopsy  statistics  from  0  to  over  57  per  cent. 
It  is  more  frequent  in  children  (from  three  to  ten  years)  and  women, 
but  has  been  observed  in  babes  of  five  weeks  up  to  men  of  eighty  years. 
It  was  found  in  1.3  per  cent,  of  3,457  persons  examined  under  the 
writer's  direction  at  the  Hygienic  Laboratory  at  Washington.  Heller 
reports  it  in  the  proportion  of  33.8  per  cent,  for  children,  21.1  per  cent,  for 

'Synoxyms. — Ascaris  vermicularis  Linnceus,  1758;  Oxyuris  vermicularis  (Lin- 
naeus) Bromscr,  1819;  Trichina  cystica  Salisbury,  1858;  Filaria  cystica  (Salis- 
bury) Railiiet,  1893,  in  part  only  (not  F.  cystica  Rudolphi,  1819). 


ROUNDWORM  INFECTION— NEMATIIELMINTIIES  GOl 

women,  and  18.8  per  cent,  for  men,  in  611  autopsies  at  Kiel,  Germany;  one 
prominent  German  helmintliologist  has  stated  that  he  beheves  there  are  few 
persons  who  have  not  harbored  this  worm  at  one  time  or  another  in  their 
lives.  Further,  infections  are  reported  as  more  common  in  the  spring  than 
at  other  seasons  of  the  year.  The  number  of  specimens  of  pinworms  in 
one  person  varies  from  a  comparatively  few  individuals  to  such  heavy 
infections  that  the  mucosa  of  the  large  intestine  may  be  covered  with  them. 

Duration. — While  the  longevity  of  the  males  appears  to  be  rather 
limited,  that  of  the  individual  female  is  not  established.  Cases  of  infec- 
tion of  ten  to  fifteen  years  and  even  much  longer  are  recorded,  but  these 
are  doubtless  due  to  repeated  auto-infection. 

Symptoms. — Doubtless  many  cases  of  light  infection  pass  unnoticed, 
and  in  case  the  person  is  of  clean  personal  habits,  the  infection  dies  out. 
In  heavy  infections,  however,  there  may  be  marked  irritation  of  the  in- 
testinal mucosa,  resulting  in  a  catarrhal  condition  and  a  diarrhoea;  there 
may  be  foul  breath,  nausea,  vomiting,  abdominal  pain,  tenesmus,  deep 
rings  around  the  eyes;  further,  one  may  find  headache,  restlessness, 
sleeplessness,  itching  at  the  nose,  vertigo,  unequal  pupils,  chorea,  and 
even  convulsions.  One  of  the  most  constant  symptoms  is  an  intense  itch- 
ing and  burning  at  the  anus,  due  to  the  wandering  of  the  female,  espe- 
cially shortly  after  the  patient  retires;  the  anus  appears  red,  irritated, 
sometimes  bloody;  reaching  the  perineum  the  worms  may  pass  to  the 
vagina  if  the  skin  is  moist,  and  may  here  cause  hypersemia,  increased  secre- 
tion of  mucus,  and  sometimes  hypersesthesia  and  leukorrhoea;  sexual 
excitement  may  result.  Wandering  pinworms  have  been  found  in  the 
vagina,  uterus,  and  even  in  the  abdominal  cavity. 

Diagnosis. — ^While  symptoms  may  indicate  pinworm  infection,  a  posi- 
tive diagnosis  may  be  made  several  different  ways :  the  adult  worms  may 
be  found  in  the  stools,  occasionally  in  considerable  numbers;  or  they  may 
be  found  in  the  crotch,  especially  if  the  child  is  examined  during  the  rest- 
less period  after  retiring;  a  microscopic  examination  of  scrapings 
around  the  anus  (taken  with  a  clean  dull  knife  or  a  microscopic  slide  or 
other  suitable  object),  or  the  cleanings  from  the  finger-nails  may  reveal 
the  characteristic  eggs ;  finally,  the  eggs  may  be  discovered  by  a  micro- 
scopic examination  of  the  ffeces. 

Opinions  are  divided  regarding  the  value  of  the  microscopic  examina- 
tion of  the  fseces;  some  authors  consider  that  the  eggs  are  not  found  free 
in  the  stools,  while  others  state  that  they  are  common.  The  writer's 
experience  is  that  the  eggs  may  be  found  in  fsecal  examinations  even  in 
some  cases  in  which  pinworm  infection  is  not  even  suspected;  but  that  a 
negative  examination  is  not  of  much  value. 

Treatment. — Treatment  should  take  into  consideration  two  distinct 
points :  namely,  not  only  the  removal  of  the  gravid  female  pinworms  from 
the  rectum,  but  also  the  removal  of  the  younger  worms  from  the  small 
intestine.  A  failure  to  consider  this  latter  point  doubtless  explains  not  a 
few  cases  of  treatment  which  have  not  met  with  the  success  the  practi- 
tioner expected.  Still,  the  emphatic  statement  so  often  met  with,  that 
persistence  is  an  essential  factor  in  favorable  results,  is  often  justified. 

For  removing  the  younger  pinworms  from  the  small  intestine,  several 
drugs  may  be  used,  as  santonin  and  calomel  (of  each  0.05  to  0.1  gram 
—  f  to  IJ  grains)  given  several  days  in  succession,  or  large  potions  of  an 


602  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

infusion  of  gentian,  or  active  saline  cathartics  repeated  several  days  in 
succession,  or  thymol  or  beta-naphthol.  Ungar  gives  immediately  after 
a  laxative,  four  doses  per  day  of  naphthalin  (0.1  to  0.4  gram — 2  to  6  grains) 
according  to  age,  for  two  or  three  days  in  succession  between  meals. 

To  expel  the  gravid  females  from  the  rectum,  rectal  injections  are  used. 
An  infusion  of  quassia  seems  to  be  one  of  the  most  popular  remedies. 
Other  commonly  used  enemata  are:  lime-water,  salt  and  water,  iced 
water,  salt  and  milk  (highly  s{)oken  of),  cold  water,  aloes,  diluted  vinegar 
(which  should  be  sterilized  before  using,  otherwise  the  patient  may  be- 
come infected  with  vinegar-eels),  perchloride  of  iron,  glycerine,  benzine 
(20  drops  to  a  pint  of  warm  water),  finely  chopped  garlic  with  water  (which 
has  stood  for  twelve  hours  and  is  then  strained  through  linen).  Diluted 
carbolic  enemata  are  advised  by  a  number  of  authors,  but  they  do  not 
seem  to  have  any  special  advantage  over  the  other  drugs  and  have  in 
some  cases  decidedly  poisonous  effects. 

The  injections  are  given  with  the  buttocks  elevated,  or  in  the  knee-chest 
position,  at  first  every  evening,  then  every  two  or  three  or  four  evenings, 
until  all  evidence  of  worms  has  disappeared.  If  too  large  an  injection  is 
given  to  be  retained  this  washes  out  a  number  of  worms;  but  it  should  be 
followed  by  a  smaller  injection,  two  to  four  ounces,  or  an  amount  which 
can  be  conveniently  held. 

Ointments  of  various  kinds  may  be  applied  in  the  evenings  to  the  anus 
and  perineum  to  relieve  the  itching. 

Physaloptera  caucasica  Linstow,  1902,  has  been  reported  but  once 
for  the  intestine,  in  Caucasus.  (Length  14  [male]  to  27  [female]  mm., 
breadth  0.71  to  1.14  mm.    Eggs  57  by  39/^.) 

Trichostrongylus  Looss,  1905. — Three  small  nematode  worms 
(r.  vitrinus,  T.  probohcrus,  and  T.  instahilis^)  have  been  reported  for 
man  in  Egypt,  and  one  of  them  {T.  instahilis)  for  man  in  Japan.  They 
do  not  seem  to  be  important  parasites,  so  far  as  our  present  knowledge 
indicates,  and  further  their  normal  habitat  seems  to  be  other  animals 
(sheep,  antelope,  dromedary,  baboon)  rather  than  man.  They  measure 
4  to  6  or  7  mm.  in  length.  Their  eggs  might  be  mistaken  for  hook- 
worm eggs,  but  are  in  general  somewhat  larger,  73  to  90//  long  and  are 
oviposited  in  the  8  to  32  cell  stage. 

Anguillulina  putrefaciens  (Kuhn,  1879).— Small  nematodes  of  vari- 
ous sorts  frequently  gain  access  to  the  stomach  by  being  swallowed 
accidentally  with  food  (vegetables,  vinegar,  water,  etc.),  and  are  likely  to 
appear  either  in  the  vomit  or  in  the  ffeces.  As  an  example  of  this  sort 
reference  may  be  made  to  Ang^dllulina  putrefacieyis  reported  by  Botkin 
(1883)  as  Trichina  contorta,  in  the  vomit.  The  worms  gained  access  to 
the  stomach  in  onions  and  caused  vomiting. 

Trichocephaliasis. — ^Whipworm  Infection.— Geographical  Distribu- 
tion.— Probably  cosmopolitan. 

Zoological  Distribution. — The  whipworm  of  man  is  also  said  to  occur 
in  various  apes  and  lemurs;  generically  identical  but  specifically  distinct 
infections  are  more  or  less  common  in  dogs,  cattle,  sheep,  and  a  number  of 
other  animals. 

*  Synonyms. — Strongylus  instahilis  Railliet,  1893a;  *S.  subtilis  Looss,  1895; 
Trichostrongylus  subtilis  (Looss,  1895)  Looss,  1905;  Tr.  instahilis  (Railliet,  1893) 
Looss,  1905.     See  also  StUes,  1902,  41-42,  figs.  14-21. 


ROUNDWORM  INFECTION— NEMATHELMINTHES  603 

The  Parasite. — Trichuris  trichiura^  (Linnicus,  1701),  tlie  whipworm, 
has  the  general  form  of  a  whip,  the  posterior  swollen  fjody  representing 
the  handle,  and  the  lash  representing  the  slender  filiform  anterior  portion. 
The  male  measures  40  to  45  mm.,  the  female  45  to  50  mm.  in  length. 
The  parasites  inhabit  the  caecum,  but  are  occasionally  ^^^  ^^ 

found  in  the  vermiform  appendix  and  in  the  colon, 
rarely  in  the  small  intestine.  They  produce  numerous 
characteristic  eggs,  50  to  54  by  21  to  23/i,  of  a 
yellowish  to  dark-brown  color,  with  unsegmented 
protoplasm  and  with  a  peculiar  light  spot  at  each 
pole  resembling  apertures. 

Source  of  Infection. — The  eggs  develop  after  being 
discharged  in  the  faeces,  and  with  the  contained  em- 
bryo are  swallowed  in  drinking-water  or  contaminated 
food.     An  intermediate  host  is  not  necessary. 

Frequency. — This  is  one  of  the  most  common  para- 

-,  £  •         •      £  i?  1  it:         1        Egg    of   whipworm. 

sites  ot  man,  varymg  m  frequency  from  less  than  1  ^^qq     (Looss.) 

per  cent,  up  to  90  per  cent,  of  persons  examined  in 
different  parts  of  the  world.  In  general  terms  it  is  more  common  in 
warmer  than  in  colder  climates.  In  Washington,  according  to  examina- 
tions made  under  the  writer's  direction  in  the  Hygienic  Laboratory,  and 
in  the  Bureau  of  Animal  Industry,  it  is  twice  as  common  in  colored  as  in 
white  children;  it  was  present  in  7.69  per  cent,  of  3,457  persons  exam- 
ined by  the  Zoological  Division  of  the  Public  Health  and  Marine  Hos- 
pital Service;  it  may  vary  greatly  in  frequency  in  different  wards  of  the 
same  asylum;  in  the  United  States  Government  Hospital  for  the  Insane 
10.8  per  cent,  of  500  white  male  patients  were  infected,  the  highest  per- 
centage being  38.98  in  soldiers  returned  from  the  Philippines.  It  is 
most  frequent  in  children  from  three  to  ten  years  of  age. 

Duration. — ^The  length  of  life  of  the  individual  parasite  is  not  estab- 
lished. 

Symptomatology  and  Pathology. — ^The  medical  opinions  expressed 
regarding  this  worm  have  been  too  frequently  characterized  by  extreme 
statements,  varying  from  the  view  that  it  is  of  no  medical  importance 
whatever,  to  the  view  that  is  the  cause  of  very  serious  disease.  That,  in  the 
vast  majority  of  cases,  it  is  of  scarcely  any  appreciable  importance,  and 
that  its  presence  can  not  be  recognized  symptomatically  may  be  con- 
servatively admitted.  But  that  severe  infections  do  not  produce  injury 
is  not  in  accordance  either  with  probability  or  with  recorded  observations. 
According  to  some  observers,  the  worm  simply  lies  loose  on  the  intestinal 
mucosa;  but  other  equally  competent  observers  report  finding  it  with  its 
head  burrowed  in  the  epithelium.  Askanazy  reports  haemoglobin  in  the 
worm's  intestine,  and  several  cases  of  severe  anfemia  have  been  recorded 
within  recent  years  which  were,  apparently  justly,  attributed  to  heavy 
infections  with  whipworms. 

Within  the  past  few  years  Guiart,  of  Paris,  has  been  defending  the 
view  that  the  wounds  made  by  whipworms  form  the  point  of  entrance  for 
the  typhoid  bacillus;  he  thus  attributes  to  whipworms  a  role  in  t}'phoid 
somewhat  similar  to  the  role  played  by  fleas  in  plague.     Examinations 

^Synonyms. — Trichuris  Biittner,  1761;  Ascaris  trichiura  Ijinn&us,  1771;  Trir- 
chocephalus  hominis  Schrank,  1788;    Trichocephalus  dispar  Rudolphi,  1801. 


604  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

made  at  Washington  do  not  boar  ont  this  hypothesis  for  this  locality. 
Of  200  typhoid  patients  examined  by  the  author  (1907),  92.5  per  cent, 
failed  to  show  any  intestinal  worms,  and  the  whipworm  infection  found 
was  only  very  slightly  above  that  of  the  normal  ])opulation.  Whipworms 
are  supposed  by  some  authors  to  be  the  initial  cause  of  some  cases  of 
appendicitis. 

Clinical  Diagnosis.— The  only  method  of  recognizing  whipworm  infec- 
tion is  by  microscopic  examination  of  the  fivces  for  the  characteristic 
eggs. 

Treatment.— Medical  writers  agree  that  treatment  is  unsatisfactory. 
Thymol  is  recommended  by  some,"^  but  in  laboratory  experiments  on  the 
dog,  Pfender  and  the  writer  have  found  it  worthless  in  whij)worm  infec- 
tions. In  the  literature  on  hookworm  disease,  frequent  mention  is  found 
of  the  expulsion  of  whipworm  by  male  fern  administered  in  treating 
uncinariasis. 

Hemmeter  (1902)  advises  irrigation  of  the  colon  with  benzine  (1  dram 
of  benzine  to  1  quart  of  warm  water)  and  at  the  same  time  internal 
administration  of  benzine. 

Prevention. — A  proper  disposal  of  the  alvine  discharges  is  of  first 
importance.  Personal  cleanliness,  the  use  of  proper  drinking  water,  and 
the  disuse  of  surface-water  for  drinking  purposes,  will  also  contribute 
largely  to  prevention. 

Infection  with  Gordiacea. — A  number  of  different  horse-hair  worms 
are  reported  as  accidental  intestinal  parasites  in  the  intestine  of  man. 
They  are,  however,  rare  and  their  effect  temporary.  Six  cases  are  known 
for  North  America;   in  4  of  these,  the  parasite  was  Paragordius  varius. 

Infection  with  Thorn-headed  Worms  (AcanthocephaU).— The 
thorn-headed  worms  differ  from  the  nematodes  in  two  chief  characters; 
namely,  in  the  absence  of  an  intestine  and  in  the  presence  of  a  retrac- 
tile rostellum  armed  with  hooks.  An  intermediate  host  (insects  of  various 
kinds)  is  required  for  their  life-cycle.  This  group  of  parasites  is  of  very 
little  known  importance  in  human  medicine,  but  of  greater  import- 
ance in  comparative  medicine.  Three  species  have  been  recorded  as 
intestinal  parasites  of  man,  namely: 

Gigcmtorhynchus  gigas^  (Goeze,  1782),  10  to  50  cm.  long;  eggs  80  to 
100/i  long,  with  three  shells;  very  common  in  hogs;  May-beetles  and 
June-bugs  are  the  intermediate  host;  alleged  to  occur  in  man  in  South 
Russia. 

Gigantorhynchus  monilijormis^  (Bremser,  1819),  4  to  8  cm.  long;  eggs 
85  by  45/^;  occurs  in  rats  and  certain  other  rodents;  a  beetle  (Blaps 
mucronafa)  is  the  intermediate  host;  raised  in  man  experimentally  by 
Grassi  and  Callandrucio  (1888c).  According  to  Magalhaes,  the  large 
roach  {Peripkmata  amcricana)  may  also  serve  as  intermediate  host. 

Echinorhynchus  hominis  (Lambl,  1859),  a  doubtful  species,  5.6  mm. 
long,  reported  but  once. 

'  Dr.  Stitt,  IT.  S.  Navy,  has  recently  expeled  over  300  whipworms  from  one 
patient  by  using  thymol.  This  result  is  much  more  encouraging  than  any  simi- 
lar case  known  to  the  writer. 

2  Synonyms. — Tcenia  hirudinacea  Pallas,  1781;  Echinorhynchus  gigas  Goeze, 
1782. 

'Synonyms. — Echinorhynchus  moniliformis  Bremser,  1819. 


ROUNDWORM  INFECTION— NEMATHELMINTHES  605 

In  all  these  infections  the  diagnosis  should  be  made  by  microscopic 
examination  of  the  faeces  to  find  the  eggs.    Treatment  is  the  same  as  for 

There  are  two  other  organisms  (each  reported  but  once)  which  have 
been  interpreted  as  thorn-headed  worms  in  man,  but  the  cases  are  such 
that  opinions  differ  as  to  whether  they  represent  protozoa  or  worms  m  one 
instance,  and  worms  or  arachnida  in  the  other. 

INTESTINAL  AND  MUSCULAR  ROUNDWORMS. 

Trichinosis  or  Trichiniasis.— Infection  with   Trichinella  spiralis-} 

Geographical  Distribution.— Trichinte  are  practically  cosmopohtan, 
because  of  the  wandering  of  rats;  but  trichinosis  as  a  recognizable  disease 
in  man  is  practically  limited  to  persons  who  indulge  in  the  mis-custom 
("Unsitte")  of  eating  raw  or  rare  pork.  _         _ 

Zoological  Distribution.— From  a  practical,  hygienic  point  of  view,  the 
zooloo-ical  distribution  of  trichinosis  extends  to  man,  hogs,  wild  boars, 
rats  docvs,  and  cats.  It  is  also  reported  for  several  other  animals,  such  as 
the  fox,  etc.,  and  has  been  transferred  experimentally  to  several  rodents 
(rabbits,  hares,  etc.)  and  other  animals  (sheep,  cattle,  etc.),  but  these  ex- 
ceptional infections  or  infections  in  animals  not  used  tor  food  do  not 
enter  largely  into  any  scheme  of  prophylaxis.  ,     ,    .  ,  • 

The  Parasite.— Three  stages  of  the  parasite  should  be  clearly  held  in 

mind:  ,  .  .  .  , 

(a)  The  adults  live  in  the  duodenum  and  jejunum;  the  males  measure 
1  4  to  1.6  mm.  in  length  by  40/i  in  diameter,  while  the  females  are  3  to 
4  mm  long  by  60/i  thick;  they  are  circular  on  cross  section  and  appear  as 
minute  thread-like  objects;  the  oesophagus  is  supported  by  a  single  rotv  of 
cells  known  as  the  cell-body;  the  male  is  without  spicules;  the  female  is 
viviparous,  the  vulva  being  situated  about  one-fifth  the  length  of  the 
body  from  the  mouth.  The  males  die  shortly  after  copulation._  ihe 
females  may  remain  for  a  few  weeks  in  the  lumen  of  the  intestine,  or 
they  bore  into  the  lymphatic  spaces  of  the  intestine  where  they  hve  about 
five  to  seven  weeks  and  deposit  their  numerous  young,  about  1,500  or 
more  per  female,  namely,  the —  i     i      c      • 

(b)  Embryos,  which  measure  about  90  to  100/x  m  length  by  bp.  in 
breadth;  these  wander,  either  with  the  lymph,  or  with  the  blood  less 
frequently  actively,  to  the  striated  muscles.  They  begm  to  reach  the 
muscle  about  the  tenth  day  after  infection;  they  enter  the  muscle  fibers 
and  there  develop  into  the —  .      .       ,    ^  n 

(c)  Encysted  Larvae.— The  cysts  vary  somewhat  m  size,  but  are  usually 
about  400  by  250/i.  These  encysted  larvae  may  remain  alive  in  the  mus- 
cles for  years,  cases  being  reported  for  as  long  periods  as  twenty  to 
thirty-one  years.  The  encysted  worm  (the  "fleshworm  )  is  the  infect- 
ing stage,  found  in  the  hog;  upon  being  swallowed  m  raw  or  rare  pork 
the  cyst  is    destroyed,   the  larvse  pass  from  the  stomach  to  the  small 

1  While  the  more  commonly  known  name  Trichirm  spiralis^  is  not  available  for 
this  parasite,  it  is  not  quite  certain  whether  its  correct  name  is  Trwhmella  spiralis 
or  Trichinus  spiralis. 


606  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

intestine  and  develop  within  about  two  days  or  less  to  the  adults;  the 
latter  copulate  and  may  have  embryos  in  the  uterus  within  less  than 
a  week  after  infeetion. 

Source  of  Infection. — Leaving  out  of  consideration  the  rare  exceptions, 
and  considering  only  the  usual  methods,  it  may  be  said  that  (a)  man 
obtains  trichinosis  from  eating  pork;  (b)  hogs  become  infected  from 
eating  (1)  uncooked  swill  containing  scraps  of  pork,  (2)  swine  offal  at 
country  slaughter  houses,  and  (3)  rats;  (c)  rats  obtain  their  infection  by 
eatino-  (1)  each  other,  (2)  scraps  of  jiork  in  houses  or  at  meat-shops  and, 
(3)  swine  offal  at  country  slaughter  houses.  Thus,  rats  alone,  swine 
alone,  or  rats  and  swine  together,  may  keep  up  an  endless-chain  infection, 
while  the  infection  which  reaches  man  terminates  with  the  death  of  the 
individual.  Accordingly,  man  must  be  viewed  as  a  more  or  less  accidental 
host  for  the  disease,  while  the  rat,  because  of  its  cannibalistic  habits,  pre- 
sents, theoretically,  ideal  conditions  to  serve  as  a  normal  host  for  this 
parasite. 

Duration. — As  a  clinical  combination  of  symptoms,  trichinosis  may 
last  from  a  fcAV  days  to  several  months,  but  usually  it  runs  its  course  in 
about  two  or  threeto  five  or  seven  weeks;  convalescence  is  slow  and  may 
require  ten  to  seventeen  weeks,  while  cases  are  recorded  where  the  pa- 
tients have  not  fully  recovered  from  the  effects  for  years.  As  an  infec- 
tion, on  the  other  hand,  it  is  reported  as  having  lasted  for  five  to  twelve 
years  in  man  and  eleven  to  twenty-four  years  in  the  hog;^  that  is,  cases  are 
reported  in  which  it  is  maintained  that  the  encysted  parasites  have  re- 
tained their  vitality  for  these  periods. 

Symptoms. — Incubation  may  last  from  several  hours  to  several  weeks, 
according  to  the  amount  of  infection,  and  according  to  whether  a  large 
number  of  parasites  are  ingested  at  one  time,  or  whether  consecutive  in- 
fections of  a  smaller  number  of  worms  have  occurred.  Some  infections 
are  so  light  as  to  be  entirely  overlooked;  other  light  cases,  which  might 
escape  proper  diagnosis,  are  recognized  because  of  their  contemporaneous 
occurrence  with  severe  cases  in  the  same  family  or  among  people  trading 
with  the  same  butcher.  The  more  severe  typical  cases  present  Rup- 
precht's  three  more  or  less  well-defined  periods,  corresponding  to  the 
three  stages  of  the  parasite  and  their  respective  location: 

1.  Period  of  Ingression. — The  adidt  parasites  are  in  the  lumen  or  the 
tissues  of  the  intestinal  tract,  hence  the  gastro-intestinal  symptoms  pre- 
dominate; but  in  some  cases  these  may  be  absent  or  very  slight.  Within  a 
few  hours  to  two  days  or  so,  there  is  a  more  or  less  heavy  feeling  in  the 
stomach,  with  eructations;  nausea  develops,  and  the  patient  may  vomit 
once  or  several  times,  or  in  some  cases  persistently  for  some  days;  the 
appetite  is  diminished,  constipation,  or  more  generally  diarrhoea  occurs, 
often  with  colic;  the  stools  are  at  first  faecaloid,  but  become  looser  even 
to  an  almost  watery  consistency;  this  diarrhoea  may  continue  for  some 
weeks  or  may  give  place  to  a  more  or  less  obstinate  constipation.  Mus- 
cular pains  may  develop  early,  even  before  the  muscular  tissue  is  invaded 
by  the  parasites;  recurrent  abdominal  pains,  especially  at  night  and  as 
frequently  as  six  attacks  within  twenty-four  hours,  may  develop  in  the 

lit  is  not  altogether  clear  to  the  writer  that  this  record  for  the  hog  must  be 
accepted  as  absohite,  for  repeated  infections  might  have  occurred  during  thes^ 
long  periods. 


ROUNDWORM  INFECTION—NEMATHELMINTHES  607 

severest  cases;  the  extremities  become  cold;  the  pulse  small  and  inter- 
mittent. Toward  the  eighth  day  a  temporary  first  cjedema  of  the  eyelids  and 
face  may  appear  lasting  for  from  two  to  five  days.  From  the  seventh  or 
eighth  day  on,  large  numbers  of  wandering  embryos  are  found  in  the  peri- 
toneal, pleural,  and  pericardial  cavities. 

2.  Period  of  Digression. — ^This  begins  on  about  the  ninth  or  tenth  or 
fourteenth  day,  rarely  as  late  as  the  forty-second  day  (repeated  small  in- 
fections ?),  and  corresponds  to  the  period  during  which  the  embryos  are 
wanderhig  and  attacking  the  muscles;  accordingly  muscular  symfjtoms 
(myositis)  are  the  most  prominent.  The  symptoms  may  be  exceedingly 
light  to  severe.  Certain  muscles,  particularly  the  biceps  and  gastrocne- 
mius, are  more  firm  than  usual,  hard  and  very  tender,  especially  when 
the  patient  extends  the  forearm  or  leg.  Movement  may  cause  excruciat- 
ing pain,  and  for  relief  the  patient  assumes  a  position  of  semiflexion. 
Mastication,  speech,  and  movement  of  the  eyes  become  painful;  more 
or  less  complete  aphonia  may  occur  and  the  eyes  become  fixed;  respira- 
tion becomes  difficult,  and  respiratory  troubles  are  likely  to  be  severe, 
especially  in  the  fourth  and  fifth  weeks;  there  may  be  severe  dyspnoea, 
accompanied  by  violent  asthma. 

3.  Period  of  Regression. — All  symptoms  become  exaggerated,  and  in 
addition  the  patient  falls  into  an  extreme  cachexia;  a  second  oedema  de- 
velops about  the  twenty-fourth  day,  occurring  in  about  90  per  cent,  of 
the  cases  and  attacking  the  head  especially;  hence  the  name,  "disease  of 
the  big  head,"  occasionally  applied  to  trichinosis  in  Europe.  The  larval 
parasites  encyst  and  the  patient  gradually  recovers. 

It  is  hardly  necessary  to  remark  that  this  rather  diagrammatic  clinical 
picture  may  vary  according  to  the  amount  and  number  of  the  infections, 
exactly  in  the  same  way  that  a  double  tertian  or  a  double  or  triple  quartan 
malaria,  or  consecutive  malarial  infections  at  different  hours,  modify  the 
clinical  picture  of  malaria. 

Early  or  late  pruritus  and  formication  may  occur  at  certain  points  or 
over  the  entire  body;  cutaneous  anaesthesia  is  rare.  Profuse  sweating 
is  likely  to  occur,  especially  during  the  myositis.  Stiffness  of  the  muscles 
of  the  neck  and  back,  extending  to  a  distinct  opisthotonos,  has  been  re- 
corded.   Thirst  is  increased. 

In  females,  anomalies  occur  in  menstruation,  and  abortion  is  reported 
for  some  pregnant  patients. 

The  urine  decreases  in  quantity  with  the  second  week,  but  toward  the 
fifth  or  sixth  week  and  in  convalescence  there  is  polyuria.  There  may  be 
an  abundant  sediment  but  the  presence  of  albumin  is  exceptional;  the 
urine  may  be  intensely  red  in  color. 

As  the  nutrition  is  poor,  extreme  emaciation  and  anaemia  may  develop, 
and  there  may  be  oedema  of  the  lungs  and  an  obstinate  bronchitis. 

The  mental  faculties  are  dulled,  and  the  patient  is  indifferent  to 
what  occurs  in  his  presence.  In  severe  cases  more  marked  nervous 
symptoms  develop — extreme  insomnia  or  somnolence,  delirium,  etc. 
Opisthotonos,  due  to  stiffness  of  the  muscles  of  the  neck  and  back,  may 
be  noticed. 

Even  in  light  cases  moderate  fever  may  be  present;  in  severe  cases  it 
appears  during  the  stage  of  ingression;  the  temperature  rises  after  the 
beginning  of  the  muscular  symptoms,  often  reaching  104°  F.,  or  even 


608 


THE  ZOO-PARASITIC  DISEASES  OF  MAN 


105.8°  F.,  its  duration  (two  or  three  to  five  or  six  weeks)  depending  upon 
the  severity  of  the  infection ;  it  may  be  remittent  or  intermittent. 

The  puis'c  follows  the  temperature;  in  high  fever  it  may  exceed  100 
and  be  extremely  feeble. 

The  skin  not  infret|uently  shows  a  miliary  or  roseolous  eruption,  more 
rarely  herpes,  and  the  oedema  is  frequently  followed  by  extensive  epider- 
mic desquamation.  , 

Lethality. — The  death-rate  in  different  outbreaks  varies  between  0  and 
100  per  cent.  Of  1 1,820  cases  in  Germany  which  were  collected  by  the 
writer  for  the  years  1860-97,  831  were  fatal,  giving  a  death-rate  of  5.6 

Fig.  CG. 


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Temperature  record  in  trichinosis. 

per  cent.  The  death-rate  is  low  before  the  second  and  after  the  seventh 
week,  and  highest  from  the  fourth  to  the  sLxth  week,  when  the  myo- 
sitis is  at  its  maximum. 

Clinical  Diagnosis. — In  its  severe  form,  trichinosis  is  a  disease  which 
occurs  in  groups  of  cases.  In  less  extreme  outbreaks  cases  may  be  mis- 
taken for  typhoid  fever  and  "muscular  rheumatism."  The  possibility  of 
trichinosis  should  always  be  held  in  mind  in  case  of  the  occurrence  of 
several  typhoid-like  attacks  in  the  same  family  or  neighborhood,  or 
among  friends  (especially  Germans  from  Saxony  or  Eastern  Prussia), 
and  following  a  celebration  (wedding,  birthday  party,  etc.)  at  which  pork 
was  served,  or  among  families  trading  with  the  same  butcher.  When 
trichinosis  is  suspected  make  the  following  microscopic  examinations : 

(a)  Of  the  pork  (if  any  has  been  left)  to  find  encysted  larvse;  if  these  be 
found,  chop  the  pork  finely,  wash  thoroughly  in  water  to  remove  the  salt, 
and  feed  immediately  to  two  or  three  rabbits,  guinea-pigs,  or  white  rats 
in  order  to  determine  whether  the  larva?  are  alive;  never  use  wild  rats 
or  mice  for  this  experiment ;  kill  one  animal  after  two  or  three  days  and 
examine  the  contents  of  the  upper  half  of  the  small  intestine  for  the 
adult  worms;  kill  the  second  animal  after  two  weeks,  the  third  after 
three  weeks,  and  examine  the  muscular  portion  of  the  diaphram  for  the 
larvse.  Even  if  live  trichinae  are  found  in  the  intestine  of  the  first  animal, 
an  examination  of  the  second  and  third  experiment  animals  may  show 
that  the  parasites  were  too  weak  to  reproduce  to  any  extent,  hence  the 
prognosis  is  favorable. 


ROUNDWORM  INFECTION— NEMATIIELMINTII EH  609 

{h)  Upon  the  first  suspicion  of  trichinosis,  the  patient's  stools  should  be 
examined  for  discharged  adult  worms,  especially  if  the  diarrhcjca  is  severe; 
dilute  the  fsecal  matter  with  warm  water,  using  a  rather  tall,  narrow  gradu- 
ate, or  similar  dish ;  shake  well  and  allow  the  worms  to  settle  to  the  bottom ; 
pour  off  any  matter  which  floats;  place  the  sediment  in  a  shallow  glass 
dish  so  that  it  will  not  be  over  one-twelfth  of  an  inch  deep,  and,  moving 
it  gently  over  a  dark  background,  by  tipping  the  dish  first  to  one  side 
and  then  to  the  other,  hunt  for  small  hair-like  objects  which  tend  to 
cling  to  the  glass  (if  the  tipping  is  not  too  rapid) ;  place  these,  if  found, 
in  a  drop  of  water  on  a  slide,  cover  with  a  coverslip,  and  examine  under 
a  low-power  lens. 

(c)  Examine  the  patient's  blood  for  eosinophilia.  The  observations 
by  Brown  of  the  enormous  increase  in  the  eosinophiles  has  led  to  the 
recognition  of  many  sporadic  cases  which  otherwise  would  have  been 
overlooked. 

{d)  If  in  the  third  week  or  later  and  diagnosis  is  not  established,  but 
trichinosis  is  suspected,  excise  a  minute  piece  of  the  patient's  deltoid; 
tease  this  on  a  slide,  add  a  drop  of  water,  or  water  and  glycerine,  flatten 
gently  by  pressure  on  the  coverglass,  and  examine  under  low  power. 

Prognosis. — This  is  better  in  children  than  in  adults,  better  in  cases 
with  severe  diarrhoea  in  the  early  part  of  the  disease,  and  good  after 
the  seventh  week.  If  appetite,  sleep,  and  respiration  remain  good, 
prognosis  is  good.  Coma,  delirium,  and,  in  the  last  weeks,  elevation  of 
temperature  and  extreme  dyspnoea,  are  bad  prognostic  signs.  Some  re- 
cover in  a  few  weeks ;  in  others,  recovery  is  tedious,  requiring  months  or 
several  years. 

Treatment. — If  from  the  occurrence  of  a  group  of  cases,  or  from  a 
microscopic  examination  of  meat,  an  early  diagnosis  is  made,  the  stomach 
should  be  washed  out  immediately.  In  case  of  an  early  diagnosis,  but  at  a 
time  too  late  to  recover  the  ingested  undigested  pork  or  the  worms  from 
the  stomach,  purge  the  patient  with  calomel,  in  order  to  remove  as  many 
of  the  worms  as  possible,  for  each  female  removed  from  the  intestine 
means  a  reduction  of  the  muscular  infection  by  from  1,500  to  several 
thousand  worms.  Calomel  has  in  addition  some  anthelmintic  property. 
Thymol  or  beta-naphthol  might  be  administered  with  good  effect.  Un- 
fortunately the  administration  of  anthelmintics  has  not  been  followed  by 
very  satisfactory  results,  the  failure  being  due  at  least  in  part  to  the  sub- 
epithelial position  of  the  females.  No  drug  is  known  to  kill  the  para- 
sites in  the  muscles.  After  the  parasites  once  leave  the  lumen  of  the 
intestine,  all  treatment  must  be  symptomatic  and  supportive.  Hot  baths 
and  morphine  may  be  used  to  relieve  pain;  the  profuse  perspiration  is 
relieved  by  atropine. 

Prevention. — The  German  school  favors  a  microscopic  examination 
of  pork  before  it  is  placed  on  sale,  but  statistics  (Stiles,  1901)  show  that 
this  system  is  not  only  very  expensive  but  also  open  to  many  practical 
sources  of  error. 

Frequent  suggestions  are  made  in  American  journals  or  text-books  that 
we  should  introduce  this  microscopic  inspection  into  the  United  States. 
There  are,  however,  numerous  difficulties  (legal,  financial,  practical,  and 
theoretical)  in  the  way  of  carrying  out  such  a  plan.  It  would  cost,  in 
the  aggregate,  several  million  dollars  per  year,  and  that  sum  of  money 

39 


610  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

could  be  spent  to  much  better  advantage  in  fighting  tuberculosis  or  some 
other  serious  disease.  The  federal  government  could  inspect  the  meat 
only  at  the  registered  abattoirs,  and  a  system  which  has  shown  such 
poor  results  in  Germany  would  certainly  not  appeal  strongly  to  national, 
state,  and  local  legislative  bodies  when  the  heavy  a])propriation  was  de- 
manded. To  inspect  tlie  ])()rk  in  s])arsely  settled  portions  of  this  country  is 
an  impracticable  proposition.  Further,  experience  has  shown  that  the 
microscopic  inspection  gi^■es  a  false  sense  of  security,  antl  even  in  (ier- 
many  the  authorities  have  repeatedly  felt  it  necessary  to  warn  the  public 
not  to  trust  to  the  inspection,  but  to  protect  against  the  disease  by 
thoroughly  cooking  the  pork.  If  a  Saxon  or  an  East-Prussian  desires, 
upon  coming  to  this  country,  to  bring  with  him  his  mis-custom  ("Unsitte") 
of  eating  raw  or  rare  pork,  let  him  see  that  his  pork  is  inspected  at  his  own 
expense;  but  let  us  carefully  study  the  German  statistics  .before  we  increase 
directly  or  indirectly  the  taxes  of  the  other  people  (who  do  not  care  to  eat 
raw  jiork)  in  this  country  by  supporting  an  uncertain  hygienic  measure 
in  order  that  a  few  immigrants  may  please  their  palates  with  a  meal  of 
raw  pork. 

If  pork  is  thoroughly  cooked  or  thoroughly  cured,  there  is  no  danger  of 
contracting  trichinosis;  and  since  cooking  and  curing  are  methods  which 
appeal  to  American  and  English  tastes,  we  can  well  urge  these  upon 
hygienic  groiuids  also.  An  extermination  of  rats  would  result  in  a  de- 
crease of  trichinosis. 

Pseudotrichinas. — Various  parasites  have  been  mistaken  for  trichinse. 
Thus,  a  sarcosporidium  {Sarcocijstis  miesclieriana) ,  which  is  exceedingly 
common  in  pork,  has  been  repeatedly  mistaken  for  trichinae,  but  the 
fleshworm  is  usually  wound  in  a  spiral  and  enclosed  in  a  much  thicker 
cyst,  while  the  Sarcocijstis  is  more  elongate,  slender,  straight,  and  with 
content  that  appears  granular  under  the  microscope;  under  high  power 
magnification,  these  granule-like  bodies  are  seen  to  be  more  or  less 
crescentic  in  form,  somewhat  similar  to  the  crescents  of  sestivo-autumnal 
malaria.  The  worms  described  as  Trichina  affinis,  T.  agilissima,  T. 
anguillce,  T.  cystica  (see  p.  600),  T.  cyprinorum,  T.  inflexa,  T.  lacertw, 
and  T .  microscopica,  from  various  animals,  are  not  trichinae.  Various 
strongyles  also  have  been  recorded  as  trichinae.  A  very  interesting  case  of 
pseudotrichinosis  is  presented  in  Rhabditis  terricola  (R.  corntoaUi-Pelodera 
setigcra).  This  nematode  was  found  in  an  exhumed  cadaver  of  an 
English  cadet,  from  the  ship  Cornwall,  and  was  mistaken  for  a  trichina; 
on  the  basis  of  this  erroneous  zoological  determination,  the  outbreak  of 
disease  which  had  occurred  was  pronounced  trichinosis  and  attributed  to 
American  pork. 


PULMONARY  ROUNDWORMS. 

Metastrongylus  apri  (GmeUn,  1790)  is  a  12  to  50  mm.  long  thread- 
worm, which  is  rather  common  in  the  lungs  of  hogs.  It  has  been  reported 
by  Diesing  (lS51a,  317)  once  for  the  lungs  of  man;  Chatin  (1888b)  states 
that  it  also  occurs  in  the  stomach  of  man,  but  such  cases  are  probably 
due  to  eating  hogs'  lungs  containing  the  worms.  Rainey's  (1855)  case  of 
Filaria  trachealis  in  the  trachea  and  larynx  of  a  human  subject  may 


ROUNDWORM  INFECTION— NEMATIIELMINTIIEB  611 

possibly  belong  under  M.  apri.    The  eggs  of  M.  apri  measure  50  to  100  by 
37  to  72/x,  and  contain  an  embryo  at  oviposition. 


SUBCUTANEOUS  ROUNDWORMS. 

Gnathostoma  siamense  (Levinsen,  1889)  is  a  very  remarkable 
nematode  which  has  been  collected  on  two  occasions,  from  three  sim- 
ilarly affected  patients  in  Siam.  It  attains  9  mm.  in  length  by  1  mm.  in 
breadth;  head  globular,  with  8  circles  of  simple  spines;  mouth  with 
two  lips;  anterior  third  of  body  with  scale-like,  tridentate  spines,  which 
become  smaller  and  more  simple  the  farther  they  are  from  the  head.  The 
brief  description  by  Levinsen  is  based  upon  a  female  parasite  collected 
from  a  Siamese  in  a  superficial  nodule  on  the  side  of  the  chest. 

Rhabditis  niellyi  (Blanchard,  1885)  is  at  present  a  nominal  species 
which  can  scarcely  be  classified  even  generically  with  any  degree  of  cer- 
tainty. It  is  known  only  as  a  rhabditiform  larva,  333/i  long  by  13/^ 
broad,  which  was  found  by  Nielly  (1882)  in  cutaneous  papules,  chiefly 
on  the  limbs,  in  a  boy  at  Brest;  small  worms  were  also  found  for  a  time 
in  the  blood,  but  examination  of  the  faeces,  urine,  and  sputum  was 
negative.  Authors  have  compared  this  case  with  craw-craw,  and  have 
explained  the  infection  upon  the  assumption  that  the  boy  might  have 
swallowed  eggs  in  drinking  water  of  poor  quality;  that  the  embryo  then 
escaped  and  reached  the  blood  and  skin.  Possibly  an  equally  plausible 
explanation  would  be  to  assume  a  direct  cutaneous  infection  after  the 
manner  of  uncinariasis. 

Dracunculosis^  or  Guinea-worm  Infection. — Geographical  Distri- 
bution.— This  is  essentially  an  Old-World  infection,  being  found  in  India, 
Persia,  Turkestan,  Arabia,  and  certain  parts  of  Africa.  It  was  intro- 
duced into  South  America  by  the  slaves,  but  does  not  appear  to  have  flour- 
ished there  to  any  great  extent.  Occasional  imported  cases  are  reported 
in  other  parts  of  the  world,  several  being  recorded  for  the  United  States 
(Francis,  1901a,  and  others). 

Zoological  Distribution. — This  parasite  is  reported  not  only  for  man 
but  also  for  cattle,  horses,  dogs,  and  several  wild  animals.  Manson  has 
suggested  that  possibly  some  of  these  cases  represent  specifically  distinct 
infections. 

The  Parasite. — The  Guinea- worm  or  Medina- worm,  Dracunculus 
medinensis  (Linnaeus,  1758),  is  a  white  to  yellowish  parasite,  50  to  80  or 
more  cm.  long  by  0.5  to  1.7  mm.  in  diameter;  its  anterior  end  is  bluntly 
rounded,  with  a  small  terminal  mouth  and  6  papillae.  A  vulva  has  not 
been  discovered,  the  genital  organs  probably  discharging  through  the 
oesophagus.  The  intestine  is  rather  reduced  and  no  anus  is  present  in 
adult  specimens.  The  uterus  is  enormovisly  developed  and  filled  with 
sharp-tailed  embryos  0.5  to  0.75  mm.  long  by  0.17  mm.  in  maximum 
diameter.    The  male  is  not  positively  known. 

Source  of  Infection. — ^The  embryos  escape,  apparently  through  organs 
prolapsed  through  the  mouth  of  the  adult  worm,  and  may  live  in  clear 
water  for  six  days,  in  muddy  water  or  moist  earth  two  to  three  weeks;  if 

^Synonyms. — Dracontiasis;  Guinea-worm  disease. 


612 


THE  ZOO-PARASITIC  DISEASES  OF  il/A.V 


Fig.  67. 


Nerv. 


slowly  dried,  they  resuscitate  in  water.  They  may  enter  small  crustaceans 
{Ci/ciops  bicuspi'dafus,  etc.),  and  within  about  three  weeks  develop  to  1  mm. 
in  ieno-th,  casting  the  skin  two  or  three  times,  losing  the  long  tail,  acquiring 
a  cylindrical  shape,  and  developing  a  trijiartite  arrangement  on  the  tip  of 

the  tail.  They  are  then  supposed  to  be 
swallowed  in  the  drinking  water.  Accord- 
ing to  Plehn's  experiments,  a  direct  develop- 
ment without  intermediate  host  is  not  ex- 
cluded. It  was  formerly  believed  that  the 
worm  entered  through  the  skin,  and,  as 
this  mode  of  infection  is  now  demonstrated 
for  certain  other  worms,  doubtless  the  possi- 
bility of  this  method  will  again  be  considered 
in  connection  with  this  species.  The  further 
history,  to  the  gravid  condition,  has  not 
been  followed,  but  probably  the  worms 
soon  leave  the  intestinal  canal  and  reach  the 
connective  tissue;  after  copulation  the  male 
probably  dies,  while  the  gravid  female, 
about  eleven  and  one-half  to  fourteen 
months  after  infection,  wanders  to  the  sub- 
cutaneous tissue. 

Frequency. — It  is  not  uniformly  distrib- 
uted throughout  the  general  area  of  infec- 
tion but  is  especially  common  in  some 
districts.  In  parts  of  Deccan,  at  certain 
seasons  of  the  year,  about  50  per  cent,  of  the 
population  is  infected ;  in  some  parts  of  the 
western  coast  of  Africa  nearly  every  negro 
has  one  or  more  specimens  (Manson). 

Symptoms. — The  gravid  parasite  pro- 
duces very  painful,  superficial,  furuncle-like 
swellings,  chiefly  on  the  feet  and  legs  (about 
85  per  cent,  of  the  cases),  and  occasionally 
on  other  parts  of  the  body,  as  the  back,  neck, 
head,  wrist,  scrotum,  penis,  etc.  A  small 
blister  forms  and  elevates  the  epidermis; 
the  blister  ruptures,  disclosing  a  superficial 
ulcer  about  three-fourths  of  an  inch  in 
diameter,  at  the  centre  of  which  there  is 
a  small  opening  about  two  millimeters  in 
diameter,  from  which  the  head  sometimes 
protrudes.  There  may  be  fever,  chill,  nausea, 
and  vomiting.  The  swelling  may  last  two 
or  three  weeks;  then  the  worm  is  extruded 
and  the  wound  heals;  or  premature  death  of  the  parasite  may  give  rise 
to  an  abscess;  or  the  worm  may  become  calcified  and  be  felt  for  years  as 
a  hard  knot. 

Treatment. — Emily's  (1894a)  treatment  consists  in  injecting  bichlor- 
ide of  mercury  (1  to  1000)  into  the  protruding  worm,  which  can  then  be 
easily  removed  twenty-four  hours  later;  or  if  the  worm  itself  is  not  visible, 


An.  Gl. 


Embryo  of  the  Guinea -worm. 
Nerv.,  nervous  system;  CEs., 
CBSophagus  ;  /ni.,  intestine;  Gen., 
genital  primordium;  An.  67., anal 
papillae  of  glandular  nature 
X 190.     (Looss.) 


ROUNDWORM  INFECTION—NEMATHELMINTHES  613 

a  few  drops  of  the  solution  are  injected  as  near  the  coil  as  possible;  the 
parasite  may  then  be  wound  out,  or  cut  out.  Another  method  is  to  protect 
the  infected  part  from  injury  and  douch  it  frequently  with  water;  when 
this  is  done  the  uterus  gradually  empties  and  the  worm  may  be  extracted 
or  it  may  come  out  of  its  own  accord.  Traction  should  not  be  used  so 
long  as  the  parasite  discharges  embryos,  a  point  which  may  be  deter- 
mined by  microscopic  examination  of  the  fluid  issuing  from  the  opening. 
The  old  method  of  extraction  is  to  pass  a  coil  of  the  parasite  through 
the  cleft  end  of  a  small  stick  and  to  wind  it  out  of  the  wound  ver7j  slowly, 
making  only  one  or  two  turns  of  the  stick  daily.  The  objection  to  this 
method  is  that  the  worm  sometimes  breaks,  the  embryos  escape  into  the 
surrounding  tissue;  violent  inflammation  ensues,  with  fever,  abscess,  and 
sloughing,  and  weeks  or  months  may  elapse  before  the  patient  recovers; 
death  may  occur  from  septic  infection. 

Prevention.— Upon  the  theory  that  the  infection  takes  place  through 
the  drinking  water,  only  filtered  or  sterilized  water,  or  water  of  unques- 
tionable origin  should  be  taken  when  traveling  in  an  infected  region. 


FILARIASIS. 

Infections  with  Threadworms  of  the  Genus  Filaria.^— The  genus 
Filaria  Miiller,  1787,  includes  long,  slender,  filiform  threadworms  with 
curved  or  spiral  tail.  The  male  is  smaller  than  the  female,  has  2  unequal 
spicules,  4  preanal  papillse,  and  a  varying  number  of  postanal  papillse; 
in  the  females  the  vulva  is  near  the  anterior  end.  The  adults  are  parasitic, 
especially  in  the  connective  tissue,  lymphatics,  and  body  cavities;  the 
embryo  or  larva  frequently  inhabits  the  blood,  and  in  several  species  for 
which  the  life-history  is  known,  insects  such  as  mosquitoes  form  the  inter- 
mediate host. 

Quite  a  number  of  species  of  this  genus  are  reported  as  parasitic  in  man, 
but  not  all  of  them  are  described  with  sufficient  accuracy  to  permit  a 
positive  zoological  determination.  In  medical  literature  the  chief  interest 
has  centered  around  the  so-called  Filaria  sanguinis  hominis.  As  a 
matter  of  fact,  the  name  Filaria  sanguinis  hominis,  as  used  in  literature, 
means  but  little  more  to  zoologists  than  does  the  expression  "the  tadpoles 
of  Virginia."  We  know  that  Filaria  sanguinis  hominis  is  intended  to 
designate  a  young  stage  of  a  threadworm  in  the  blood  of  man,  the  same 
as  we  know  that  "the  tadpoles  of  Virginia"  is  intended  to  designate  young 
stages  of  frogs  found  in  Virginia.  In  recent  years  Filaria  sanguinis 
hominis  is  becoming  confined  more  and  more  to  one  species,  namely, 
to  Filaria  hancrofti;  but  as  a  scientific  name  it  should  be  eliminated  from 
medical  literature.  The  various  young  filarise  described  for  the  blood  of 
man  may  be  tabulated  as  follows : 

KEY    TO    THE    FILARIA   LARVAE    FOUND    IN   HUMAN    BLOOD. 

Sheath  present: — 

Periodicity  absent;  sheath  very  close;  tail  constricted,  then  sharply  pointed; 
body  292  to  330by  65/(;  type  locality,  Manila  P.I. ;  F.  philippinensis,  p.  624. 

^For  the  most  recent  zoological  summary  of  the  species  reported  for  man,  see 
Penel,  1905,  Les  filaires  du  sang  de  I'homme.     Paris. 


614 


THE  ZOO-PARASiTIC  DISEASES  OF  MAM 


Periodicity  present: — 

Nocturnal  periodicity  (?);  tail  truncated;  131by5.3«;  type  locality,  Bombay;' 

F.  poiLiclli,  p.  624. 
Nocturnal  periodicity; — • 
Tail  sharply  pointed;   317by7.5^u;  type  locality,  Australia;  (F .  nocturtia) 
F.  bancrojti,  p.  615. 

Tail  truncated;    164  by  8//;  type  locality,  Japan;  F.  taniguchii,  p.  622. 
Diurnal  periodicity;  317  by  7«;    type  locality,  West  Africa;    {F.  diuma) 
F.  loa;  p.  620. 
Sheath  absent;  no  periodicity: — 
Tail  sharply  pointed: — 

210  by  OIL]    type  locality,  West  Indies;  F.  demarquayi,  p.  622. 
215  by  5,h;   type  locality,  British  Guiana;  F.  ozzardi,  p.  622. 
Tail  blunt,  truncated: — 

195  by  4.5/(;  type  locality.  West  Africa;  F.  perstans,  p.  622. 

220  to  240  by  8  to  12^«;  type  locality.  West  Africa;  F.  gigas,  p.  624. 

So  far  as  can  be  discovered,  none  of  these  young  worms  does  any  appre- 
ciable injury  in  the  blood,  and  of  the  adult  worms  only  one,  namely, 
Filaria  bancrofti,  can  at  present  be  viewed  as  serious;  while  a  second 

THE  FOLLOWING  IS  A  LIST  OP  THE  FILARIA  REPORTED  FOR  MAN. 


ADULT  WORM. 

LARVA^  KNOWN  AS 

TYPE  LOCALITY 
AND  GENERAL  DIS- 
TRIBUTION. 

Filaria  bancrofti  Cobbold 
F.  loa  (Cobbold) 

F.  perstans  Manson 
F.  ozzardi  Manson 
F.  demarquayi  Manson 
F.  volvulus  Leuckart 

Filaria  nocturna  Manson 
F.  diuma  Manson 

F.  perstans  Manson 

F.  ozzardi  Manson 

F.  demarquayi  Manson 

Australia;  tropics. 
West   Africa;   In- 
dia. 
West  Africa. 
British  Guiana. 
West  Indies. 
Gold  Coast;  West 

F.  magalhaesi  Blanchard 

Africa. 
Rio  de  Janeiro. 

F.  taniguchii  Penel 
F.  equina  (Abildgaard) 

F.  taniguchii 

Japan. 

Europe ;   rather 
cosmopolitan. 

Pennsylvania; 
probably  cosmo- 
politan. 

Europe. 

F.  immitis  Leidy 

F.  lentis  Diesing 

F.  conjunctivae  Addario 

Italy;  Hungary. 
West  Virginia. 

F.  restiformis  Leidy 

F.  hominis  oris  Leidy 

Pennsylvania. 
Italy. 
Kilimara,  East 

F.  labialis  Pane 

F.  kilimarce  Kolb 

F.  romanorum  orientalis  Sarcani 

Africa. 
Roumania. 

[Unknown] 

Unknown] 
Unknown] 

F.  gigas  Prout 

F.  powelli  Penel 
F.  philippinensis   Ashburn 
and  Craig 

Sierra  Leone;  West 

Africa. 
Bombay. 
Manila,  P.  I. 

'  The  custom  of  giving  to  the  larva  a  special  name  is  not  admissible  under 
the  International  Code  of  Zoological  nomenclature.  Were  we  to  give  the 
egg  of  a  mosquito  one  name,  its  larva  a  second,  its  pupa  a  third,  and  the 
adult  a  fourth,  no  end  of  confusion  would  result.  A  species  is  entitled  to 
only  one  valid  name. 


RO UNDWORM  INFECTION— NEMA THELMINTHES 


615 


Fig.  68. 


Nerv. 


species,  F.  loa,  Is  more  or  less  troublesome.  We  are  hardly  justified  at 
present  in  assuming  that  all  the  other  species  are  entirely  without  effect 
upon  their  hosts,  but  just  what  their  effect  is  has  not  been  shown,  and 
whatever  it  may  be,  the  indications  are  that  at  least  in  cases  of  light  in- 
fection, that  effect  is  of  secondary  importance  when  compared  with  /''. 
bancrofti. 

It  is  especially  by  the  personal  influence  of  Sir  Patrick  Manson  that  our 
knowledge  of  the  filariae  of  man  has  been  advanced,  and  any  article  written 
upon  the  subject  must  necessarily  be  based,  to  no  little  degree,  upon  his 
work. 

Infection  with  Filaria  Bancrofti. — Geo- 
graphical Distribution. — Australia  is  the 
type  locality  for  this  parasite,  but  it  may 
be  designated  in  general  terms  as  a  tropical 
and  subtropical  infection  of  Asia,  Africa, 
and  America.  It  is  especially  common  on 
the  west  coast  of  Africa,  in  South  China, 
certain  parts  of  India,  Samoa,  Friendly 
Islands,  West  Indies,  etc.  In  the  United 
States  cases  are  occasionally  found  in  the 
Southern  States;  Mobile  (Anderson); 
Charleston,  S.  C.  (Guiteras  and  others); 
occasional  cases  are  found  further  n  rth. 

Zoological  Distribution. — ^The  ad  t  worm 
is  thus  far  known  only  for  man.  The  L.rva 
occurs  in  a  number  of  mosquitoes  (Ano- 
pheles, Culex  and  Panoplites). 

The  Parasite.^ — Bancroft's  filaria^  (Filaria 
bancrofti  Cobbold,  1877)  is  a  whitish  or 
brownish  ( ?)  transversely  striated  worm,  44 
to  95  mm.  long  by  0.1  to  0.26  mm.  in  diame- 
ter; male  with  two  spicules,  0.2  and  0.6 
mm,  long,  anogenital  pore  138/^  from  tail, 
preanal  papillae  uncertain,  but  apparently  3 
pairs  of  postanal  papillae;  vulva  of  the 
female  0.66  to  0.75  (or  1.2  to  1.3  mm.)  from 
head,  anus  225/z  from  tip  of  tail.  Vivipa- 
rous. The  larvse,  300  to  340 ^«  long,  by  6.6 
to  8.5  or  11//  in  diam.eter,  are  found  in  the 
circulating  blood  and  are  provided  with  a  sheath  and  sharply  pointed 
tail ;  they  show  a  more  or  less  marked  periodicity  in  that  they  are  much  more 
numerous  in  the  peripheral  circulation  during  the  night;  but  if  sleep  is 
reversed  to  day-time,  the  periodicity  also  is  reversed.  Mosquitoes,  while 
biting  patients,  swallow  these  larvse,  which  then  undergo  development  in 
the  muscles,  and  finally,  after  fourteen  to  seventeen  days,  or,  by  lower 


Larva  of  Filaria  bancrofti  in  the 
blood  of  man,  in  Egypt.  Nerv., 
nervous  system;  Ex.,  excretory; 
An..,  anus.    X514.     (Looss.) 


^  Synonyms. — Filaria  sanguinis  hominis  Lancet,  Lond  ,  1872,  Aug.  31,  p. 
310;  larva;  type  locality,  Calcutta  (Lewis).  F.  dermathemica  da  Silva 
Araujo  (1875) ;  type  locality,  Bahia.  F.  bancrofti  Cobbold,  1877g,  July  14; 
adult;  type  locality,  Australia.  F.  wuchereria  Magalhaes,  1877,  and  F. 
wuchereria  da  Silva  Lima,  1877;  type  locality,  Brazil.  Wuchereria  filaria 
Silva  Araujo,  1877.    F.  nocturna  Manson,  1891;  larva. 


616  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

temperature,  up  to  thirty-five  or  forty-one  days  from  time  of  infection,  the 
worms  reach  a  stage  in  which  they  are  transmitted  to  man  during  the  bite 
of  the  mosquito. 

Nothing  is  known  of  the  biology  of  the  worm  from  the  time  it  enters 
man  up  to  the  aduU  stage.  The  aduH  worms  occur  alone  or  as  several 
coiled  together,  chiefly  in  the  lymphatics,  but  also  occasionally  in  the 
fluids  in  swollen  organs.  There  is  no  satisfactory  explanation,  as  yet,  of 
the  periodicity  shown  by  the  larva. 

Source  of  Infection. — While  it  was  formerly  assumed  that  infection  took 
place  through  tiie  tirin king- water,  this  view  may  now  be  definitely 
abandoned  and  the  mosquito  bite  regarded  as  the  only  known  or  probable 
source  of  infection. 

Frequency. — The  frequency  of  the  infection  in  man  varies  with  the 
exposure  to  the  infected  mosquitoes,  and  this  of  course  varies  with  the 
habits  of  the  community,  combined  with  proximity  of  mosquito-breeding 
places.  In  some  places  the  infection  is  rare;  in  others  it  increases  to  5, 10, 
20,  50,  or  more  per  cent,  of  the  inhabitants. 

Duration. — Nothing  positive  is  known  regarding  the  longevity  of  the 
adult  or  larva,  but  apparently  neither  is  very  short  lived. 

Symptoms.— That  numerous  cases  of  infection  show  no  appreciable 
symptoms  is  well  established,  but  that  in  other  cases  the  worms  produced 
serious  results  must  be  admitted,  especially  if  the  adult  parasites  are 
present  in  large  numbers  or  unfortunately  located.  According  to  Manson, 
Filaria  bancrofti  may  produce  the  following  conditions;  abscess,  lymph- 
angitis, varicose  groin-glands,  varicose  axillary  glands,  lymph  scrotum, 
cutaneous  and  deep  lymphatic  varix,  orchitis,  chyluria,  elephantiasis  of 
the  leg,  scrotum,  vulva,  arm,  mamma,  etc.,  chylous  dropsy  of  the  tunica 
vaginalis,  chylous  ascites,  and  chylous  diarrhoea.  In  not  all  of  these  cases 
is  the  exact  method  by  which  the  parasites  act  fully  understood,  and  the 
relation  of  the  parasites  to  elephantiasis  is  based  chiefly  upon  circum- 
stantial evidence.  In  general,  the  adult  parasites,  or,  Manson  believes,  in 
some  cases,  "their  immature  products  of  conception,"  cause  two  principal 
types  of  filariasis,  one  characterized  by  a  varicosity  of  the  lymphatics,  the 
other  by  a  more  or  less  solid  oedema. 

The  frequency  of  these  various  manifestations  does  not  seem  to  be 
uniform  in  filarial  patients  in  different  geographical  areas,  but  the  reason 
for  this  variation  is  not  at  present  clear.^ 

Filarial  Abscess. — These  may  be  present  in  various  affected  organs  and 
may  contain  the  dead  adult  worms.  They  may  discharge  or  be  opened, 
if  in  the  thorax  or  abdomen  they  may  be  serious.  According  to  Manson, 
deep-seated  pain  in  the  thorax  or  abdomen,  with  inflammatory  processes 
followed  by  hectic  fever  and  a  diminution  in  the  number  of  or  disappear- 
ance of  filaria  larvje  in  the  peripheral  blood,  suggest  filarial  abscess  and 
indicate  exploration,  and,  if  feasible,  operation. 

Lymphangitis — ijlep^ianioid  Fever. — This  is  common  in  all  forms  of 
filariasis  due  to  F.  bancrofti;  it  may  or  may  not  be  followed  by  more  severe 
conditions,  as   elephantiasis,  lymph  scrotum,  varicose  glands,  etc.    It 

^Is  it  possible  that  local  conditions,  incident  to  the  geographical  distribution, 
have  resulted  in  differentiating  F.  bancrofti  into  several  subspecies,  each  with 
special  tendency  to  a  given  clinical  manifestation.  Or  have  we  in  man  even 
a  larger  number  of  distinct  species  of  Filaria  than  have  yet  been  described? 


ROUNDWORM  INFECTION— NEMATIIELMINTIIES  617 

usually  appears  on  the  extremities,  but  may  be  confined  to  other  parts  of 
the  body  (groin-glands,  testis,  spermatic  cord,  or  abdominal  lymphatics). 
The  attack  continues  for  several  (usually  two)  days,  then  may  recur  after 
weeks,  months,  or  years.  It  begins  with  a  severe  and  prolonged  chill 
(rigor),  followed  by  high  fever,  105.8°  F.;  is  accompanied  by  headache, 
loss  of  appetite,  frequently  vomiting,  and  even  delirium;  it  ends  with 
profuse  perspiration.  At  the  onset  of  lymphangitis  of  the  extremities,  the 
painful  cord-like  swelling  of  the  lymphatic  trunks  and  of  their  glands, 
with  a  red,  congested  streak  in  the  overlying  skin,  is  visible;  abscess  or 
gangrene  may  develop;  finally  the  tension  is  relieved  by  lymphous  dis- 
charge and  the  swelling  partially  subsides,  but  the  skin  and  subcutaneous 
tissue  do  not  return  to  quite  their  normal  condition,  some  permanent 
thickening  remaining.  Elephantoid  fever  has  been  repeatedly  mistaken 
for  malaria,  but  a  differential  diagnosis  should  not  be  difficult.  The 
filaria  embryos  are  not  always  found  in  the  blood.  In  treatment,  elevate 
the  affected  part,  compelling  absolute  rest;  give  a  milk  diet;  use  mild  laxa- 
tives, cooling  lotions  or  warm  fomentations,  opium  to  relieve  pain,  and 
scarify  the  swollen  area  if  necessary  to  relieve  tension. 

Varicose  Groin-glands,  H elmintlioma  Elasticum. — These  frequently 
accompany  lymph  scrotum  but  may  occur  with  other  filarial  manifes- 
tations; the  affection  may  be  unilateral  or  bilateral.  They  are  soft, 
doughy,  obscurely  lobulate,  and  stationary  in  position ;  but  the  skin  may  be 
readily  moved  over  them.  They  may  be  easily  mistaken  for  hernia.  If 
the  patient  lies  with  raised  pelvis  the  swelling  slowly  disappears;  but  if  he 
stands  erect  the  swelling  slowly  returns  while  the  hand  is  pressing  against 
the  saphenous  or  inguinal  openings.  The  contents  are  white  to  red, 
chylous,  rapidly  coagulable  fluid,  and  usually  contain  filaria  larvae.  This 
condition  is  frequently  mistaken  for  hernia,  but  the  swellings  are  not 
tympanitic  on  percussion ;  upon  pressure  they  disappear  slowly,  and  there 
is  no  gurgling;  there  is  little  or  no  impulse  on  coughing.  Manson  empha- 
sizes the  fact  that  chronic  swellings  about  the  groin,  cords,  testes,  and 
scrotum  in  patients  from  the  tropics  should  always  be  regarded  as  of 
possible  filarial  origin.  They  are  best  left  alone  unless  they  result  in  an 
incapacitating  discomfort,  when  they  may  be  removed.  Operation  is  not, 
however,  always  satisfactory,  as  it  may  be  follow^ed  by  lymphorrhagia, 
excessive  dilatation  of  some  other  part  of  the  lymphatic  area,  chyluria,  or 
by  elephantiasis.  Upon  Manson's  advice,  Godlee,  in  order  to  prevent 
lymph  stasis,  drained  the  lymphatics  of  the  region  operated  on  into  the 
vena  spermatica  and  v.  saphena,  obtaining  good  results. 

Superficial  or  Deep  Lymph  Varices. — These  are  not  rare,  and  may  be 
superficial  on  the  abdomen,  legs,  or  other  parts  of  body;  or  they  may  be 
more  deeply  located.  If  they  rupture,  lymphorrhagia  results.  They  may 
appear  and  disappear  within  a  few  hours,  and  indicate  lymphatic  ob- 
struction. 

Lymph  Scrotum. — ^This  is  frequently  accompanied  by  varicose  groin  and 
femoral  glands.  The  skin  is  silky  to  the  touch,  but  presents  lymphatic 
varices  which  may  open  and  discharge  milky  to  bloody,  rapidly  coagu- 
lating lymph,  usually  containing  filarial  larvae,  which  are  also  present  in  the 
blood.  Elephantoid  fever  probably  results  from  external  mechanical 
irritation;  the  scrotum  may  become  thickened,  and  elephantiasis  may 
develop.    In  treatment,  support  and  protect  the  scrotum,  which  should  be 


618  THE  ZOO-PARASITIC  DISEASES  OF  MAN' 

kept  clean  and  powdered;  but  otherwise  leave  it  alone  unless  inflam- 
mation be  frequent,  debilitating  lymphorrhagia  be  present,  or  elephantiasis 
develops.  If  operation  is  decided  upon,  excise  all  the  diseased  tissue, 
obtaining  flaps  from  the  thigh  if  necessary.  The  patient  should  be  warned 
of  the  possible  occurrence  of  chyluria  or  of  elephantiasis  of  the  leg  as  a 
result  of  this  surgicjil  interference. 

Chyluria ;  Hannaioclu/hiria. — This  is  very  common,  but  intermittent; 
it  may  appear  without  warning  or  may  be  preceded  by  pains  in  the  back, 
pelvis,  and  groin;  the  first  symptoms  may  be  retention  of  urine  due  to 
chylous  coagulation  in  the  bladder;  the  color  of  the  discharge  varies  from 
a  milky-white  to  a  blood  tinge,  not  only  in  different  cases  but  also  in  the 
same  case.  It  is  rarely  continuous;  attacks  occur  usually  lasting  weeks 
or  months  or  up  to  two  years  (Sheube),  with  more  or  less  i)rolonged  inter- 
vals. ^Yhile  not  directly  dangerous,  the  continued  drain  upon  the  system 
may  result  in  anannia,  debility,  depression,  and  incapacity  for  active  life. 
Attacks  are  favored  by  pregnancy,  childbirth,  running,  and  other  violent 
exertions  which  lead  to  rupture  of  a  lymphatic  varix  in  the  bladder-wall. 

Treatment  consists  in  absolute  rest  in  bed,  with  elevated  pelvis,  a  light 
saline  purge,  vesical  irrigation,  and  restriction  of  food  (especially  fats)  and 
fluids.  Various  drugs  (gallic  acid,  benzoic  acid,  salol,  chromic  acid,  gly- 
cerine, tincture  of  perchloride  of  iron,  methylene  blue,  quinine,  ichthyol, 
etc.)  have  gained  some  reputation,  but  INIanson  is  of  the  opinion  that 
they  have  no  effect  whatever.  P^ilarial  larvae  may  be  numerous  in  the 
urine. 

Orchitis. — This  occurs  as  an  acute  manifestation  accompanied  by  head- 
ache and  vomiting  and  disappears  as  rapidly  as  it  appears.  It  is  preceded 
by  elephantoid  fever;  there  is  a  very  rapid  and  very  painful  inflammation 
of  the  testes,  which  are  much  swollen;  the  swelling  may  also  involve  the 
epididymis,  spermatic  cord,  and  entire  scrotum.  Afterward,  the  fluid  in 
the  tunica  vaginalis  may  not  be  entirely  absorbed  but  may  lead  to  chy- 
locele.  Filarife  are  often  present  in  the  blood.  Manson  suggests  the  pos- 
sibility that  the  "malarial  orchitis"  of  certain  authors  may  in  reality  be 
a  filarial  orchitis. 

Chylocele. — This  manifestation  is  more  or  less  common,  either  alone  or 
more  frequently  with  or  as  a  result  of  varicose  lymph  glands,  lymph 
scrotum,  etc.  In  the  morning  it  is  always  soft  and  it  is  never  so  tense  as 
common  hydrocele.  Numerous  filarial  larvse  are  present  in  the  milky, 
reddish,  quickly  coagulating  content.  Treatment  is  identical  with  that 
of  ordinary  hydrocele. 

Elephantiasis. — The  recurring  attacks  of  elephantoid  or  erysipelatoid 
fever,  with  resulting  and  accumulative  thickening  of  the  affected  part, 
gradually  give  rise  to  an  elephantiasis,  which,  according  to  Manson,  is  the 
most  frequent  manifestation  of  this  filarial  infection.  Occasionally,  how- 
ever, progressive  elephantiasis  may  occur  after  only  one  or  several  attacks 
of  elephantoid  fever.  It  is  estimated  that  in  95  per  cent,  of  the  cases, 
the  elephantiasis  occurs  in  the  legs,  either  alone  or  viiih  elephantiasis  of 
the  scrotum  or  arms.  Elephantiasis  of  the  scrotum  is  also  common,  while 
that  of  the  arms,  mammae,  vulva,  and  limited  areas  of  the  skin  (peduncu- 
lated elephantoid  tumors),  is  more  rare.  In  only  a  proportion  of  the 
cases  are  the  filarise  found  in  the  blood  or  in  the  fluid  of  the  diseased 
organ. 


ROUNDWORM  INFECTION— NEMATHELMINTIIES  619 

The  skin  is  rough  and  coarse,  the  hair  is  coarse  and  sparse,  and  the 
nails  thick  and  deformed.  The  part  pits  but  sHghtly  or  not  at  all  on  pres- 
sure, and  does  not  glide  over  the  underlying  tissues.  The  skin  is  dense, 
fibrous,  and  enormously  hypertrophied;  the  connective  tissue  is  hyper- 
trophied  and  "blubbery"  from  its  infiltration  v^^ith  lymph;  bloodvessels 
are  large;  the  lymphatics  are  dilated  and  the  lymphatic  glands  enlarged. 
As  even  slight  injury  to  the  affected  part  may  induce  a  recurrence  of  the 
elephantoid  attacks,  care  must  be  taken  to  protect  it.  Violent  exercise, 
exposure  to  the  hot  sun,  etc.,  should  be  avoided.  Massage,  elevation  of 
the  affected  part  to  drain  out  the  lymph,  and  elastic  bandaging,  are  to  be 
encouraged.  Absolute  rest  in  the  recurrent  attacks  of  fever  should  be 
insisted  upon;   unfortunately  permanent  recovery  never  occurs. 

In  extreme  cases  of  elephantiasis  of  the  leg,  good  results  are  sometimes 
obtained  by  excising  a  longitudinal  strip  3  to  4  inches  in  breadth  by  12 
or  more  inches  in  length;  during  the  febrile  attacks,  tension  may  be 
relieved  by  punctures  with  a  lancet  under  aseptic  conditions. 

Elephantiasis  of  the  scrotum  frequently  develops  to  tumors  of  10, 
15,  20,  40,  or  50  pounds;  Manson  gives  224  pounds  as  the  largest  case 
on  record.  These  enormous  growths  are  unsightly  and  inconvenient, 
but  not  as  a  rule  directly  dangerous.  Occasionally  they  endanger  life 
by  becoming  gangrenous  or  by  abscess  formation.  They  may  develop 
either  rapidly,  in  tv/o  or  three  years,  or  very  slowly.  Upon  reaching 
such  a  size  that  they  are  unsightly  or  inconvenient,  surgical  interference 
is  indicated.  The  reader  must  be  referred  to  works  on  surgery  or  to 
special  papers  on  this  subject  for  the  full  technique  of  operation.  In 
brief,  the  scrotum  is  drained  by  ;3uspension,  and  the  position  of  the  testes 
determined,  also  of  hernia,  if  present;  the  lines  of  intended  separation  are 
marked  and  should  extend  only  through  sound  tissue,  since  otherwise 
disease  is  very  likely  to  occur  in  the  scar  or  flaps.  Perineal,  pubic,  and 
connecting  cuts  are  made;  elastic  webbing  is  used  to  expel  the  blood;  a 
figure-of-eight  is  made  with  rubber  cord  around  the  neck  of  the  tumor 
above  the  guiding  incisions  and  over  the  pelvis;  the  testes  and  cord  are 
dissected  out;  the  prepuce  channel  is  dissected  up  to  the  pubic  incision;  the 
penis  is  released;  the  perineal  and  pubic  incisions  are  deepened  and  the 
neck  of  the  tumor  is  cut  close  to  the  perineum.  The  bloodvessels  are 
ligated;  the  redundant  tunica  vaginalis  excised;  the  rubber  cord  removed; 
and  the  flaps  brought  together  in  a  T-  or  Y-line,  the  penis  emerging  at  the 
point  of  union.  The  mortality  of  the  operation  should  not  exceed  5 
per  cent. 

For  elephantiasis  of  the  arm,  massage  and  elastic  bandaging  are  used. 

A  number  of  authors  doubt  whether  elephantiasis  is  due  to  Filaria 
bancrofti.  The  general  weight  of  circumstantial  evidence  seems  however 
to  indicate  that  at  least  some  cases  are  due  to  this  cause,  while  other  cases 
which  might  formerly  have  been  attributed  to  this  worm  may  perhaps  be 
due  to  other  causes — as  streptococcus  infection.  Brault,  for  instance, 
recognizes  a  bacterial  (streptococcus)  and  a  filarial  elephantiasis. 

Diagnosis  in  General. — An  attempt  should  always  be  made  to  find  the 
larval  filaria  in  the  blood,  urine,  or  chylous  accumulation.  There  are 
chances  for  error  in  connection  with  the  examination  of  the  urine,  and 
probably  all  those  cases  in  which  eggs  are  reported  for  the  urine  should 
be  definitely  rejected.     Trichina  cystica  Salisbury,  for  instance,  which 


620  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

nearly  all  authors  have  identified  with  Filaria  bancrofti,  is  doubtless  Ox- 
yuris  vermicularis;  vinegar  eels  (Anguillula  aceti)  have  also  been  mis- 
taken for  filarite. 

Blood. — The  lymphocytes  increase  to  24  or  40  per  cent. ;  the  eosinophiles 
to  S  or  IS  per  cent. 

Treatment  in  General. — It  is  quite  generally  admitted  that  treatment 
to  exterminate  the  larv;e  in  the  blood  is  not  only  rather  unsuccessful  but 
also  unnecessary.  Authors  have  claimed,  however,  that  they  may  be 
reduced  in  numbers  with  thymol,  ichthyol,  etc.  The  writer  takes  excep- 
tion to  the  view  that  such  treatment  is  undesirable,  if  found  to  be 
practicable,  as  such  eradication  of  the  larvre  would  naturally  be  an  im- 
portant point  gained  in  jirevention.  Anthelmintic  treatment,  directed 
against  the  adult,  is  in  our  present  knowledge  not  only  useless,  but  appar- 
ently imdcsirablc,  as  the  dead  worm  is  viewed  as  more  dangerous  than 
the  live  ]>arasitc. 

With  Manson,  the  symptomatic  treatment  is  generally  admitted  as 
consisting  in  rest,  lowering  the  tension  of  the  lymphatics  by  saline  purga- 
tives, by  appropriate  food,  and  limitation  of  fluids  ingested.  Several  drugs 
(potassium  iodide,  gallic  acid,  methylene  blue,  ichthyol,  etc.)  have  gained 
a  temporary  reputation,  but  the  conclusion  drawn  is  that  their  adminis- 
tration accidentally  coincided  with  the  time  of  spontaneous  remission. 

The  necessity  for  asepsis  in  operation  is  so  self-evident  that  it  need  not 
be  emphasized  here.  Manson  advises  postponement  of  operation  as  long 
as  convenient,  but  some  authors  are  less  conservative  on  this  point. 

General  Prognosis. — While  filariasis  is  generally  admitted  to  be  a  dis- 
ease which  cannot  be  absolutely  cured,  the  prognosis  in  uncomplicated 
cases  is  reported  as  good.  Even  in  severe  infections  life  may  not  be  in 
danger. 

Prevention. — Every  person  who  shows  the  filaria  larvae  m  the  blood, 
independently  of  the  fact  whether  any  pronounced  symptoms  are  present, 
should,  because  of  the  danger  of  spreading  the  infection  by  mosquitoes, 
be  considered  a  danger  both  to  himself  and  to  the  persons  in  his  neigh- 
borhood. This  danger  can  be  checked  by  compelling  him  to  sleep  under 
a  mosquito-bar.  Thus,  the  rule  for  prevention  is :  protect  the  mosquitoes 
from  the  patient,  protect  the  patient  himself  and  others  from  mosquitoes, 
and  destroy  mosquitoes. 

Infection  with  the  Loa. — Geographical  Distribution.— This  infection 
is  known  particularly  for  the  west  coast  of  Africa,  but  imported  cases 
are  reported  for  other  localities,  chiefly  in  slaves  or  in  missionaries  who 
have  visited  western  Africa.  Ward  (1906)  has  recently  collected  all  of  the 
recorded  cases  and  has  published  several  new  cases  for  North  America. 

Zoological  Distribution. — The  loa  is  positively  known  only  for  man,  but 
Blanchard  states  that  according  to  Plehn  (1898)  the  natives  say  that  it  also 
occurs  in  sheep  and  goats. 

The  Parasite. — Filaria  (Loa)  loa'-  (Cobbold,  1864)  is  a  filiform,  colorless 
to  yellowish-white  threadworm,  16  to  57  mm.  long  by  0.3  to  0.57  mm.  in 

'Synonyms. — Filaria  oculi  Gervais  and  van  Beneden,  1859;  Dracunculus  oculi 
(Gervais  and  van  Beneden,  1859)  Diesing,  1860;  Dracunculus  loa  CohholA,  1864; 
Filaria  subconjunctivalis  Guyon,  1864;  Filaria  diurna  Manson,  1891;  F.  san- 
guinis hominis  major  Manson,  1891*  Filaria  sanguinis  diurna  Fagge  and  Pye 
Smith,  1902;  F,  bourgii  Brumpt. 


ROUNDWORM  INFECTION— NEMATHELMINTHES  021 

diameter;  the  cuticle  is  not  striated  but  is  provided  with  numerous  wart- 
like structures,  not  known  for  any  other  Filaria  found  in  man;  male  with 
lateral  caudal  alaj;  3  pairs  of  preanal  pedunculated  pajoillte,  decreas- 
ing in  size  from  the  anterior  to  the  posterior,  and  two  or  possibly  three 
pairs  of  smaller  postanal  papillae;  spicules  unequal,  113  and  176/7.  long; 
vulva  of  female  2.35  to  2.4  mm.  from  head;  viviparous.  The  larva 
(F.  diurna)  circulates  in  the  peripheral  blood  during  the  day,  disappearing 
at  night,  and  is  indistinguishable  morphologically  from  that  of  F.  ban- 
crofti.    Life-history  unknown. 

Manson's  view  that  F.  diurna  represents  the  larva  of  F.  loa  is  not 
accepted  by  all  authors,  and  in  fact  he,  himself,  merely  suggested  it  as  a 
possibility.  The  point  raised  by  several  authors  that  not  all  loa  patients 
show  F.  diurna  in  the  blood  examinations,  is  not  a  very  strong  argument 
against  the  hypothesis,  for  it  is  perfectly  possible  that  they  were  not 
examined  at  a  time  when  the  parasites  were  laying  their  young.  In 
September,  1904,  through  the  kindness  of  Sir  Patrick  Manson,  the  writer 
saw  in  London  a  lady  who  had  been  in  West  Africa  and  had  just  come  to 
him  to  have  a  loa  extracted;  she  also  had  F.  diwma  and  gave  a  history  of 
Calabar  swelling.  Other  recent  observations  seem  to  raise  Manson's 
hypothesis  practically  to  a  certainty. 

Source  of  Infection. — This  is  not  yet  determined.  There  is  a  popular 
impression  that  infection  occurs  through  the  drinking-water,  but  analogy 
would  point  to  some  insect  as  intermediate  host.  Manson  suspects  that 
mangrove  flies  (Chrysops  dimidiatus)  play  this  role;  experiments  on 
certain  mosquitoes  {Anopheles  costalis  and  A.  funestus)  have  been  neg- 
ative. 

Duration. — Filaria  loa  is  apparently  rather  long-lived;  it  has  been  seen 
in  persons  who  had  been  away  from  the  infectious  locality  for  from  four  to 
ten  or  eleven  years. 

Symptoms. — This  parasite  inhabits  the  connective  tissue  all  over  the 
body,  which  it  traverses  freely;  recent  observations  indicate  that  it  is 
quite  superficial;  it  is  seen  especially  around  the  eye  in  the  subcutaneous 
fascia  about  the  orbit,  between  the  conjunctivae  and  bulbus;  it  travels 
over  the  nose,  in  the  fingers,  penis,  etc.  It  disappears  from  the  surface  in 
two  or  three  days  and  reappears  after  some  days,  weeks,  or  months.  Its 
appearance  is  favored  by  warmth  and  retarded  by  cold. 

The  loa  causes  an  itching,  creeping,  prickling  sensation,  with  occasional 
oedematous  swellings  and  in  some  cases  lachrymation  or  considerable  pain; 
it  may  determine  a  more  or  less  intense  conjunctivitis  and  disturbances  in 
vision. 

Several  authors  have  associated  with  loa  infections  the  so-called  "Cala- 
bar swellings";  these  appear  suddenly  on  various  parts  of  the  body  as 
elevations  about  half  the  size  of  a  goose-egg,  or  40  to  60  mm.  in  diameter; 
they  wander  slowly,  about  20  to  30  mm.  per  day,  then  disappear  in  about 
three  days  to  reappear  after  some  months  or  years ;  they  are  painless,  but 
slightly  irritating;  do  not  pit  on  pressure,  and  feel  "somewhat  hot  both 
objectively  and  subjectively";  they  may  occur  on  any  part  of  the  body, 
but,  according  to  one  patient,  are  caused  by  rubbing  or  scratching  to 
relieve  the  irritation  produced  by  the  worm. 

Treatment. — When  the  loa  approaches  the  surface  it  can  readily  be 
seen  beneath  thin  skin;  for  instance,  in  the  eyelid  or  over  the  bridge  of  the 


622  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

nose.  It  is  then  secured  by  means  of  forceps,  an  incision  is  made,  and  a 
second  pair  of  forceps  used  directly  on  the  worm;  the  first  pair  of  forceps 
is  then  released  and  the  worm  drawn  out  with  the  second  pair.  Manson 
relates  that  the  natives  extract  the  parasite  by  means  of  a  sharp  thorn,  or 
drive  it  into  the  deeper  tissue  by  (lrop])ing  a  grain  of  salt  into  the  con- 
junctival sac.  He  suggests  the  injection  of  bichloride  of  mercury  (1  to 
1,000)  when  the  worni  appears  in  parts  of  the  body  other  than  near  the  eye. 

Filaria  taniguchii  Penel,  1905,  is  reported  as  G<S  mm.  long  (female), 
0.2  mm.  in  ma.ximum  diameter;  the  vulva  is  1.3  mm.  from  the  anterior 
extremity,  the  anus  0.23  mm.  from  caudal  end;  cuticle  unstriated;  an- 
terior end  with  2  pairs  of  buccal  papilla?;  eggs  40  by  25/z;  embryos  in 
utero  measure  290/z  long  by  7/i  in  diameter.  The  adult  is  found  in  the 
lymphatic  ganglia.  INIale  unknown.  The  larvae  show  a  nocturnal  per- 
iodicity in  the  peripheral  blood;  they  measure  164/i  long  by  8/t  in  diam- 
eter; a  sheath  is  present,  the  tail  is  truncated.  Type  locality,  Ama 
Kusha,  Japan. 

Filaria  perstans  Manson,  1S91,  was  based  upon  filarial  larvae  (see  p. 
614)  found  in  West  Africa  in  the  peripheral  circulation  both  night  and  day. 
Adult  worms,  45  to  80  mm.  long,  have  now  been  found  in  the  fat  connective 
tissue  in  upper  part  of  the  mesentery  and  elsewhere,  which  are  assumed  to 
be  its  adult  stage.  The  male  is  said  to  have  4  pairs  of  preanal  and  1 
pair  of  postanal  papillae;  in  the  female,  the  vulva  is  0.6  mm.  from  the 
mouth,  the  anus  0.145  mm.  from  the  tail.  The  head  in  both  sexes  is  large 
and  the  tail  is  described  as  having  2  minute  triangular  projecting 
appendages,  giving  it  a  mitred  appearance.  This  parasite  is  also  reported 
for  British  Guiana. 

Filaria  ozzardi  INIanson,  1897,  is  reported  for  connective  tissue  in 
British  Guiana;  the  worms  are  38  to  81  mm.  long;  male  without  (  ?)  any 
caudal  papillae;  in  female,  vulva  0.71  mm.  from  mouth,  anus  0.23  mm. 
from  tail.  Larvae  (see  p.  614)  in  peripheral  blood  night  and  day.  This 
species  is  not  thoroughly  established. 

Filaria  demarquayi  Manson,  1895,  is  a  threadworm  which  has  been 
reported  for  St.  Vincent,  West  Indies  (type  locality),  St.  Lucia,  Dominica, 
and  Trinidad.  The  male  is  not  known.  The  female  measures  65  to  80 
mm.  long  by  0.210  to  0.2.50  mm.  in  diameter;  the  vulva  is  0.76  mm.  from 
the  mouth;  anus  0.25  mm.  from  the  tail;  it  lives  in  the  subperitoneal  con- 
nective tissue  and  is  known  only  for  man.  The  embryo  lives  in  the  blood, 
is  200  to  210/i  long  by  5/i  in  cUameter,  without  sheath;  the  tail  is  sharply 
pointed;  movements  are  very  active;  they  do  not  exhibit  any  daily 
periodicity.  The  life-history  is  unknown  and  experiments  on  mosquitoes 
have  thus  far  been  negative. 

Filaria  volvulus  Leuckart,  1893,  has  been  reported  in  subcutaneous 
tumors,  from  5  patients  from  West  Africa.  The  male  measures  30  to  35 
cm.  long,  and  has  two  unequal  spicules  (Prout),  82  and  177/f  long;  tail 
strongly  incurved.  The  female  measures  60  to  70/i,  and  is  viviparous. 
The  embryos  are  250//  by  5  to  6//,  without  sheath,  and  with  sharp  tail. 
These  have  been  found  in  tumors,  but  not  in  the  blood.  According  to 
Labadie  Lagrave  (1899)  the  worm  is  in  a  lymphatic  canal. 

Filaria  magalhaesi  Blanchard,  1895,  has  been  found  but  once,  in  the 
left  heart  of  a  child  in  Rio  de  Janeiro.  The  male  is  83  mm.  long,  with  4 
preanal    and    4    postanal    peculiar   papillse,    with   scalloped    outlinej 


ROUNDWORM  INFECTION— NEMATHELMINTHES  623 

shorter  spicule  0.23  min.  long,  longer  spicule  not  measured;  female  155 
mn?  iong;  vulva  2.5G  mm.  from  head;  cuticle  with  transverse  striation. 
NotJxmg  is  known  regarding  the  life-history  or  medical  importance  of  this 
worm, 

Fuaria  conjunctivse  Addario,  1885,  is  a  filiform,  5.5  to  16  cm.  long, 
white  to  brownish  nematode  which  occurs  in  the  eye  and  ligamentum 
gastro-lineale  of  man,  and' in  the  eye  of  horses  and  asses,  in  Europe 
(Italy,  Hungary).  Three  or  four  cases  are  reported  for  man.  Only  the 
female  parasite  has  been  seen  and  nothing  is  known  of  the  life-cycle. 

(?rilaria)  labialis  Pane,  1864,  has  been  reported  but  once,  from  the 
upper  lip,  in  Naples.  It  measures  about  30  mm.  long;  mouth  with  4 
papilli3e;  vulva  2.5  mm.  from  anus;  anus  0.5  mm.,  from  tip  of  tail. 

Filaria  immitis  Leidy,  1856,  is  a  12-to-30-cm.  long  threadworm 
found  in  the  right  half  of  the  heart  of  dogs.  Mosquitoes  {Anopheles  and 
Culex)  form  the  intermediate  host.  Bowlby  is  said  to  have  reported  its 
presence  in  the  portal  vein  of  man,  but  the  zoological  determination 
is  open  to  question.  It  has  been  claimed  that  the  worm  in  question 
was  undoubtedly  a  blood  fluke  {Schistosoma  hcematobmm.) 

Agamofilaria  OCUli  {F.  lentis  Diesing,  1851)  is  a  species  inquirenda; 
worms  varying  from  1.72  to  12.6  mm.  in  length  have  been  classified  here; 
they  were  found  in  3  cases  of  cataract.  Errors  in  interpretation  of 
supposed  filarige  in  the  eye  are  likely  to  occur,  and  remnants  of  the 
hyaloid  artery  may  be  mistaken  for  nematodes  unless  a  microscopic 
examination  of  the  structure  is  made.  Braun  excludes  the  cases  reported 
by  Quadri  (1857),  Fano  (1868a),  Schoeler  (1875),  and  Eversbusch 
(1891),  but  accepts  those  of  Nordmann  (1832),  Gescheidt  (1833a, 
p.  405),  and  Kuhnt  (1891). 

Agamofilaria  georgiana  Stiles,  1907,  is  an  immature  worm  of  uncer- 
tain systematic  position,  found  in  a  superficial  sore  on  the  ankle  of  a 
negress  in  Georgia.  It  measures  32  to  53  mm.  long  by  560  to  640/«  in 
maximum  diameter  and  its  mouth  is  surrounded  with  2  small  lateral 
papillae  and  4  large  submedian  lip-like  papillae. 

Filaria  (Hamularia)  equina  (Abildgaard,  1789)  is  a  more  or  less 
common  parasite  in  the  abdominal  cavity,  occasionally  in  the  pleural 
cavity,  liver,  skull,  and  elsewhere,  of  horses  and  asses;  and  several  cases 
of  its  accidental  presence  in  man  have  been  reported.  (Pleural  cavity, 
Linstow,  1902;  bronchial  glands,  Treutler,  1793;  Brera,  1811;  Blanch- 
ard,  1890a,  16.)  The  parasite  measures  6  to  22  mm.  long,  and  has  a 
very  characteristic  blunt  cephalic  end,  provided  with  two  lateral  semilu- 
nar lips.    Its  life-history  is  not  known. 

(?  Filaria)  restiformis  Leidy,  1880,  is  a  vivid-red  worm,  26  inches  long, 
1.5  mm.  in  diameter,  which  is  supposed  to  have  been  passed  per  urethram 
by  man  in  West  Virginia.  Only  one  case  has  been  reported  and  the  anat- 
omy of  the  worm  is  very  imperfectly  known. 

(? Filaria)  hominis  oris  Leidy,  1850,  has  been  reported  once  "from  the 
mouth  of  a  child";  it  measured  5  inches,  7  fines  long,  by  gi  of  an  inch  in 
diameter.  Nothing  is  known  of  its  anatomy.  It  seems  very  possible 
that  this  may  have  been  a  Mermis  obtained  in  eating  an  apple. 

(?  Filaria)  kilimarse  Kolb,  1898,  is  at  present  a  nominal  species  (type 
locality  Kilimara,  British  East  Africa).  It  attains  10  to  20  cm.  in  length 
by  0.5  to  1  mm.  in  diameter;  is  white  in  color,  and  resembles  Gordiits  aqua- 


624  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

ticiis  in  general  api)ea ranee,  while  the  oral  papillre  are  very  similar  to  those 
of  Dmcunculus  ))icdinen.si,'i,  ]Man  is  the  type-host,  and  the  worms  are  saia 
to  occur  in  the  abdominal  cavity,  vomit,  and  stools.  Kolb  has  classifieo 
with  this  form  not  only  free-living  worms  but  also  worms  which  were  founc 
in  hippopotamus,  zebra,  rhinoceros,  oryx,  crocodile,  and  fish,  but  undoubt- 
edly he  has  fallen  into  error  in  his  zoological  determinations. 

(?Filaria)  romanonim  orientalis  Sarcani,  ISSS,  is  said  to  be  an  adult 
threadworm  1  mm.  long,  fount!  in  Roumania. 

Filaria  [Microfilaria]  powelli  Penel,  1905,  is  a  small  larval  filaria 
reported  for  the  blood  in  Bombay;  it  measures  131  microns  long,  5.3/i 
in  diameter,  is  provided  with  a  sheath,  and  has  a  slender  truncated  tail; 
periodicity  "nocturnal?";  the  adult  is  unknown. 

Filaria'  [Microfilaria]  philippinensis  Ashburn  and  [Craig,  1906,  a 
larval  filaria  found  in  the  blood  of  man  in  the  Phihppines  (see  p.  613). 
Its  medical  importance  is  not  yet  known. 

(?  Filaria)  gigas  Prout,  1902,  is  based  upon  two  embryonic  filaria  struc- 
tures, 220  to  340/{  long  by  S  to  12/f  broad,  found  in  the  blood  of  a  native 
at  Moyamba,  Sierra  Ijcone.  The  head  is  rounded,  tail  tapers  but  ends 
bluntly,  no  sheath  could  be  seen,  and  the  animal  stained  readily  with 
fuchsin.  Looss  (1905,  p.  170)  suggests  the  possibility  that  these  represent 
empty  sheaths — namely,  cast  skins;  Low  (1905)  considers  that  this  sup- 
posed species  Avas  based  upon  a  contamination,  probably  with  insect 
hairs. 

NEMATODES  OF  THE  UROGENITAL  SYSTEM. 

Anguillula  aceti  (IMiiller,  1783),  the  vinegar-eel,  has  been  reported 
several  times^  for  the  human  bladder.  It  is  a  very  small  worm,  1  to  2  mm. 
long  by  24  to  40/t  broad;  male  with  two  equal  spicules,  3S/i  long,  and 
accessory  piece ;  vulva  near  equator ;  embryos  222«  long  by  12/x  in 
diameter.  The  mode  of  infection  has  not  been  demonstrated,  but  in  at 
least  one  case  it  was  possibly  by  means  of  vaginal  douches  acidulated 
with  vinegar. 

No  symptoms  traceable  to  the  parasite  were  noticed.  The  chief  im- 
portance in  connection  with  this  parasite  is  the  possibility  of  mistaking  it 
for  Filaria. 

Leptodera  pellio  (Schneider,  1866)  is  recorded  (as  Rhahditis  genitalis 
Scheiber,  1880)  as  a  chance  parasite  of  the  vagina  and  thence  in  the 
urine,  in  a  case  in  Hungary  reported  by  Scheiber  (1880).  The  worms 
measure  0.8  to  1.3  mm.  in  length;  caudal  bursa  of  male  with  7  to  10  rays 
each  side ;  spicules  27  to  33/i ;  vulva  slightly  posterior  of  equator; 
eggs  60  by  35//.  Infection  may  have  taken  place  by  means  of  poul- 
tices made  of  moist  earth.  Rhabditiform  worms  are  also  reported  foi 
the  urine  by  Baginsky  (1887b)  and  Peiper  and  Westphal  (1888),  Upon 
several  occasions  the  writer  has  found  rhabditiform  embryos  in  the  urine 
which  he  has  been  unable  to  identify  zoologically. 

Dioctophyme  renale'  (Goeze,  1782),  the  giant  strongyle,  or  canine  kid- 
ney-worm, measures  40  cm.  (male)  to  100  cm.  (female)  long,  and  is  re<? 

»See  Stiles  and  Frankland,  1902,  pp.  3.5-40,  figs.  7-13;  and  Billings  and  Miller, 
1902a. 
^Synonym. — Eustrongylus  gigas  (Rudolphi,  1802)  Diesing. 


PLATE  IX 


The  Kidney  Worm  (Dioetophyme  renale)  of  Man,  from  a 
Specimen  in  a  Dog.     Natural  size.     Original. 


ROUNDWORM  INFECTION— NEMATHELMINTHES  625 

in  color.  It  is  found  in  the  kidneys  of  dogs  and  various  other  animals,  and 
about  a  dozen  authentic  cases  have  been  recorded  for  man.  Most  of  the 
cases  reported  for  man  involve  erroneous  zoological  determinations;  as 
eelworms,  clots,  etc.,  are  mistaken  for  the  giant  strongyle.  Diagnosis  is 
made  by  finding  the  characteristic  eggs,  64  to  40/f,  with  peculiar  mosaic- 
like shell,  in  the  urine.  Treatment  is  surgical.  The  source  of  infection  is 
not  determined, 


40 


CHAPTER  XXVII. 

LEECHES,     ACARIASIS,     TONGUE     WORINI     INFECTIONS, 
MYRIAPODA,  PARASITIC  INSECTS. 

By  CHARLES  WARDELL  STILES,  Ph.D.,  D.Sc. 

INFECTION  WITH  LEECHES   (HIRUDINEI). 

The  blood-suckers  resemble  earthworms  much  more  closely  than  they 
do  the  intestinal  worms.  They  have  a  mouth  at  one  end  and  a  sucker  at 
the  other.  The  ordinary  medicinal  leech  belongs  to  this  group.  Several 
species  are  troublesome  to  man,  more  especially  in  the  tropics. 

Limnatis  nilotica  (Savigny,  1820)  occurs  in  North  Africa;  it  is  occasion- 
ally taken  into  the  mouth  with  drinking-water,  and  it  fastens  in  the  nose, 
pharynx,  oesophagus,  or  larynx.  It  has  also  been  found  in  the  vagina  and 
on  the  conjunctiva.  When  found,  it  should  be  secured  with  a  pair  of 
tweezers,  then  injected  with  salt  water  by  means  of  a  hypodermic  syringe, 
and  removed  as  it  loosens  its  hold. 

Some  blood-suckers,  such  as  the  Mexican  Hcemenferia  ojjicinalis,  oc- 
casionally cause  symptoms  of  poisoning,  when  used  to  draw  blood. 
Other  leeches  in  certain  tropical  localities  are  said  to  cause  considerable 
irritation  by  fastening  to  the  body  as  persons  walk  through  the  grass 
or  brush. 

ACARIASIS— INFECTION  WITH  ACARINES. 

The  acarines  include  the  mites  and  ticks;  they  have  a  segmented  or 
an  unsegmented  body  with  8  legs  in  the  adult  stage  and  6  legs  in  the 
larval  stage.  Quite  a  large  number  of  these  animals  attack  man  and  ani- 
mals, in  some  cases  acting  as  the  direct  cause  of  disease,  in  other  cases  as 
the  transmitter  of  other  parasites. 

Treatment. — The  general  rule  applies  that  in  all  treatment  sulphur 
should  be  used  in  some  form,  as  sulphur  ointment,  etc.,  as  this  is  particu- 
larly obnoxious  to  this  group  of  parasites. 

Ixodiasis— Tick  Infection. —The  ticks  (Ixodoidea)^  are  divided  into 
two  families:  the  Argasidcc,  in  which  the  capitulura  ("head")  is  sub- 
terminal  in  the  adults,  and  the  IxodidcB,  in  which  the  head  is  terminal  in 
adults.  Quite  a  number  of  different  species  are  known  to  attack  man.  In 
the  United  States  the  two  species  which  have  attracted  the  most  attention 
within  recent  years  are  Bonphilus  annulatus  (the  intermediate  host  of 
Texas  fever)  and  Dermacentor  occidentalis  (which  Wilson  and  Chowning 

*For  the  North  American  species,  see  Salmon  and  Stiles,  1902. 

626 


ACARIASfS.      TONGUE  WORM  INFECTIONS,   ETC.  G27 

have  suggested  acts  as  the  carrier  of  Rocky  Mountain  "spotted 
fever.")^ 

The  Persian  Argas  (Argas  persicus)  enjoys  the  unenviable  reputation 
in  North  Persia  of  causing  a  disease  accompanied  by  extreme  lassitude, 
fever,  perspiration,  severe  pain,  deUrium,  convulsions,  and  sometimes 
death.  Argas  reflexus,  the  pigeon-tick,  attacks  man,  as  an  ectoparasite, 
causing  a  general  erythema  and  a  rapidly  developing  oedema. 

Argas  miniatus  is  also  known  to  attack  man. 

The  spinose  ear-tick  {Ornithodoros  megnini)  is  an  American  species 
which  enters  the  ears  of  cattle,  deer,  dogs,  and  swine,  and  occasionally  of 
man,  causing  considerable  suffering.  It  can  best  be  removed  by  pouring 
some  bland  oil  into  the  ear. 

South  African  tick-fever  is  an  African  disease  which  is  trans- 
mitted by  ticks  belonging  to  the  species  Ornithodoros  savignyi,  and 
is  accompanied  about  five  to  ten  days  after  the  tick-bite  (which  causes  a 
small  swelling)  by  a  sensation  of  pain  and  itching  followed  by  vomiting 
and  purging,  fever  and  rigors,  often  delirium;  the  attack  lasts  about  two 
days  to  a  week,  or  fever  may  continue  three  or  four  weeks.  This  should 
not  be  confused  with  Anderson's  tick-fever  (Rocky  Mountain  "spotted 
fever.") 

0.  turicata  and  0.  talaje  are  reported  as  ectoparasites  of  man  in  Central 
America,  and  0.  iholozani  in  Persia. 

Dermacentor  occidentalis  is  known  at  present  for  the  northwestern 
portion  of  the  United  States,  from  California  to  Montana;  cases  of 
rather  severe  lymphangitis  and  various  swellings  and  sores  developing 
from  the  bite  of  this  tick  have  been  seen  by  the  writer.  J.  J.  Buckley 
showed  me  quite  a  severe  case,  the  patient  having  been  bitten  near  the 
elbow;  the  arm  became  very  much  swollen,  causing  the  patient  to  remain 
in  bed  for  several  days. 

Dermacentor  reticulatus,  D .  electus,  Rkipicephalus  sanguineus,  Booph- 
ilus  annulatus,  Hyalomma  oegyptium,  Amhlyomma  dissimile,  A.  ameri- 
canum,  Ixodes  ricinus,  and  I.  hexagonus  are  also  reported  as  ectoparasitic 
on  man. 

Treatment. — Ticks  not  infrequently  hang  tenaciously  to  the  skin, 
but  if  they  are  covered  with  oil  or  vaseline,  thus  closing  their  breathing- 
pores  (situated  back  of  the  fourth  pair  of  legs),  they  release  their  hold 
more  easily.  If  pulled  too  roughly,  the  capitulum  ("head")  is  likely  to 
break  off  and  remain  in  the  skin. 

Sarcoptic  Acariasis.—Sarcoptic  Itch.— Geographical  Distribution.— 
Judging  from  present  records,  this  infection  is  almost  cosmopolitan. 

Zoological  Distribution. — In  the  species  Sarcoptes  scabiei,  zoologists 
recognize  a  number  of  different  varieties  peculiar  to  different  animais.  In 
some  cases  the  mites  are  intertransmissible  between  man  and  animals, 
and  it  is  not  an  easy  matter  to  distinguish  between  the  different  varieties. 

The  Parasites. — Sarcoptes  scabiei,^  as  it  occurs  on  man,  is  whitish- 
yellow,  round  to  oval,  with  transverse  rows  of  small  spines  and  a  number 
of  longer  bristles.  In  the  female,  both  the  third  and  fourth  pairs  of  legs 
are  armed  with  long  setse;  in  the  male,  the  third  pair  of  legs  possesses 
setse,  but  the  fourth  pair  has  a  sucking-disk.    The  male  measures  0.2  to 

^King  (1906)  and  Ricketts  (1906)  have  recently  succeeded  in  conveying  the 
disease  experimentally  by  means  of  this  tick. 
^See  especially  Railliet,  1893a. 


628  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

0.3  by  0.145  to  0  190  mm.;  the  female  is  0.33  to  0.45  by  0.25  to  0.35  mm. 
The  parasites  bore  irreguhir  galleries,  0.5  mm.  to  4  or  5  cm.  or  more  in 
length,  in  the  epidermis,  especially  on  portions  of  the  body  where  the  skin 
is  thin  and  soft,  as  on  the  flexor  surface  of  the  carpus,  between  the  fingers, 
in  the  groins,  at  knee  and  elbow,  on  penis,  breast,  etc.,  or  at  points  subject 
to  pressure,  as  at  the  waistband.  The  female  is  found  at  the  blind  end  of 
the  gallery;  she  deposits  her  eggs  (15  to  50  in  number)  and  freces  as  she 
progresses.  The  eggs  measure  140/<  and  hatch  in  four  to  eight  days; 
the  parasite  becomes  mature  twenty-eight  days  after  birth.  The  male 
dies  shortly  after  copulation.  The  fecundity  is  very  great.  This  species 
is  slightly  transmissible  to  horses,  dogs,  goats,  and  apes,  but  not  to  cats. 

Sarcopies  scahici  crusiosac  Furstenberg,  ISGl  is  associated  with  Nor- 
wegian itch.  There  is  a  difference  of  opinion  as  to  whether  this  represents 
a  distinct  variety,  or  the  ordinary  itch-mite,  or  the  itch  of  the  wolf,  which 
has  been  transmitted  to  man.  It  leads  to  a  more  severe  condition  than 
the  ordinary  form  of  itch.  S.  s.  equi  may  be  transmitted  to  man  but  the 
infection  is  shortlived — about  three  to  eight  weeks.  S.  s.  ovis  has  been 
transmitted  from  sheep  to  man.  S.  s.  caprw,  of  goats,  may  be  transmitted 
to  man  and  spread  from  man  to  man.  S.  s.  eameli,  of  the  camel  and 
dromedary,  may  cause  a  severe  and  persistent  itch  when  transmitted  to 
man.  S.  s.  auchenice,  of  the  llama,  also  causes  a  rather  serious  itch  on 
man.  *S.  s.  suis,  of  hogs,  sometimes  attacks  man.  S.  s.  canis,  of  dogs, 
when  transmitted  to  man,  may  be  temporary  or  more  permanent;  the 
symptoms  are  similar  to  those  caused  by  S.  scabiei.  S.  s.  vulpis,  S.  s. 
leonis,  S.  s.  wombati,  and  S.  minor  cati,  will  all  develop  on  man,  that  of 
the  cat  most  easily  but  it  does  not  persist. 

Source  of  Infection. — Infection  takes  place  directly  from  person  to 
person  through  prolonged  contact,  indirectly  through  bedclothes,  towels, 
clothes,  etc.,  or  in  other  cases  by  direct  contact  in  handling  animals. 

Frequency. — Itch  seems  to  be  decreasing  in  frequency.  It  increases 
during  and  immediately  following  a  war.  It  is  more  especially  a  disease 
of  the  ignorant  classes,  but  may  appear  in  well-to-do  persons.  In  some 
localities  it  is  exceedingly  common,  and  in  others  it  appears  especially 
among  soldiers,  sailors,  laborers,  shoemakers,  and  prisoners.  Bulkley 
reports  it  in  slightly  less  than  1  per  cent,  in  10,000  skin  cases  in  private 
practice;  and  the  American  Dermatological  Association,  in  4.05  percent, 
of  about  200,000  skin  cases. 

Duration. — x\s  successive  generations  develop  in  the  skin,  the  un- 
treated condition  is  not  limited  by  the  longevity  of  a  single  generation,  but 
is  potentially  indefinite.  It  may  last  for  years  or  even  decades;  it  may 
disappear  temporarily  but  not  completely.  Spontaneous  cure  is  said  to  be 
unknown. 

Symptoms. — The  penetration  of  the  mites  (namely,  in  forming  the  gal- 
leries or  burrows)  causes  an  intense  itching  which  leads  to  scratching,  and 
increases  under  influence  of  heat,  exercise,  and  especially  when  the  patient 
is  in  bed.  Various  eruptions  appear;  papules,  vesicles,  and  pustules,  form. 
The  galleries  may  be  white,  but,  because  of  the  presence  of  eggs  and  acar- 
ine  excrements,  they  usually  become  grayish  to  blackish;  these  galleries 
are  not  equally  distinct  in  all  cases.  Vesicles  are  usually  present  and 
vary  in  number;  they  appear  early  in  the  same  localities  as  the  galleries; 
they  are  transparent  at  the  summit,  rose-colored  at  the  base,  and  contain 


ACARIASIS.     TONGUE  WORM  INFECTIONS,  ETC.  629 

a  limpid  fluid;  in  time  they  dry  and  form  a  small,  thin,  yellowish  crust; 
but  if  scratched  they  may  become  pustular.  Vesicles  may  also  appear  at 
other  places  than  mentioned  above,  as  on  the  arms,  chest,  etc.  The  pap- 
ules appear  at  various  places  on  the  hands,  arms,  etc.,  and  are  the  seat 
of  intense  itching;  they  rapidly  increase  in  number,  but  rarely  attack 
the  face. 

It  is  stated  that  in  99  per  cent,  of  cases  in  men  lesions  are  found  on 
the  penis,  and  in  99  per  cent,  of  cases  in  M^omen,  on  the  breast,  around 
the  nipple. 

The  action  of  the  parasites  is  both  mechanical,  in  tunneling  through  the 
skin,  and  chemical,  as  shown  experimentally  by  Delafond  and  Bour- 
guignon  and  by  Hardy.  Additional  injury  is  of  course  incurred  by 
scratching;  sleep  may  be  seriously  disturbed  by  the  itching;  fatal  cases 
seem  to  be  unknown. 

Norwegian  itch  (scabies  crustosa)  is  reported  for  Norway,  Germany, 
Austria,  France,  Denmark,  Russia,  Turkey,  and  the  United  States,  but  is 
rare.  It  is  characterized  by  the  development  of  adhesive  yellowish  or 
grayish  crusts,  in  which  numerous  mites  are  found  in  irregular  galleries. 
On  the  palms,  soles,  and  knees,  these  epidermic  callosities  develop  1  to  6 
mm. — even  12  to  30  mm. — in  thickness;  they  may  also  form  on  the  head; 
the  hair  falls ;  the  nails  thicken  and  become  like  claws,  reaching  20  mm. 
in  thickness  in  some  cases.  Cases  of  Norwegian  itch  are  of  long  standing, 
three  to  sixteen  years,  and  in  very  slovenly  people.  Treatment  must  be 
prolonged  and  energetic. 

Diagnosis. — The  affection  is  recognized  from  the  presence  of  the  gal- 
leries with  the  female  at  the  end.  These  become  more  distinct  if  the  part 
is  washed.  In  case  of  doubt  the  parasite  or  its  eggs  may  be  recognized 
microscopically. 

Treatment. — In  treatment  two  essential  points  should  be  considered: 
(1)  To  prepare  the  skin  so  that  an  acaricide  can  act;  (2)  to  apply  the  acar- 
icide.  Various  modifications  in  technique  are  adopted;  the  following  may 
be  taken  as  a  rather  radical  guide,  to  be  modified  according  to  facilities 
and  according  to  the  delicacy  of  the  skin  or  condition  of  the  patient: 

1.  The  patient,  stripped  naked,  is  energetically  rubbed  all  over  (except 
the  head)  for  twenty  minutes  with  green  soap  and  warm  water.  2.  He  is 
then  placed  in  a  warm  bath  for  thirty  minutes,  during  which  time  the 
rubbing  is  continued.  3.  The  parasiticide  (see  below)  is  next  rubbed  in  for 
twenty  minutes  and  is  allowed  to  remain  on  the  body  four  or  five  hours; 
in  the  meantime  the  patient's  clothes  are  sterilized,  to  kill  eggs  or  mites 
attached  to  them.    4.  A  final  bath  is  taken  to  remove  the  parasiticide. 

In  treating  thousands  of  cases  of  acariasis  (particularly  the  psoroptic 
form)  in  domesticated  animals,  it  is  common  experience  that,  whatever 
acaricide  is  used,  much  better  results  are  obtained  if  it  is  applied  as  hot  as 
can  be  conveniently  borne.  It  is  also  common  experience  that  while 
acaricides  kill  the  mites,  they  can  not  be  depended  upon  to  destroy  the 
eggs;  hence,  time  (about  ten  days)  is  allowed  after  the  first  treatment  for 
the  eggs  to  hatch  out,  but  not  enough  time  for  them  to  become  adult  and 
begin  to  lay  eggs;  then  the  treatment  is  repeated.  Lime-and-sulphur  dips 
(one  part  of  lime  to  three  parts  of  sulphur),  and  tobacco-and-sulphur  dips, 
are  used;  carbolic  dips  seem  to  have  a  greater  effect  upon  the  eggs  than 
these,  but  have  some  objections.    Hand  applications  are  unsatisfactory. 


630  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

In  treating  itch  in  man,  hand  appUcations  are  used.  Kaposi  does  not 
consider  the  baths  and  frictions  necessary.  He  uses  an  unguentum 
naphthoU  compositum  prepared  as  follows:  adipis  100.0,  sapon.  virid. 
50.0,  cretiie  prjeparata^  10.0,  naphthol  15.0. 

Hehnerich's  fornuila  (which  is  very  irritating  to  the  skin)  is:  sulphuris 
sublimat.  10.0,  potass,  carbonat.  5.0,  aqua  dist.  5.0,  ol.  amyg.  dul.  5.0, 
adipis  35.0. 

Bourguigon's  ointment  is  composed  of:  ol.  lavand.,  et  menthae,  et 
caryophyll.,  et  cinnamomi,  each  2.0,  gumm.  tragacanth.  5.0,  potass, 
carbonat.  30.0,  flor.  sul])h.  90,  glycerine,  ISO.O. 

Hebra's  modified  Wilkinson  ointment  is  made  of:  flor.  sulph.  et  ol. 
cadini,  each  180.0,  adipis  et  sap.  virid.,  each  500,  crette  praperatae  120.0, 

A  lime-and-sulphur  wash,  somewhat  similar  to  that  used  for  sheep-scab 
but  containing  more  lime,  is  adopted  by  some  authors. 

Demodectic  Acariasis.— Infection  with  the  hair-follicle  mites. 

Geographical  Distribution. — Exact  data  on  this  point'are  lacking,  but 
the  infection  is  probably  more  or  less  cosmopolitan. 

Zoological  Distribution. — The  hair-follicle  mite,  Demodex  folliciilorum, 
is  reported  not  only  for  man  but  also  for  quite  a  number  of  animals,  as 
dogs,  cats,  horses,  cattle,  hogs,  etc.  The  forms  which  attack  animals  are 
usually  considered  specifically  identical  with  that  which  attacks  man, 
but  as  representing  distinct  varieties.  There  is  some  doubt  at  present 
regarding  the  intertransference  of  these  varieties  between  animals  and 
man;  if  such  infection  does  occur  it  seems  to  be  rare.  The  infection  in 
dogs  is  the  classical  example  of  the  disease;  it  is  very  difficult  to  cure,  and 
quite  fatal.  In  cattle  the  infection  is  of  considerable  economic  importance 
from  its  effect  upon  the  hides. 

The  Parasite. — Demodex  foUicidorum;^  as  found  in  man,  is  an  elongate, 
worm-like  mite,  300  to  380//  long  by  40  to  45/<  broad,  with  rather  fehort, 
broad  rostrum,  and  4  pairs  of  short  legs.  It  is  very  common  in  the 
sebaceous  glands  of  the  face,  alas  of  nose,  lips,  cheeks,  forehead. 
Meibomian  glands,  and  is  also  found  in  the  cerumen,  ventrum,  dorsum, 
hair  follicles  of  the  chest,  and  at  the  root  of  the  pubic  hairs.  In  healthy 
glands  only  a  few  (one  or  two  specimens)  are  found,  but  the  number  may 
increase  to  15  or  20  or  even  many  more;  usually  the  head  is  toward  the 
bottom  of  the  follicle.  This  parasite  multiplies  very  slowly,  passing 
through  the  stages  of  egg,  hexapod  larva,  octopod  nymph,  second  nymph, 
and  adult.    It  may  live  six  or  more  days  after  the  death  of  the  host. 

Source  of  Infection. — So  far  as  known,  and  judging  from  analogy, 
infection  may  be  direct  or  indirect  from  person  to  person. 

Frequency. — Guiart  (1902b)  has  found  this  parasite  in  all  cases  in 
which  he  has  looked  for  it;  Gruby  found  it  in  40  out  of  60  persons 
examined.  It  is  apparently  much  more  common  in  adults  than  among 
children. 

Duration. — The  longevity  of  the  individual  parasite  is  not  established, 
so  far  as  known  to  the  writer,  but  judging  from  the  life-cycle  of  the 
parasite  a  case  of  infection  is  potentially  indefinite. 

Symptoms. — That  the  effect  of  the  hair-follicle  mite  has  been  both 
overestimated  and  underestimated  is  probably  quite  certain.    The  vast 

*  Synonyms. — Acarus  folliculorum  Simon,  1842;  Demodex  folliculorum 
Owen,  1843;  Demodex  folliculorum  hominis. 


ACARIASIS.     TONGUE  WORM  INFECTIONS,  ETC.  631 

majority  of  cases  pass  unnoticed,  but  one  case  has  been  seen  by  the  writer 
(in  man)  of  nodular  formation  as  large  as  a  pea,  caused  by  these  parasites. 
The  relation  of  the  mite  to  acne  is  sub  judice;  that  they  may  be  one  cause 
of  acne  seems,  a  priori,  probable. 

Treatment. — Several  authors  intimate  that  these  parasites  are  easily 
killed,  but  in  view  of  the  difficulty  experienced  in  treating  the  affection  in 
dogs,  etc.,  a  question  regarding  the  correctness  of  the  interpretation  in  the 
cases  in  man,  naturally  and  legitimately  arises. 

OTHER  FORMS  OF  ACARIASIS. 

Of  the  numerous  other  mites  reported  for  man,  probably  the  most  im- 
portant for  this  country  are: 

The  harvest  mites  (Leptus  americanus  and  L.  irritans  Riley;  L. 
autumnalis  Shaw,  1790,  is  a  European  species)  also  known  as  the  "red 
bug"  or  "harvest  bug,"  or  occasionally  as  the  "jigger."  These  are  hexa- 
pod  larvse  of  mites,  of  the  genus  Trombidium,  They  attack  man  in  the 
fields  in  summer  and  burrow  into  the  skin,  causing  a  very  irritating 
sensation,  and  even  a  considerable  amount  of  suffering,  which  is  increased 
by  scratching.    The  symptoms  disappear  after  a  few  days. 

Treatment. — A  warm  bath  within  a  few  hours  after  exposure;  carbol- 
ized  vaseline,  sulphur  ointment,  or  corrosive  sublimate  (2  to  1,000); 
extraction  of  the  parasite  with  a  fine  needle. 

Of  the  other  mites  reported  for  man,  the  following  may  be  mentioned: 

Trombidium  tlalsahuate  (Lemair,  1867)  occurs  in  Mexico,  and  attacks 
the  eyelids,  axillae,  navel,  and  prepuce,  causing  itching,  redness,  swelling, 
and  even  pus-formation;   symptoms  usually  disappear  in  about  a  week. 

The  kedani  mite  is  a  Japanese  acarine  supposed  to  be  connected  indi- 
rectly with  "river-fever";  the  bacterium  associated  with  the  disease  is 
supposed  by  Takana  (1889)  to  enter  through  the  puncture  in  the  skin 
made  by  the  mite. 

Tetranychus  molestissimus  occurs  in  South  America.  Pedic7iloides 
ventricosus  attacks  people  who  handle  grain. 

Tydeus  molestUS  Moniez,  1889,  was  probably  imported  into  Belgium 
with  Peruvian  guano.     It  also  attacks  man. 

Chicken  mites  {Dermanyssus  gallincB),  and  a  closely  allied  species 
(Do  hirundinis)  from  swallows,  may  attack  man,  causing  a  cutaneous 
eruption  with  considerable  itching. 

Holoth3miS  COCCinella  Gervais  attacks  birds,  especially  ducks  and 
geese,  in  Mauritius ;  it  attacks  man,  causing  a  cutaneous  swelling  with 
a  burning  sensation;  it  is  said  to  enter  the  mouth  of  children. 

Various  mites  are  accidentally  swallowed  in  food  (cheese,  etc.)  or  water, 
and  are  found  in  the  faeces.  Among  the  acarines  reported  for  the  faeces 
may  be  mentioned  Glyciphagus  domesticus  (de  Geer),  and  G.  pruno- 
rum  (Her). 

Tjrroglyphus  farinas  (de  Geer)  attacks  men  handling  grain;  T.  longior 
(Gervais,  1844)  and  T.  siro  (Linnaeus)  are  reported  as  occurring  on  man 
or  in  the  urine. 

Histiogaster  spermaticus  Trouessart,  1900,  is  a  mite  reported  as 
having  been  found  in  a  cyst  in  the  testicles;  it  may  possibly  have  gained 
access  by  being  introduced  into  the  urethra  in  catheterizing. 


632  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

NecrophagUS  sanguinarius  Miyake  and  Scriba,  1S03,  was  found 
dead  in  the  urine  in  a  Japanese  case  of  fibrinuria  with  haMiiaturia  and 
chyluria;  it  was  supposed  to  have  come  from  the  kidneys,  but  there  is 
room  for  grave  doubt  concerning  this  point. 

TONGUE  WORM  INFECTION. 

At  least  two  species  of  tongue  worms  (Linguatulidoe)  are  known  to 
occur  in  man.  They  are  not  true  worms,  but  belong  to  the  arthropods. 
Neither  form  is  especially  dangerous. 

Linguaiida  serraia  Frolich,  1789,  measures  18  to  20  mm.  (male)  long 
by  3  to  4  mm.  broad,  and  8  to  13  cm.  (female)  long  by  8  to  10  mm.  broad. 
The  adult  stage  inhabits  the  nasal  passages  of  canines,  while  the  larvae, 
which  measure  only  4.5  to  5.5  mm.  long,  are  encysted  in  the  liver,  lungs, 
etc.,  of  rabbits,  cattle,  sheep,  and  various  other  animals.  Both  the  larval 
and  the  adult  stages  are  recorded  for  man,  especially  in  Europe.  The 
larva  has  been  found  also  in  American  cattle.  In  cases  of  nasal  infec- 
tion with  gravid  females,  the  diagnosis  may  be  made  by  finding  the  four- 
legged  embryo,  enclosed  in  its  egg-shell,  in  the  nasal  discharge;  diagnosis 
of  infection  by  the  encysted  larva  is  made  postmortem. 

Porocephalus  vioniliformis  (Diesing,  1836)  is  an  African  tongue  worm 
which,  in  the  adult  stage,  lives  in  the  lungs  of  the  python.  The  larva  lives 
encysted  in  the  giraffe,  Proteles  cristatus,  the  mandril  {Cynocephalus 
Tnormon),  and  Cercopithecus  albogularis;  it  has  also  been  reported  several 
times  for  man  in  the  liver  and  lungs,  causing  considerable  irritation. 

MYRIAPODA. 

None  of  the  myriapods  are  true  parasites  in  man,  but  occasionally, 
though  rarely,  they  are  found  as  accidental  parasites  in  the  nose  or  intes- 
tine.    Blanchard  (1898c)  has  collected  35  such  cases. 


PARASITIC  INSECTS.' 

Adult  insects  have  6  legs,  and,  usually,  2  or  4  wings.  The  larvae  are 
more  or  less  worm-like,  and  are  known  as  "grubs,"  "bots,"  etc.  Both 
the  larval  and  the  adult  stages  may  be  parasitic.  They  are  of  more 
importance  in  medicine  as  transmitters  of  disease  (mosquitoes  and  ma- 
laria, yellow  fever,  and  filariasis)  than  they  are  as  parasites  (fleas,  lice, 
grubs,  etc.),  and  we  may  lay  down  the  general  rules  that  diseases  (such 
as  malaria,  filariasis)  which  are  dependent  upon  insects  and  other  arthro- 
pods for  their  distribution,  are  caused  by  animal  parasites,  while  those 
(such  as  typhoid)  which  may  be  disseminated  by  arthropods,  but  are  not 
dependent  upon  them,  are  usually  caused  by  plant  parasites.^ 

*See  especially  Osbom,  1896,  "Insects  Affecting  Domestic  Animals,"  Bull. 
5,  n.  s.,  Div.  Entomol.,  U.  S.  Dept.  Agric.,  Wash. 

^Whether  the  African  tick  fever  and  the  Rocky  Mountain  "spotted  fever"  form 
exceptions  to  these  rules  is  a  point  for  further  study. 


ACARIASIS.     TONGUE  WORM  INFECTIONS,  ETC.  633 

Burrowing  Fleas:  Jigger  Flea,  Chigger  or  Chigoe.— Geographical 

Distribution. — This  is  a  tropical  and  subtropical  parasite;  of  Airicrican 
origin;  it  has  now  been  introduced  into  Africa  and  adjacent  islands,  where 
it  has  spread  rapidly;   it  is  also  reported  for  Persia,  India,  and  China. 

Zoological  Distribution. — This  parasite  attacks  not  only  man,  but  also 
horses,  cattle,  swine,  and  dogs.  It  is  said  to  attack  chickens  and  certain 
other  birds;  but,  as  a  distinct  species  {Argo'psylla  r/allinacea)  is  found  on 
chickens  and  also  reported  as  attacking  man,  it  might  be  well  to  re- 
examine this  infection  to  see  whether  a  confusion  in  determination  has 
occurred. 

The  Parasite. — Sarcopsylla  penetrans^  (Linnfeus,  1758)  is  about  1  to 
1.2  mm.  long;  when  young,  the  female  resembles  other  fleas,  but,  after 
mating,  it  burrows  into  the  skin  and  swells  into  a  body  resembling  a  beet 
in  appearance,  but  fortunately  not  in  size.  The  males  do  not  burrow. 
The  eggs  hatch  out  on  the  ground  and  the  larvse  undergo  a  pupation  or 
resting  stage. 

Frequency. — In  some  localities  this  infection  is  very  common.  Man- 
son  reports  that  it  causes  a  large  amount  of  invalidism  among  the  coolies 
in  East  Africa.  There  may  be  only  one  or  two  parasites  present,  or  the 
fleas  may  be  so  numerous  and  thickly  set  as  to  give  the  infected  part  a 
honeycombed  appearance. 

Duration. — The  female  remains  in  the  skin  about  three  weeks. 

Symptoms  and  Pathology. — The  fertilized  female  burrows  into  the 
skin,  especially  on  the  feet,  but  also  on  other  portions  of  the  body,  forming 
small,  pea-like,  elevated  swellings ;  the  caudal  end  of  the  flea  may  be  seen 
at  the  opening  of  the  burrow.  The  parasite  causes  considerable  irrita- 
tion; pus  forms  around  it;  the  skin  may  ulcerate,  leaving  a  small  sore. 
In  extreme  cases,  as  among  very  indolent  negroes,  the  trouble  may  extend 
to  the  loss  of  toes.  Bacterial  infection  of  the  wound  (tetanus,  etc.)  may 
lead  to  serious  results. 

Diagnosis. — The  diagnosis  is  not  difficult.  The  pea-like  swellings  on 
the  feet,  especially  under  the  nails  and  between  the  toes,  are  in  themselves 
suspicious,  and  a  closer  examination  reveals  the  caudal  end  of  the  parasite. 

Treatment. — The  entire  parasite  should  be  pried  out  with  a  sharp  knife 
or  similar  instrument,  when  possible  without  breaking.  Application  of 
chloroform,  or  mercurial  ointment  may  first  be  used  to  kill  the  flea.  The 
wound  is  thoroughly  cleansed  and  dressed. 

Prevention. — ^The  wearing  of  shoes  in  the  infected  districts  will  greatly 
reduce  the  chances  for  infection. 

Jumping  Fleas  :^  Pulex  and  Ctenocephalus. — Geographical  Distribu- 
tion.— Cosmopolitan. 

Zoological  Distribution. — Fleas  are  common  on  numerous  different 
species  of  animals,  and  some  of  the  species  are  intertransmissible  between 
man  and  their  normal  hosts. 

The  Parasites. — There  are  two  fleas  in  particular  which  attack  man: 

Pulex  irritans  (Linnseus,  1758),  known  as  the  "house  flea"  or  "com- 
mon flea,"  is  more  common  in  Europe  than  in  the  United  States. 

^Synonyms. — Pulex  penetrans  Linnseus,  1758;  Sarcopsylla  penetrans  (Linnaeus) 
Westwood,  1840. 

^Por  a  zoological  revision  of  the  fleas,  with  a  list  of  all  species  on  various 
animals,  see  Baker,  1905,  Proc.  U.  S.  Nat.  Mus. 


634  THE  ZOO-PARASITIC  DISEASES  OF  MAN 

Ctenocephalus  canis  (Curtis,  1S2G),  the  ordinary  "cat  and  dog  flea," 
seems  to  be  more  common  in  the  United  States  than  P.  irritans;  it  differs 
from  P.  irritans  in  the  presence  of  a  comb-like  structure  on  the  first 
thoracic  segment. 

The  flea-eggs  develop  in  cracks  in  tlic  tfloor  and  other  suitable  places. 
In  the  case  of  C.  canis  the  egg  stage  lasts  one  day,  the  first  larva,  three  to 
seven  days,  second  larva,  three  to  four  days.  They  commence  spinning 
from  seven  to  fourteen  days  after  hatching,  and  the  imago  appears  five 
days  later;  thus  an  entire  generation  may  develop  in  a  little  more  than  a 
fortnight. 

Medical  Importance. — Adult  fleas  may:  (a)  attack  man  as  ectopara- 
sites; {b)  act  as  intermediate  host  for  certain  tajieworras  (Diptjlidium 
caninnm,  see  p.  567);  {c)  act  as  disseminators  of  plague.  Flea-larvae  are 
also  reported  as  pseudoparasites  in  man. 

Prevention. — Many  methods  are  suggested  to  protect  against  the 
attacks  of  fleas,  as,  for  instance,  the  use  of  essential  oils;  but  the  reports 
from  their  use  heard  by  the  writer  are  not  very  encouraging.  A  more 
radical  method  is  to  clear  the  fleas  out  of  the  house  by  fumigation  with 
sulphur,  by  sprinkling  pyrethrum  powder,  or  by  washing  the  floor  with 
benzine  or  with  hot  soap-suds. 

Pediculosis:  Lousiness. — There  are  three  species  of  lice  which  at- 
tack man;  namely,  the  head-louse,  the  body-louse  and  the  pubic-louse. 

Geographical  Distribution. — Cosmopolitan. 

Zoological  Distribution. — The  three  lice  typical  for  man  do  not  nor- 
mally live  on  other  animals ;  occasionally  lice  from  various  animals  attack 
man,  but  remain  on  him  only  a  short  time. 

The  Parasites. — The  head-louse  {Pediculus  humanus^  Linnaeus,  1758) 
lives  among  the  fine  hairs  of  the  head;  the  female  lays  50  to  60  eggs, 
or  "nits,"  within  six  days;  these  white  "nits"  are  attached  to  the  hair, 
especially  back  of  the  ears;  they  hatch  on  the  sixth  day;  the  young  become 
mature  in  seventeen  to  twenty  days. 

Pediculus  corporis^  de  Geer,  1778,  the  body-louse,  secretes  itself  in  the 
folds  of  clothing,  but  draws  its  food  from  the  body;  it  lays  70  to  80 
eggs  in  the  folds  of  the  clothing;  these  hatch  in  three  to  four  days  and 
mature  in  fifteen  to  eighteen  days. 

The  pubic-louse,  or  crab-louse,  Phthirius  pubis^  (Linnaeus,  1758)  is 
much  more  common  on  men  than  on  women;  it  is  found  chiefly  on  the 
pubes,  occasionally  on  the  eyelashes,  and  is  reported  also  for  the  head.  It 
lays  10  to  15  eggs,  which  hatch  in  six  to  seven  days  and  become  mature 
in  fifteen  days. 

Source  of  Infection. — Lice  may  pass  directly  from  one  person  to 
another,  or  may  be  carried  by  flies.  The  beds  in  hotels  and  sleeping-cars 
arc  also  sources  of  infection.  One  instance  is  known  to  the  WTiter  in 
which  a  large  number  of  girls,  in  a  fashionable  Eastern  boarding-school, 
developed  lousiness  a  short  time  after  traveling  in  a  sleeper  from  Chicago. 

*  Synonyms. — P.  capitis  de  Geer,  1778;    P.  cervicalis  Latreille,  1803. 

^Synonyms. — Pediculus veshmenti  Nitzsch,  1818;  P.  tabescentium  Alt,  1824. 

^Synonyms. — Pediculus  pubis  Linnteus,  175S;  P.  inguinalis  Reichard,  1759; 
Phthirius  inguinalis  (Reichard)  Leach,  1815;  Phthirius  pubis  (Linnaeus,  1758) 
Kiichenmeister,  1855. 


ACARIASIS.    TONGUE  WORM  INFECTIONS,  ETC.  635 

Symptoms. — Head-lice  may  cause  an  irritation  accompanied  by  an 
eczema  or  pustular  dermatitis.  The  discharge,  mixed  with  excoriations 
due  to  scratching,  mats  the  hair  together;  scabs  and  crusts  form;  if 
allowed  to  run,  a  regular  carapace  may  form,  called  trichoma,  and  the 
head  exudes  a  foetid  odor.  Various  low  plants  may  grow  in  the  trichoma, 
the  entire  structure  being  known  as  the  plica  palonica. 

Body-lice  cause  rose  elevations,  analagous  to  urticaria,  and  papules 
which  become  excoriated  at  the  summit  and  covered  with  brownish 
crust;  itching  and  scratching  result,  and  white  scars  are  found,  surrounded 
by  brownish  pigment;  the  skin  may  become  thickened  and  takes  on 
a  bronzed  tinge,  presenting  a  melanoderma  which  is  one  of  the  chief  attri- 
butes of  vagabonds'  disease. 

Pubic-lice  cause  an  irritating  pruritus,  especially  at  night;  a  dry  prurigo, 
represented  by  small  rose  or  reddish  papules;  and  in  some  cases  in  the 
subumbilical  region,  on  the  flanks  and  internal  surface  of  the  thigh,  bluish- 
gray  temporary  spots,  7  to  8  mm.  in  diameter,  not  painful  and  not  paling 
much  on  pressure. 

Treatment. — If  feasible,  as  in  male  patients,  it  is  well  to  cut  the  hair, 
although  this  is  not  at  all  necessary.  Saturation  of  the  head  with  kerosene 
will  kill  the  lice,  but  carbolic  washes^  are  more  severe  on  the  eggs  ("nits"). 
Washing  with  tincture  of  Cocculus  indicus  is  advised  by  some  authors, 
its  advantage  being  the  absence  of  odor.  Combing  with  a  fine-tooth 
comb  is  an  old  home-measure  of  relief. 

The  same  measures  may  be  used  for  the  pubic-louse;  or  mercurial 
ointment  may  be  applied.  In  treating  for  the  body-louse,  it  is  the  clothes 
more  than  the  body  which  need  radical  treatment.  The  entire  clothing 
should  be  baked  or  boiled. 

The  itching  may  be  allayed  by  warm  baths,  sodium  bicarbonate  being 
added  to  the  water. 

Bed-bugs. — Geographical  Distribution. — Cosmopolitan. 

Zoological  Distribution. — ^The  popular  view  that  bed-bugs  are  carried 
by  swallows  and  bats  is  erroneous;  generically  identical  but  specifically 
distinct  parasites  infest  these  animals. 

The  Parasite. — There  are  two  bed-bugs  which  infest  dwellings. 

The  "common  bed-bug,"  Cimex  lectularius  Linnseus,  1758,  is  too  well 
known  to  require  description.  It  is  a  very  intelligent  animal,  which 
secretes  itself  in  crevices,  in  cracks,  in  draperies,  and  around  the  buttons 
of  mattresses  during  the  day,  seeking  its  food  at  night.  It  lays  eggs  from 
which  the  larval  stage  issues ;  in  its  development  it  sheds  its  skin,  and  it 
feeds  once  between  every  two  moultings,  then  once  again  after  the  last 
moult  before  it  lays  its  eggs.  The  odor,  supposed  to  be  peculiar  to  the 
bed-bug,  is  common  to  the  entire  group  to  which  this  insect  belongs. 

The  Mexican  bed-bug  or  blood-sucking  cone-nosed  bug  {Conorhinus 
sanguisuga)  is  spreading  from  Mexico  toward  the  North  The  adult 
possesses  wings.  This  is  normally  a  predaceous  insect  rather  than  a 
parasite,  and  it  feeds  upon  the  bed-bug.  Having  tasted  human  blood 
from  this  source,  it  is  now  acquiring  the  habit  of  attacking  man.  Other 
species  of  Conorhinus  are  reported  for  other  parts  of  the  world. 

^A  2  per  cent,  carbolic  solution,  or  any  of  the  ordinary  carbolic  sheep-dips, 
may  be  used. 


636  THE  ZOO-PAIiASITIC  DISEASES  OF  MAN 

Frequency. — Tlie  common  bod-bug  varies  in  frequency  inversely  to 
the  care  exercised  iu  housekeeping. 

Source  of  Infection. — 13ed-l)ugs  wander  from  liouse  to  house,  but  they 
are  usually  spread  through  the  moving  of  old  bedding,  or  in  clothes.  The 
laundry  is  a  common  source  of  importation,  esi)ecially  in  localities  like 
Washington,  where  negroes  take  the  laundry  to  their  homes  for  washing. 
The  writer  has  known  of  bed-bugs  being  carried  on  the  coats  of  workmen 
such  as  carpetcleaners,  paperhangers,  etc.,  and  even  of  w'ell-to-do 
bachelors  whose  flats  were  cared  for  by  negresses. 

Symptoms  and  Pathology. — Aside  from  the  fact  that  the  bed-bug  has 
fallen  under  suspicion  as  the  intermediate  host  of  relapsing  fever,  the 
Avriter  is  convinced  that  the  common  bed-bug  may  occasionally  be  of 
greater  medical  importance  than  is  usually  attached  to  it.  He  knows, 
for  instance,  of  one  case  where  a  young  man  underwent  treatment  for 
neurasthenia,  the  diagnosis  being  agreed  upon  by  several  prominent 
clinicians;  all  symptoms  promptly  disappeared,  however,  immediately 
following  a  thorough  fumigation  of  his  rooms,  where  nearly  a  pint  of 
bed-bugs  was  collected!  The  effect  of  bed-bugs  upon  delicate  or  young 
children,  in  loss  of  sleep,  is  occasionally  a  matter  not  to  be  entirely 
ignored. 

Treatment. — Treatment  of  this  trouble  consists  in  removing  the  cause. 
Above  all  methods,  the  writer  favors  thorough  fumigation  of  the  house 
with  flower  of  sulphur  (2  pounds  to  1,000  cubic  feet  of  space).  For  prac- 
tical reasons,  in  order  not  to  attract  attention,  it  is  best  to  start  the  fumi- 
gation in  the  evening  after  dark.  In  experiments^  in  Washington,  and  in 
New  Jersey,  he  has  generally  placed  ordinary  flower  of  sulphur  in  wash- 
basins, old  kettles,  etc.,  and  set  these  dishes  on  bricks  in  larger  basins  or 
tubs  containing  water  enough  to  come  close  to  the  top  of  the  dish  contain- 
ing the  sulphur;  a  small  well  is  made  in  the  sulphur  with  the  finger  and  a 
small  amount  of  alcohol  poured  in;  the  alcohol  is  then  set  on  fire  and  the 
sulphur  allowed  to  burn  out.  All  windows  should  be  tightly  shut,  and 
the  house  should  remain  closed  for  twelve  to  twenty-four  hours.  One 
room  may  be  fumigated  at  a  time  if  desired.  Metal  ornaments,  clocks, 
fine  instruments,  valuable  tapestries,  etc.,  should,  of  course,  be  removed 
before  fumigating.  The  sulphur  odor  remains  in  the  pillows  and  mat- 
tresses for  some  days,  but  this  objection  may  be  obviated  by  sending 
them  to  a  steam-cleaner  instead  of  fumigating  them. 

The  treatment  with  hydrocyanic-acid  gas,  as  advised  by  the  Bureau  of 
Entomology,  is  too  dangerous  and  too  expensive.  As  the  fumigation  is 
usually  carried  out  by  women  in  the  family,  who,  in  their  haste  to  leave 
the  room  when  the  gas  is  started,  may  trip  on  their  dresses,  fatal  accidents 
may  occur,  quite  aside  from  the  injury  done  to  rugs,  etc.  The  sulphur 
fumigation  does  not  present  this  danger. 

The  ordinary  methods  of  washing  with  kerosene,  gasoline,  etc.,  are 
good  so  far  as  they  go,  but  are  less  reliable  than  thorough  fumigation 
with  sulphur.  A  saturated  solution  of  corrosive  sublimate  in  water  may 
be  used  in  the  cracks  of  wooden  beds,  floors,  etc.,  if  desired,  as  a  general 
preventive. 

^  There  is  nothing  new  or  original  in  this  method. —  C.  W.  S. 


ACAEIASIS.     TONGUE  WORM  INFECTIONS,  ETC.  637 

Myiasis. — Dipterous  Infection. — The  term  "myiasis"  is  used  todenote 
aninfection  with  the  larval  ("grub")  stage  of  dipterous  insects.  Various 
authors  distinguish  a  myiasis  externa  and  interna,  M.  intestinalis  and 
dermatosa,  or  M.  oestrosa  and  muscida,  the  first  four  terms  being  based 
upon  the  position  of  the  parasites,  the  last  two  on  the  zoological  classi- 
fication. 

For  American  physicians,  probably  the  most  important  grub-parasite 
is  the — 

Screw-worm. — Compsomyia  macellaria  is  a  fly  which  deposits  its  eggs 
in  wounds.  It  may  also  oviposit  in  the  nostrils  of  persons  (particularly 
those  with  offensive  catarrh)  when  sleeping  out  of  doors.  The  larva, 
known  as  the  "screw-worm,"  issues  within  a  few  hours,  and  burrows  into 
the  tissues;  it  feeds  for  five  to  seven  days,  then  exits  to  pupate.  Accord- 
ingly, in  case  of  infection  the  larvse  continue  their  active  injury  for  five  to 
seven  days.  Infection  with  this  larva  may  be  serious,  and  in  a  high  per- 
centage of  the  cases  (21  in  31,  Maillard)  fatal.  An  effort  should  be  made 
to  kill  the  larvse;  for  this  purpose  the  infected  parts  are  douched  with  a 
20  per  cent,  solution  of  chloroform  in  sweet  milk,  or  a  carbolic  wash;  some 
of  the  parasites  may  be  removed  with  simple  salt  water,  or  with  a  small 
pair  of  forceps. 

Dermatobia  hominis  is  a  tropical  American  fly,  the  larval  stage  of  which 
is  found  under  the  skin  of  man  and  various  animals.  Hypoderma  bovis, 
H.  lineata,  so  common  in  the  backs  of  cattle,  and  H.  diana  of  deer,  may 
also  parasitize  in  man. 

Ochromyia  anthropophaga,  the  Cayor-worm,  attacks  man  in  Senegal. 
Gastrophilus  is  reported  in  Russia  in  connection  with  "creeping  erup- 
tion." Sarcophaga  (flesh-fly)  larvse  are  found  in  wounds,  in  the  nose, 
ears,  anus,  vagina,  intestine,  etc.  Quite  a  number  of  other  species  are 
known  as  parasites  or  as  pests  of  man. 

Various  dipterous  larvse  are  reported  as  chance  parasites  in  the  intestine 
(intestinal  myiasis)^  having  been  swallowed  accidentally  in  the  food  or 
water:  the  common  house-fly  (Musca  domestica) ,  M.  vomitoria,  the  small 
house-fly  {AntJiomyia  canicularis,  also  reported  for  the  vagina),  the  cheese- 
fly  (PiopJiila  casei),  Phora  rufipes,  mosquito  larvae,  and  other  species.  In 
some  cases  these  chance  parasites  produce  considerable  uneasiness  or 
more  or  less  serious  gastric  disturbance,  until  vomited  or  passed  in  the 
faeces. 

Various  larval  insects  are  also  found  in  fresh  wounds,  and  have  been 
especially  troublesome  in  time  of  war. 

Scoleciasis. — Scoleciasis  is  a  term  used  to  designate  accidental  infection 
with  coleopterous  larvse. 

Miscellaneous. — The  reported  cases  of  snakes,  frogs,  earthworms,  etc., 
as  parasites,  are  instances  of  spurious  parasitism. 

1  For  the  larva3  which  breed  and  feed  in  faeces,  and  thus  come  into  consideration 
in  connection  with  typhoid  fever,  see  especially  Howard,  1900. 


PART  VIII. 
NUTRITION. 


CHAPTER  XXVIII. 

GENERAL  CONSIDERATION  OF  METABOLISM,  NORMAL 
AND  IN  DISEASES. 

By  RUSSELL  H.  CHITTENDEN,  Ph.  D.,  LL.  D.,  Sc.  D., 

AND 

LAFAYETTE  B.  MENDEL,  Ph.D. 

General  Statements. — Broadly  speaking,  the  study  of  metabolism  em- 
braces a  consideration  of  the  collective  chemical  changes  taking  place 
in  living  matter.  The  animal  organism  as  a  whole,  and  its  compo- 
nent tissues  and  cells  are  the  seat  of  incessant  chemical  transformations, 
modified  in  character  and  extent  by  variations  in  the  degree  of  activity  of 
the  individual  tissues  and  cells.  This  activity  likewise  implies  a  more  or 
less  continuous  interchange  between  the  individual  cells  of  the  body  and 
the  blood  and  lymph  by  which  they  are  bathed.  Our  conception  of  an 
active  tissue  carries  with  it  the  idea  of  more  or  less  continuous  construction 
and  destruction,  accompanied  by  an  exchange  of  pabulum  and  waste  pro- 
ducts, thereby  presenting  an  ever  varying  environment.  It  is  the  pur- 
pose of  this  chapter  in  physiology  to  trace  out  the  exact  character  of  these 
alterations,  the  relationship  which  they  bear  to  each  other,  the  influence 
of  modification  in  cell  and  tissue  environment  on  metabolic  phenomena, 
and  the  relative  importance  of  the  varied  processes  in  health  and  in 
disease. 

When  the  metabolic  processes  are  constructive  in  character,  they  are 
termed  anabolic;  when  they  are  destructive  in  character,  they  are  called 
katabolic.  Anabolism,  therefore,  means  the  building-up  of  the  inert  and 
dead  food  material  into  living  protoplasm,  which  usually  imphes  the 
transformation  of  relatively  simple  molecules  into  more  complex  ones. 
Katabolism,  on  the  other  hand,  carries  with  it  the  idea  of  destructive 
decomposition  or  disintegration ;  i.  e.,  a  transformation  of  the  living  proto- 
plasm into  various  decomposition  products,  and  the  cleavage  or  breaking- 
down  of  the  latter  into  still  simpler  chemical  compounds,  with  liberation  of 
energy.    There  are,  however,  many  metabolic  processes  which  are  more 

639 


640  NUTRITION 

advantageously  treated  of  under  a  different  heading,  as  those  of  secretion, 
excretion,  digestion,  etc.  These  processes  are  strictly  metaboUc,  involv- 
ing alteration  and  exchange  of  material  in  individual  glands  or  organs;  but 
since  they  have  to  do  with  specific  or  localized  functions  of  the  botly,  they 
can  be  considered  more  appropriately  in  separate  chapters  deaUng  with 
the  processes  as  a  whole. 

]\Ietabolism  is  a  part  of  that  broader  process  or  scries  of  processes 
spoken  of  as  nutrition,  having  to  do  more  concisely  with  the  changes  taking 
place  in  the  body  other  than  those  ordinarily  classed  under  the  head  of 
secretion,  excretion,  etc.  The  metabolic  processes  are  especially  con- 
cerned with  the  life,  growth,  and  functional  activity  of  those  organs  and 
tissues  which  are  preeminently  associated  with  the  maintenance  of  physio- 
logical rhythm.  The  muscle  and  nerve  tissues  are  eminently  the  meta- 
bolic tissues  of  the  body.  The  liver  is  preeminently  a  glandular  organ 
endowed  with  metabolic  power.  The  secretion  of  bile  is  in  a  measure  a 
metabolic  process,  but  we  classify  this  phenomenon  preferably  under  the 
head  of  secretion.  The  glycogenic  f miction  of  the  liver,  on  the  other  hand, 
is  more  appropriately  classed  as  a  metabolic  phenomenon  pure  and  sim- 
ple; while  the  transformations  of  many  crystalline  amino-acids  which  take 
place  in  the  hepatic  cell  with  formation  of  urea  are  likewise  typical  meta- 
bolic processes.  These  facts  are  to  be  emphasized  simply  as  illustrating 
the  principle  that  while  many  processes  in  the  body  are  strictly  metabolic, 
not  all  are  classed  under  this  head,  because  of  the  greater  convenience  of 
treating  certain  of  them  in  connection  with  other  phenomena  more  easily 
recognizable. 

It  is  obvious  that  the  character  of  the  metabolic  transformations  taking 
place  in  the  body  cannot  remain  exclusively  of  one  type,  if  the  organism  or 
individual  is  to  preserve  its  integrity  and  peculiar  make-up.  Thus,  if  dis- 
integrative processes  were  to  continue  without  any  compensatory  con- 
structive activity,  a  complete  break-down  would  occur.  Under  ordinary 
conditions,  accordingly,  building-up  (synthetic)  processes  go  on  side  by 
side  with  the  disruptive  changes  which  liberate  energy.  There  are,  how- 
ever, types  of  organisms  that  are  eminently  synthetic  in  respect  to  the 
chemical  changes  which  are  inaugurated  within  them ;  this  is  the  character- 
istic of  plants  as  a  class.  In  animals,  degradative  changes  are  most  con- 
spicuous. Nevertheless,  anabolism  and  katabolism  manifest  themselves 
in  both  plants  and  animals;  and  it  is  merely  in  the  preponderance  of  one 
or  the  other  type  of  metabolic  phenomena  that  any  essential  difference  in 
the  fundamental  behavior  of  these  li^dnff  forms  becomes  evident. 


NATURE  OF  METABOLISM. 

A  study  of  the  products  which  arise  in  the  animal  body,  incidental 
to  the  metabolic  activities  resulting  in  a  liberation  of  energy,  indicates 
that  the  chemical  changes  involved  are  in  large  part  those  of  oxidation 
and  cleavage.  Complex  molecules  of  fat,  carJbohydrate  and  proteid  are 
transformed  into  relatively  simple  compounds  which  are  uniformly 
richer  in  oxygen  than  the  constituent  components  of  animal  protoplasm. 
The  sulphur  and  phosphorus  of  the  proteids,  for  example,  become  oxi- 
dized in  their  transformations  within  the  body  and  reappear  in  the  excre- 


GENERAL  CONSIDERATIONS  OF  METABOLISM  641 

tions  as  salts  of  sulphuric  and  phosphoric  acids.  The  reactions  involved 
are  generally  more  complex  than  the  illustration  here  selected  would 
indicate.  Many  substances,  however,  are  merely  split  up  into  simpler 
compounds;  some  are  subjected  to  hydrolytic  changes  without  further 
chemical  transformation;  while  not  a  few  undergo  a  cleavage  prelimi- 
nary to  subsequent  oxidation  or  synthesis,  or  both.  In  thus  indicating 
how  food  or  tissue  constituents  may  be  burned  up  in  the  body,  the  anal- 
ogy with  the  familiar  combustion  processes  of  every-day  life  must  n  )t 
be  carried  too  far,  since  combustion  within  the  animal  organism  is  oi  a 
peculiar  and  characteristic  type.  The  reactions  do  not  proceed  with 
the  unchecked  vigor  manifested  in  the  oxidation  of  fuel  in  a  fire-box. 
In  the  body  we  are  dealing  with  a  gradual  process,  regulated  by  condi- 
tions with  which  we  are  still  largely  unacquainted — a  succession  of 
chemical  changes  rather  than  a  sudden  and  continuous  burning  of  or- 
ganic materials.  Whenever  they  occur,  the  oxidations  are,  moreover, 
indirect;  that  is,  the  tissue  combustion  nowhere  proceeds  through  direct 
intermediation  of  the  oxygen  inspired  and  held  in  the  circulating  fluids. 

It  was  the  recognition  of  these  facts  and  the  demonstration  that  oxi- 
dative changes  for  the  most  part  do  not  go  on  in  the  circulating  medium, 
which  led  to  the  abandonment  of  the  view  that  the  blood  is  the  seat  of 
these  most  important  metabolic  changes.  To-day  we  recognize  the  living 
cell  as  the  place  where  the  events  occur  with  which  the  story  of  metab- 
olism is  concerned.  The  details  of  these  events  are  still  largely  unknown 
and  the  minute  mechanism  of  the  tissue  changes  has  only  partly  been 
disclosed.  The  role  of  enzymes  in  the  chemical  organization  of  the  cell 
is,  however,  assuming  an  increased  importance.  In  agreement  with  the 
views  of  Hofmeister  the  cell  may  be  considered  as  a  machine  working 
with  chemical  and  physico-chemical  means.  The  microscope  reveals 
a  complexity  of  morphological  structure  which  lends  probability  to  the 
existence  of  equally  diverse  and  intricate  chemical  powers.  By  way  of 
illustration  of  this  view  we  may  recall  the  manifold  capacities  of  the 
liver  cells.  In  them  a  series  of  important  physiological  reactions  are 
perfected.  Glycogen  is  built  up  and  deposited,  or  released,  converted 
and  discharged;  bile  pigments  are  elaborated  from  blood  constituents; 
urea  is  synthesized;  uric  acid  formed  from  precursors,  or  further  oxidized; 
cholic  acid  constructed  and  united  with  glycocoll  and  taurin;  phenols 
conjugated  with  sulphuric  acid;  toxic  compounds  chemically  trans- 
formed, not  to  mention  many  less  perfectly  understood  reactions. 

It  can  no  longer  be  doubted  that  ferments,  or  enzymes,  are  prominent 
in  the  chemical  work  of  such  cells;  and,  indeed,  the  liver  tissue  has  been 
conspicuous  in  affording  evidence  of  the  presence  of  a  large  variety  of 
soluble  ferments  acting  under  a  diversity  of  conditions.  Thus,  a  proteo- 
lytic enzyme  is  conspicuous  in  autolysis  of  the  hepatic  tissue;  hpase, 
maltase,  laccase,  amidase,  oxidase,  as  well  as  ferments  which  facilitate 
reactions  with  the  purin  compounds,  are  further  specific  examples  of 
enzymes  already  recognized  in  this  tissue.  Whether,  indeed,  the  essen- 
tial chemical  reactions  of  all  tissue  cells  are  facilitated  by  enz}TQes  in 
the  way  which  the  investigation  of  the  liver  cells  has  made  plausible, 
remains  to  be  ascertained;  but  in  any  event  it  is  very  probable  that 
enzymes  of  many  kinds  do  exist  in  the  different  tissues  and  organs 
of  the  body,  and,  if  so,  they  must  be  important  factors  in  metabolic 

41 


642  NUTRITION 

changes.  Further,  recent  investigations  on  the  reversibility  of  enzyme 
action  have  placed  fat  and  carbohydrate  synthesis  in  a  new  light,  and 
make  the  somc\\hat  obscure  anabolic  processes  and  the  redistribution 
of  tissue  constituents  more  susceptible  of  interpretation.  These  matters 
will  be  discussed  in  connection  with  the  metabolism  of  the  proximate 
principles  themselves.  Enough  has  been  said,  however,  to  indicate  the 
possible  function  of  enzymes  in  the  intermediary  processes  of  metabolism, 
and  to  point  out  some  of  the  ways  in  which  living  cells  may  react.  In 
the  recognition  of  these  facts  a  great  step  in  advance  has  been  made  from 
the  old  view  that  oxygen  is  the  immediate  cause  of  all  decomposition  in 
the  organism,  as  originally  formulated  by  Lavoisier. 


EXCHANGE  OF  MATERIALS;  METHODS  OF  STUDY. 

The  study  of  metabolism  has  for  its  primary  object,  then,  the  investi- 
gation of  the  "exchange  of  materials"  (Stoft'wechsel) — the  extent  and 
character  of  the  incessant  transformations  which  accompany  and  deter- 
mine the  changes  occurring  within  the  living  tissues.  It  aims  to  ascer- 
tain the  conditions  under  which  "the  conversion  of  chemical  tension 
into  living  energy"  proceeds.  In  the  past,  various  methods  have  been 
employed  to  furnish  the  data  from  which  the  physiology  of  metabolism 
can  be  understood.  In  the  first  place,  the  activities  of  the  individual 
organs  and  tissues  have  been  subjected  to  analysis  in  various  ways.  This 
method  may  yield  fruitful  results.  For  example,  the  blood  supply  to  an 
organ  may  be  regulated,  the  composition  of  the  blood  entering  and 
leaving  it  may  be  accurately  determined,  and  from  the  differences  in 
chemical  composition  presented  conclusions  may  be  drawn  in  regard 
to  the  storing  up,  utilization,  or  destruction  of  the  tissue  components. 
Such  methods  have  been  applied  with  success  to  the  investigation  of 
the  gaseous  metabolism  of  different  secretory  structures  such  as  the 
kidneys,  pancreatic,  and  salivary  glands.  Quantitative  measurements 
of  the  oxygen  intake  and  carbon-dioxide  output  of  the  kidney  during 
rest  and  diuresis,  show  that  there  is  an  increased  consumption  of  oxygen 
during  the  increased  secretory  activity  without  any  simultaneous  corre- 
sponding removal  of  carbon  dioxide  (Barcroft  and  Brodie).  During 
active  secretion  of  pancreatic" juice  the  consumption  of  oxygen  by  the 
pancreas  is  likewise  increased  (Barcroft  and  Starling).  These  examples 
indicate  how  perfusion  of  normal  or  "surviving"  organs  may  facilitate 
the  study  of  their  metabolism.  Changes  of  composition  within  the  or- 
gans themselves  may  be  ascertained  by  chemical  analysis,  and  compari- 
sons instituted  between  different  tissues.  In  this  way,  much  has  been 
learned  of  the  physiological  and  pathological  role  of  the  liver,  as  indi- 
cated by  the  relative  abundance  of  characteristic  carbohydrates  and  fats 
under  varied  conditions. 

Altered  functions  of  the  body  and  changes  in  the  chemical  behavior 
of  certain  tissues  after  removal  of  specific  organs  are  noted  in  many 
"extirpation"  experiments.  We  need  only  refer  to  the  alterations  in  the 
composition  of  blood  and  urine  which  follow  the  partial  or  complete 
exclusion  of  the  liver  from  the  circulation.  Again,  much  has  been 
learned,  particularly  in  regard  to  synthetic  and  secretory  processes,  by 


GENERAL  CONSIDERATIONS  OF  METABOLISM  643 

comparisons  of  the  products  of  specific  cells  with  the  constituents  of  the 
blood  and  lymph  surrounding  them.  In  this  way  the  metabolism  of  the 
mammary  gland,  for  example,  has  been  subjected  to  investigation,  and 
the  phenomena  of  milk  production,  as  related  to  other  nutritive  changes 
or  activities  within  the  body,  carefully  studied.  The  comparison  of  the 
extent  of  chemical  change  during  rest  and  activity  in  muscular  and  nerv- 
ous tissues  respectively  has  made  it  evident  that  the  functions  of  these 
two  types  of  physiologically  active  tissues  are,  quantitatively  at  least, 
not  attended  by  similar  metabolic  changes.  Corresponding  studies  in 
other  cases,  the  salivary  glands  for  example,  have  demonstrated  that 
anabolism  and  katabolism  may  proceed  simultaneously  during  activity, 
and  the  destruction  of  the  cell  substance  during  secretion  be  largely 
compensated  for  by  a  synthesis  of  new  protoplasm  (Y.  Henderson). 

A  second  method  has  long  been  employed  with  equal  or  greater  suc- 
cess, namely,  the  study  of  the  exchange  of  materials  in  the  body  as  a 
whole.  Indeed,  it  is  this  total  exchange  of  the  body  which  is  more  com- 
monly referred  to  by  the  expression  "metabolism."  For  many  years  it 
has  been  customary  to  investigate  the  metabolism  of  the  organism  as  a 
unit,  and  to  determine  the  influences  of  many  factors  upon  it  by  ascer- 
taining what  materials  have  been  utilized  in  the  manifestation  of  the 
body-functions.  The  method  is  based  essentially  upon  a  recognition  of 
the  fact  that  certain  chemical  fragments  of  the  body  or  its  intake  uni- 
formly escape  decomposition  or  oxidation  within  the  organism,  thereby 
constituting  the  true  end-products  of  the  chemical  transformations  nor- 
mally occurring.  A  measure  of  the  decomposition  taking  place  is  thus 
afforded  by  comparing  the  elements  or  substances  which  enter  the  body 
with  those  which  leave  it  through  various  channels.  We  may  there- 
fore inquire  more  closely  into  the  chemical  nature  of  the  intake  and 
output,  and  consider  what  interpretation  they  allow  regarding  the  pro- 
cesses of  metaboHsm. 

Intake. — ^The  substances  which  compose  the  ingesta  of  man  are  found 
to  be  made  up  in  large  measure  of  the  same  groups  of  compounds  which 
constitute  the  organs  and  tissues  of  the  animal  body.  Broadly  classified, 
they  consist  of  inorganic  and  organic  materials;  the  former  are  present 
in  relatively  small  amounts,  while  the  organic  compounds  are  found  to 
belong  in  great  part  to  three  distinct  groups^  viz.,  carbohydrates,  fats, 
and  proteids.  All  examples  of  these  groups  contain  the  elements  carbon, 
hydrogen,  and  oxygen;  the  proteids  contain,  in  addition,  nitrogen  and 
sulphur;  and  phosphorus  is  further  present,  for  example,  in  the  nucleo- 
proteids  characteristic  of  all  cellular  food  materials.  Many  other  organic 
compounds  enter  into  the  composition  of  the  intake.  Some  of  them, 
like  citric,  malic  and  other  acids,  glucosides,  ethereal  oils,  etc.,  are 
derived  from  vegetable  sources;  others  accompany  or  are  associated  with 
the  typical  foodstuffs,  and  are  exemplified  in  compounds  like  the  creatin 
of  meat,  purin  derivatives,  alkaloids,  amino-acids,  and  numerous  others. 
The  proportion  of  such  substances  contained  in  the  ordinary  diet  is, 
however,  very  small  in  comparison  with  the  three  prominent  groups  or 
"proximate  principles"  mentioned.  The  former  contain  little  potential 
energy  and  appear  to  be  more  important  in  relation  to  regulating  or 
stimulating  metabolic  processes  than  in  maintaining  the  material  integ- 
rity of  the  body.    This  is  equally  true  of  the  inorganic  constituents  of 


644  NUTRITION 

the  body's  intake,  represented  by  c()ni})ounds  of  the  elements  sulphur, 
phosphorus,  chlorine,  potassium,  sodium,  magnesium,  calcium,  and  iron, 
with  traces  of  silicon,  Huorine,  and  iodine.  Perhaps  water  should  be 
classed  with  these  substances.  They  are  for  the  most  part  highly  oxi- 
dized compounds,  and  play  only  a  subordinate  part  in  the  dynamic  func- 
tions of  the  organism.  However,  they  are  none  the  less  indispensable. 
The  importance  of  calcium  for  the  proper  growth  of  bone,  or  of  chlor- 
ides for  the  secretion  of  gastric  juice,  is  obvious;  yet  too  little  considera- 
tion has  been  devoted  in  the  past  to  the  possible  significance  of  many  of 
these  elements  in  metabolism  and  the  perfect  maintenance  of  the  body's 
mtegrity. 

If  oxygen  be  added  to  these  enumerated  elements,  the  list  of  elements 
forming  the  intake  will  be  essentially  complete  A  very  small  propor- 
tion leaves  the  body  practically  unchanged  and  without  having  entered 
into  the  metabolic  processes  at  all  This  is  true  not  only  of  indigestible 
or  undigested  food  residues  which  escape  absorption  and  are  rejected 
with  the  fiieces,  but  also  of  compounds  which  are  exempt  from  hydrolysis, 
cleavage  or  oxidation  even  in  health,  and  find  their  way  into  the  excre- 
tions slightly  or  totally  unchanged.  Many  alkaloids  behave  in  this  way; 
compounds  like  caffeine  or  creatinin  are  eliminated  in  unaltered  or  only 
shghtly  altered  form;  and  many  foreign  pigments  reappear  in  their  orig- 
inal make-up  in  the  excreta. 

Output. — ^The  losses  of  the  body  are  continually  being  manifested, 
and  include  all  of  the  elements,  the  physiological  role  of  which  has 
already  been  discussed.  They  occur  in  the  form  of  solid,  lic(uid,  and  gas- 
eous compounds,  by  far  the  greatest  part  of  which  represents  typical 
end-products.  A  smaller  portion  of  the  output  may  include  products 
of  hydrolytic  cleavage;  and  in  addition  to  the  relatively  insignificant 
imaltered  excreta  mentioned  above,  a  portion  of  the  substances  elim- 
inated, such  as  hippuric  acid,  represents  synthetic  operations  carried 
on  within  the  body.  Aside  from  the  familiar  paths  of  elimination — the 
lungs,  skin,  intestine,  and  kidneys — the  body  may  experience  slight  losses 
in  the  removal  of  hair  or  other  dead  epidermal  structures,  the  discharge 
of  ova,  the  ejection  of  semen,  in  menstrual  flow,  or — what  may  become 
more  important — in  the  secretion  of  milk.  Under  ordinary  circumstances 
the  latter  losses  are  insignificant  and  negligible  in  any  general  account 
of  the  exchange  of  materials  in  the  body.  The  gaseous  products,  leav- 
ing the  body  almost  entirely  by  the  lungs,  are  carbon  dioxide  and  water. 
The  kidneys  eliminate  the  greater  portion  of  the  inorganic  compounds 
and  the  nitrogenous  excretory  products,  such  as  urea,  creatinin,  uric 
acid  and  other  purm  derivatives,  hippuric  acid,  and  ammonia  (in  com- 
bination), as  well  as  large  quantities  of  water;  the  latter,  together  with 
traces  of  the  preceding  compounds,  escapes  in  perspiration  from  the 
skin;  while  the  fteces  contain  secretions  from  the  wall  of  the  gut  and 
the  glands  discharging  into  it,  in  addition  to  indigestible  and  undigested 
food  masses  which  have  never  actually  entered  the  organism  itself.  It 
may  not  be  amiss  to  point  out  in  this  place  that  the  physiological  concep- 
tion of  the  faeces  has  experienced  considerable  modification  in  recent 
years.  It  is  now  recognized  that  they  may,  under  certain  dietary  condi- 
tions, represent  to  no  inconsiderable  extent  materials  actually  metabo- 
lized, as  well  as  the  waste  or  "unutilized"  residues  of   the  ingesta. 


GENERAL  CONSIDERATIONS  OF  METABOLISM 


645 


Experimental  investigations  have  also  emphasized  the  importance  of  the 
intestine  as  a  true  excretory  channel  which  may  be(;ome  even  more  im- 
portant than  the  kidneys  in  the  case  of  certain  elements.  Calcium 
and  iron  tend  to  leave  the  body  in  good  measure  through  the  stools  in 
the  form  of  phosphates,  etc.,  as  well  as  in  the  urine.  To  what  extent 
the  intestine  may  act  as  a  compensatory  organ  of  excretion  in  renal 
insufficiency  remains  to  be  learned.  The  relative  importance  of  the 
various  excretory  channels  may  vary  greatly  according  to  external 
circumstances.  Hammarsten  has  grouped  the  losses  in  an  adult  man 
in  the  following  way:  by  respiration,  about  32  per  cent.;  by  evaporation 
from  the  skin,  17  per  cent.;  with  the  urine,  46  to  47  per  cent.;  and  with 
the  jcBces,  5  to  9  per  cent. 

Comparison  of  Intake  and  Output. — In  the  past,  attention  has 
been  devoted  almost  exclusively  to  the  elements  carbon,  hydrogen,  and 
nitrogen;  latterly,  the  quantitative  occurrence  of  sulphur  and  phos- 
phorus has  begun  to  claim  the  recognition  which  it  deserves.  From  the 
data  obtained  by  analytical  methods  a  comparison  between  certain  feat- 
ures of  the  income  and  outgo  of  materials  in  the  body  under  various 
conditions  can  be  instituted.  The  balance  of  matter  can  thereby  be 
determined,  and  the  gain  or  loss  to  the  body  in  the  elements  considered 
can  be  accurately  ascertained.  No  evidence  is  needed  to  indicate  that 
continued  loss  of  any  element  without  corresponding  intake  must  inevit- 
ably lead  to  serious  results.  When  a  condition  of  perfect  balance  is 
reached  the  body  is  said  to  be  in  nutritive  equilibrium,.  As  an  illustration 
of  the  establishment  of  this  condition,  with  respect  to  both  carbon  and 
nitrogen  in  a  man  of  70  kilograms  body-weight,  the  following  table  is 
offered : 

Balance  of  Nutrition  on  an  Adequate  Diet. 


Income. 

Expenditure. 

Foods — Grams . 

Nitrogen 
Grams. 

Carbon 
Grams. 

Excretions. 

Nitrogen 
Grams. 

Carbon 
Grams. 

Proteid 100 

15.5 

5.3 
79 
93 

14.4 
1.1 

6.16 

Fat 100 

Carbohydrate.  .  .    250 

Faeces 

Respiration  (CO2) .  . 

10.84 
208.00 

15.5 

225 

15.5 

225.00 

Perfect  equilibrium  in  respect  to  carbon  and  nitrogen  is  by  no  means 
always  attained  under  normal  conditions.  The  table  on  page  646  is  se- 
lected to  give  some  quantitative  idea  of  the  changes  incidental  to  meta- 
bolic processes  and  the  balance  of  matter  in  the  case  of  three  or  four 
of  the  elements  more  commonly  studied.  The  data  are  summarized 
from  experiments  by  Atwater  and  Benedict  on  a  young  man  of  76  kilo- 
grams body-weight. 

Nitrogen  Balance. — ^The  balance  of  nitrogen  demands  special  con- 
sideration, because  this  element  is  derived  almost  exclusively  from 
a  single  group  of  the  ingested  materials — the  proteids — in  which  it  occurs 
to  the  extent  of  15  to  18  per  cent.  Since  all  active  tissues,  as  well  as 
nearly  all  of  the  body  fluids,  contain  proteid  compounds  in  considerable 


646 


NUTRITION 


abundance,  no  marked  metabolic  changes  ordinarily  take  place  without 
an  attendant  katabolism  or  anabolism  of  proteid  material.  The  disin- 
tegrated nitrogenous  tissue  constituents  are  eliminated  almost  exclusively 

Estimated  Inco.me  and  Outgo  of  Matter  in  a  Man,  ax  Rest  and  on 
Ordinary  Diet. — Total  Amounts  for  Fotr  D.vys. 


Materials. 

Weight. 

Njitro- 
gen. 

Carbon. 

Hydro- 
gen. 

Oxygen 

(esti- 
mated). 

Ash. 

Income. 

Grams. 
3,687.6 

Grams. 

Grams. 

Grams. 

412.6 
139.3 
447.6 

Grams. 

3,275.0 

605.5 

3,552.4 

Grams. 

1,892.4 
4,000.0 

64.2 

944.4 

49.0 

Total 

9,580.0 

64.2 

944.4 

999.5 

7,522.9 

49.0 

Outgo. 

310.7 

84.6 

5,455.5 

227.9 
3,524.0 
3,248.3 

34.8 

5.7 

610.5 

11.9 
394.3 

275.9 

19.1 

4,845 . 0 

80.5 

3,129.7 

2,362.3 

4.9 

39.9 

15.0 

63.4 

47.2 

24.9 

COo  of  respiration,  etc 

886.0 

Total       

12,851.0 

68.3 

973.1 

1,057.2 

10,712.5 

39.9 

Outgo  greater   ( +  )  or  less   (  —  ) 
than  income 

-1-3,271.0 

-  25.6 

-  19.8 

-  479.0 

+        9.3 

+  4.1 
-4.1 

+  28.7 

-13.6 
-15.1 

+  57.7 

-  1.8 

-  2.3 
-53 . 6 

+  3,189.6 

-  5.9 

-  2.4 

-  425.4 

-9.1 

Body  material. 
Protein  lost,  estimated  to  furnish 

-   .2 

Water  lost,  estimated  to  furnisli. 

Ash    constituents     gained,    fur- 
nished  

+  9.3 

Oxygen  from  air 

2,755.9 

2,755.9 

through  the  kidneys,  a  smaller  portion  being  excreted  through  the  intes- 
tines. An  estimation  of  the  nitrogen-content  of  the  output  through 
these  channels  gives  a  measure  of  the  extent  of  proteid  katabolism  occur- 
ring in  the  body.  For  it  is  now  well  established  that  no  nitrogen  is  ex- 
creted in  gaseous  form  by  the  lungs;  and  the  amount  of  nitrogenous 
waste  contained  in  the  perspiration  is  practically  negligible,  except  in 
cases  of  profuse  sweating  after  muscular  work,  where  over  one  gram 
of  nitrogen  per  day  has  been  estimated  (Benedict).  The  balance  of 
nitrogen  can  be  ascertained  with  a  high  degree  of  accuracy,  and  with 
greater  readiness  than  is  the  case  for  any  other  element. 

In  the  condition  described  as  nitrogenous  equilibrium,  it  is  assumed 
that  the  proteids  of  the  tissues  are  neither  increased  nor  diminished  in 
amount;  whereas  when  a  deficit  or  gain  of  nitrogen  is  made  evident 
by  the  balance-sheet,  the  tissues  are  supposed  to  lose  or  store  up  such 
compounds  as  the  ordinary  proteids  or  nucleoproteids.  A  gain  or  loss 
of  carbon,  without  corresponding  change  in  the  nitrogen  balance,  may 


GENERAL  CONSIDERATIONS  OF  METABOLISM  647 

affect  the  fat  content  of  the  body  or  the  quantity  of  glycogen  deposited. 
The  peculiar  significance  of  the  nitrogen  balance  as  an  index  to  proteid 
changes  in  metabolism,  is  derived  from  the  fact  that  the  cellular  activity 
constantly  going  on  during  hfe  involves  an  incessant  katabolism  of  the 
nitrogenous  protoplasm.  During  hunger,  there  is  an  uninterrupted  loss 
of  nitrogen  from  the  body.  An  organism  can  be  kept  in  nutritive  equilib- 
rium on  an  exclusive  but  abundant  diet  of  meat,  consisting  essentially 
of  proteids.  When,  on  the  other  hand,  the  proteid  is  replaced  by  an 
equally  abundant  intake  of  non-nitrogenous  foods — fats  and  carbohy- 
drates— a  loss  of  nitrogen  cannot  be  prevented.  The  tissue  proteids  are 
continuously  disintegrated  and  their  nitrogenous  katabolites  eliminated. 

Although  the  animal  body  readily  stores  up  carbon  in  the  form  of  fat 
and  glycogen,  there  is  under  ordinary  conditions,  i.  e.,  in  healthy  adults, 
no  tendency  to  retain  or  construct  proteid  to  a  similar  degree.  When 
nitrogen  in  the  form  of  proteids  is  taken  into  the  organism  in  more  than 
certain  minimal  quantities,  the  katabolism  of  the  nitrogenous  compounds 
is  increased  and  the  body  attempts  to  establish  a  condition  of  nitrogenous 
equilibrium.  Herein  lies  a  further  distinctive  characteristic  of  proteid 
metabolism. 

Balance  of  Sulphur  and  Phosphorus. — Up  to  the  present  time,  rela- 
tively little  attention  has  been  given  to  the  balance  of  other  elements, 
notably  sulphur  and  phosphorus,  in  metabolism.  The  data  are  obtainable 
in  a  similar  way,  but  the  conclusions  are  by  no  means  equally  clear  and 
concordant.  Both  of  these  elements  are  eliminated,  for  the  most  part, 
in  the  form  of  highly  oxidized  compounds,  through  the  kidneys  and 
intestine.  Volatile  compounds,  like  hydrogen  sulphide,  are  formed  nor- 
mally in  traces  only.  Although  very  small  quantities  of  simple  sulphur 
compounds,  like  sulphates,  are  found  in  food  and  water,  almost  the 
entire  intake  of  this  element  occurs  in  the  form  of  proteid  compounds 
containing  from  0.3  to  2.4  per  cent,  of  it.  Within  the  proteid  molecule 
the  sulphur  presumably  exists  in  the  complex  represented  by  cystin.  In 
the  excretions  it  is  found  as  inorganic  or  ethereal  sulphates  and  in  minor 
degree  in  the  form  of  less  highly  oxidized  compounds  whose  composition 
is  at  present  unknown.  Under  normal  conditions,  metabolism  and  elim- 
ination of  sulphur  tend,  as  might  be  expected,  to  run  parallel  with 
that  of  nitrogen,  although  the  variable  content  of  sulphur  in  proteids 
renders  a  strict  comparison  impossible.  Otherwise  expressed,  the  ratio 
between  nitrogen  and  sulphur  is  liable  to  vary  with  the  kind  of  proteid 
substance  disintegrated,  the  proportions  in  the  latter  varying  all  the  way 
from  44  to  1  in  oxyhsemoglobin  to  5  to  1  in  tendon  mucin. 

The  role  of  phosphorus  in  the  nutritive  balance  is  even  less  certain 
than  that  of  sulphur.  Under  ordinary  conditions,  the  phosphorus  intake 
is  confined  very  largely  to  the  phosphates  of  the  food.  Phosphorus 
occurs,  however,  in  the  phosphorized  proteids,  like  the  casein  of  milk 
and  vitellin  of  the  egg-yolk,  as  well  as  in  the  nucleoproteids  and  the  com- 
plex fat  lecithin,  and,  perhaps  also,  organic  phosphorus  compound  of 
vegetable  origin  (like  the  salts  of  anhydro-oxymethylene  disphosphoric 
acid).  The  body  fluids  and  tissues  abound  in  inorganic  phosphates, 
which  are  especially  conspicuous  in  the  bones.  The  distribution  of  phos- 
phorus in  the  important  tissues  of  man  has  been  estimated  by  Voit  as 
follows:    In  nervous  tissues,  12  grams;   in  the  muscles,  130  grams;   in 


648  NUTRITION 

the  bones,  1,400  o;rams.  These  figures  indicate  the  degree  to  which  the 
various  ]xirts  may  be  expected  to  participate  in  the  metaboHsm  of  phos- 
phorus Avhcn  either  loss  or  retention  of  the  element  occurs.  At  one 
time  it  was  assumed  that  the  elimination  of  phosphorus  might  be  taken 
as  an  index  of  changes  in  the  nervous  system.  At  ])resent,  however, 
physiologists  are  more  inclined  to  associate  disturbances  in  the  phosphorus 
balance  with  changes  in  other  tissues.  In  view  of  the  presumal)ly  slight 
metabolic  activity  in  the  bones  of  adults  during  health,  the  elimination 
of  phosphorus  not  directly  attributable  to  ])hosphatcs  ingested  has  lately 
more  frequently  been  attributed  to  katabolism  of  the  nucleoproteid  con- 
stituents of  the  tissues.  Since  the  active  cells  of  the  body  everywhere 
contain  the  phosphorus-holding  nucleoproteids,  the  possible  significance 
of  phosphorus  elimination  in  its  relation  to  cell  katabolism  cannot  be 
overlooked.  From  the  synthetic  side,  similarly,  the  question  of  the  im- 
portance of  phosphorus  for  the  anabolism  of  cell  protoplasm  at  once 
suggests  itself.  Phosphorus  is  excreted  almost  entirely  in  the  form  of 
phosphates  of  the  alkalis  and  alkali  earths,  minimal  quantities  escaping 
in  the  form,  perhaps,  of  glyceryl-phosphate. 

The  laws  which  govern  the  metabolism  of  phosphorus  cannot  yet  be 
formulated  with  that  certainty  which  applies  to  some  of  the  other  ele- 
ments in  the  body,  although  the  subject  is  now  attracting  the  attention 
of  numerous  investigators.  One  of  the  most  significant  problems  in- 
volves the  relative  importance  of  organic  phosphorus  compounds  as  con- 
trasted with  inorganic  phosphates  in  the  building  up  of  new  protoplasm. 
For  example,  are  phosphorus-free  proteids,  like  albumin  or  muscle 
myosin,  fed  with  simple  phosphates,  capable  of  inducing  a  construction 
of  the  typical  phosphorized  cell  constituents  ?  And,  if  so,  are  such  com- 
binations equally  as  effective  as  the  phosphoproteids,  casein  and  vitellin  ? 
It  is  noteworthy  that  the  food  of  the  growing  young  in  every  case  abounds 
in  these  phosphorus-containing  proteids,  whether  it  be  in  the  milk  or 
the  egg-yolk.  Moreover,  more  recent  observations  indicate  that  the 
organism  retains  phosphorus  with  greater  readiness  when  it  is  exhibited 
in  the  organic  form  described  above.  Whether  the  more  ready  assimila- 
tion of  organic  phosphorus  also  applies  to  the  phosphorized  fats,  like  the 
lecithins  (lecithans)  remains  to  be  demonstrated. 

The  differences  in  the  behavior  of  the  different  types  of  phosphorus 
compounds  in  metabolism  is  well  illustrated  by  the  following  balance- 
sheet  for  phosphorus  and  nitrogen,  taken  from  experiments  on  a  dog 
fed  with  the  same  quantities  of  these  elements  contained  in  the  form  of 
the  phosphorized  proteid  casein,  and  the  phosphorus-free  proteid  edes- 
tin  and  phosphates,  respectively  (from  Zadik): 

Period.  Nitrogen.  Phosphorus. 

J I  +■^1;!  +o!34}  Feeding  with  casein. 

II  -    2.4  -0.71  1  Feeding  with  ede.stin  and 

III  +    .5.9  -0.05/  phosphates. 

The  importance  of  such  facts  for  the  theory  of  nutrition,  and  in  con- 
nection with  some  practical  aspects  of  dietetics  will  be  pointed  out 
later.  Enough  has  been  said  to  make  it  clear  that  the  balance  of  phos- 
phorus in  metabolism  demands  special  interpretation.    It  appears,  fur- 


GENERAL  CONSIDERATIONS  OF  METABOLISM 


649 


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650  NUTRITION 

thermore,  as  if  there  is  far  less  tendency  toward  equalization  between 
intake  and  output  than  has  been  found  so  conspicuous  in  the  case  of 
nitrogen  and  sulphur.  Otherwise  expressed,  the  organism  is  capable  of 
storing  up  (synthetically  or  otherwise)  comparatively  large  quantities  of 
phosphorus  during  longer  periods  of  time,  and  this  without  close  relation 
to  simultaneous  changes  in  the  metabolism  of  nitrogen.  All  the  foregoing 
facts  must  be  taken  into  consideration,  before  any  wide-reaching  attempt 
is  made  to  connect  the  excretion  of  phosphates  with  the  katabolism  of 
any  specific  phosphorus-containing  constituents  of  the  body^  like  the 
nucleoproteids,  osseous,  or  nervous  tissues. 

The  table  on  page  G49,  containing  data  taken  from  experiments  on  a 
single  individual,  will  give  some  idea  of  the  relations  actually  pertaining 
in  man  under  average  conditions  (Sherman). 

In  general,  the  metabolism  and  balance  of  sulphur  will  be  found  to 
run  approximately  parallel  with  that  of  nitrogen.  ^Yith  phosphorus  the 
parallelism  is  less  apparent;  and  in  no  case  is  the  gain  or  loss  here  great 
enough  to  justify  calculations  of  the  materials  stored  or  broken  down. 
Finally,  the  relatively  large  proportion  of  phosphorus  leaving  the  body 
in  the  fpeces  is  here  referred  to  in  illustration  of  M'hat  we  have  already 
stated  regarding  the  importance  of  the  intestine  as  an  excretory  channel 
for  some  compounds. 


METABOLISM  OF  ENERGY. 

The  consideration  of  metabolism  in  which  we  have  been  engaged  up 
to  this  point  suggests  some  idea  of  the  transformations  in  the  functional 
activities  of  the  organism,  and  we  have  gained  some  conception  of  the 
character  of  the  chemical  reactions  thereby  involved.  A  more  intimate 
study  of  the  topics  outUned  would  afford  a  clearer  understanding  of  the 
workings  of  the  individual  organs  and  tissues,  as  well  as  of  the  body  as 
a  whole;  and  with  the  development  of  physiological  chemistry,  we  may 
confidently  hope  to  gain  a  deeper  insight  into  the  chemical  changes 
which  underlie  metabolism,  and  to  formulate  more  definitely  the  laws 
which  govern  these  processes  There  are,  however,  quite  different  and 
equally  important  aspects  of  metabolism  which  deserve  careful  study 
The  simple  comparison  of  the  income  and  outgo  of  matter,  or  the  in- 
vestigation of  the  synthesis  or  combustion  of  proteid,  fat,  and  carbohy- 
drate in  the  body  leaves  many  of  the  problems  of  nutrition  completely 
unsolved.  They  merely  afford  incomplete  data  from  which  to  estimate 
the  actual  needs  of  the  body  for  its  work  or  to  determine  the  relative 
nutritive  value  of  the  different  types  of  ingesta  under  varying  conditions. 
When,  however,  it  is  remembered  that  the  chemical  iransjormations  of 
the  body  are  accompanied  by  physical  phenomena  and  that  the  exchange 
of  materials  goes  hand  in  hand  with  a  transformation  of  energy,  the  study 
of  metabolism  presents  a  new  and  broader  aspect.  We  are  thus  prepared 
to  take  a  new  view  of  the  organism  as  a  mechanism  in  which^  incidental 
to  the  life-processes,  potential  energy  becomes  kinetic.  The  chemical 
energy  latent  in  the  food  and  body  materials  is  liberated  by  oxidation  or 
cleavage  in  the  form  of  work  and  heat.  It  must  now  be  apparent  that 
food  has  two  functions  in  the  body,  namely,  the  building,  or  repair,  of 


GENERAL  CONSIDERATIONS  OF  METABOLISM  651 

tissues  and  the  yielding  of  energy.  The  uses  of  the  food  and  its  service 
to  the  organism  are  thus  extended  beyond  the  conception  which  the  con- 
sideration of  transformation  of  materials  alone  has  suggested.  Metab- 
olism implies  a  transformation  of  energy  as  well  as  an  exchange  of 
materials. 

It  is  in  connection  with  the  chemical  changes  in  metabolism  that  the 
transformation  of  energy  from  a  potential  to  a  kinetic  form  takes  place; 
and  precisely  as  the  nature  of  the  former  (the  chemical  changes)  is  im- 
perfectly understood,  so  the  physical  changes  require  more  extensive 
investigation  in  anticipation  of  a  complete  interpretation  of  how  they 
occur.  The  oxidative,  or  combustion  processes  are  unquestionably  the 
most  important  ones,  although  undoubtedly  potential  energy  also  be- 
comes kinetic  in  the  cleavage  of  complex  compounds  to  simpler  ones. 
But  the  physiological  energy  transformations  correspond  with  the  chem- 
ical processes  of  metabolism  in  being  more  complex  apparently,  than  is 
the  case  in  combustion  outside  of  the  body,  and  also  more  gradual.  In 
general  the  end-products  of  combustion  within  the  organism  are  the 
same  as  those  obtained  by  burning  the  compounds  in  oxygen ;  and  there 
is  every  reason  to  believe  that  the  quantity  of  potential  energy  trans- 
formed in  the  combustion  of  any  substance  within  the  body  will  be 
the  same  as  that  noted  by  the  usual  physical  measurement  in  the 
laboratory. 

Without  disclosing  the  ultimate  nature  of  life  itself,  experience  has 
shown  that  the  animal  organism  does  not  have  the  capacity  to  create 
or  destroy  energy.  The  manifestations  of  life  are,  however,  accompanied 
by  the  transformation  of  energy.  This  energy  is  obtained  with  the  food, 
in  the  form  of  chemical  compounds;  it  is  in  the  manifold  transforma- 
tions of  the  latter  that  heat  production,  body  work,  and  electrical  phenom- 
ena have  their  origin.  The  energy  so  liberated  in  the  body  and  its 
organs  manifests  itself  continually  in  such  ways  as  the  beating  of  the 
heart,  the  respiratory  movements,  peristaltic  movements,  circulatory 
phenomena,  osmotic  exchanges,  etc.,  ultimately  being  lost  to  the  body 
in  external  work,  heat,  or  water  vapor.  A  very  small  part  escapes  in  the 
organic  constituents  of  the  urine  and  faeces. 

It  is  therefore  quite  plain  that  just  as  the  cells  require  certain  materials 
to  replace  the  waste  and  disintegration  going  on  within  them,  they  also 
need  the  energy  which  they  derive  from  the  contributions  brought  to 
them  by  the  circulating  fluids  of  the  body  or  stored  up  within  themselves. 
The  demands  for  energy  may,  however,  be  satisfied  in  more  diverse 
ways  than  is  the  case  with  the  demand  for  materials.  For  while  there 
are  certain  compounds,  like  the  proteids,  which,  owing  to  their  peculiar 
composition,  are  always  essential  for  the  maintenance  of  cellular  life, 
we  shall  see  that  the  body  can  satisfy  its  energy-yielding  requirements 
from  a  variety  of  sources  with  equal  readiness.  The  metabolism  of 
matter  accordingly  is  characterized  by  certain  qualitative  features;  that 
is,  under  determined  conditions  definite  kinds  of  compomids  must  be 
available  if  the  fimctions  are  not  to  suffer  deterioration.  In  the  metab- 
olism of  energy,  on  the  other  hand,  quantitative  relations  play  the  im- 
portant part.  The  potential  energy  must  be  renewed  and  adequate 
provision  made  for  the  maintenance  of  body  temperature  and  activity. 
This  means  that  proper  quantities  of  nutrients  must  be  furnished,  without 


Co2  NUTRITION 

emphasizing  the  type  of  compound  in  which  the  energy  is  stored.  The 
fact  that  in  man  and  many  other  organisms  energy  is  H  berated  by  cleav- 
age witli  intermediation  of  respired  oxygen  has,  as  Rubner  pointed  out^ 
a  tUstinct  atlvantage;  for  o.vidaiive  cleavages  render  latent  energy  avail- 
able in  greater  j)roportion  than  many  other  forms  of  decomposition. 
Thus,  the  heat  afforded  in  such  living  processes  as  alcoholic  fermen- 
tation or  lactic  acid  fermentation  is  com])arativcly  slight.  And  if  the 
ferment  organisms  involved  in  them  regulate  their  fot)d  supply  in  cor- 
respondence with  the  proportion  of  energy  set  free  in  the  decompositions 
which  they  incite,  it  becomes  apparent  why  they  afford  so  large  a  yield 
of  fermentation  ])roducts. 

Methods  of  Study. — Since  the  organic  foodstuffs  contain  a  store  of 
potential  energy  which  may  become  transformed  sooner  or  later  in  metab- 
olism, we  may  take  this  energy  as  a  measure  of  their  "fuel  value," 
that  is,  their  value  in  accomplishing  work  and  forming  heat  when  they 
are  metabolized  in  the  body.  The  quantity  of  heat  set  free  when  a 
given  organic  food  compound  is  burned  with  oxygen  in  a  calorimeter  is 
an  equivalent  and  measure  of  its  potential  energy.  We  may,  therefore, 
appropriately  estimate  the  fuel  value  of  a  nutrient  substance  by  its  heat 
of  combustion.  And  inasmuch  as  the  greater  portion  of  the  energy 
changes  in  the  body  result  in  the  liberation  of  heat,  it  has  become 
customary  to  measure  these  transformations  by  similar  heat  units.  The 
"heat  of  combustion"  of  a  substance  is  expressed  in  large  calories  or 
kilogram-degree  units  of  heat,  and  in  small  calories,  i  e.,  gram-degree 
units  of  heat.  The  former  represent  the  quantity  of  heat  required  to  raise 
1  kilogram  of  water  1°  C;  the  small  calorie  represents  the  heat  required 
similarly  to  raise  the  temperature  of  1  gram  of  water.  Therefore,  1,000 
^nall  calories  =  1  large  calorie. 

In  the  calorimeter,  substances  are  burned  up  in  an  atmosphere  of 
oxygen;  as  is  the  case  in  the  body,  fats  and  carbohydrates  are  decom- 
posed to  carbon  dioxide  and  water.  Proteids  yield  nitrogen,  sulphuric 
(and  sometimes  phosphoric)  acid,  in  addition  to  carbon  dioxide  and 
water.  In  metabolism  the  combustion  of  proteids  is  less  complete.  The 
nitrogenous  moiety  of  the  molecule  is  eliminated  in  the  form  of  less 
simple  bodies  in  the  urine  and  fseces.  We  have,  accordingly,  to  dis- 
tinguish between  their  physiological  fuel  value  and  that  determined  by 
direct  measurement  in  the  calorimeter.  This  physiological  fuel  value 
of  the  proteids  can  be  ascertained  by  subtracting  from  the  fuel  values  of 
the  total  material,  the  heat  of  combustion  of  the  incompletely  oxidized 
excretory  products — such  as  the  urea,  uric  acid,  creatinin,  etc  ,  of  the 
urine — and  the  unutilized  nitrogenous  residues  of  the  food  excreted  by 
the  intestine,  corresponding  to  the  proteid  considered.  That  is  to  say, 
"If  we  subtract  the  potential  energy  of  these  products  from  that  of  the 
total  material  from  which  they  are  formed,  the  difference  will  be  the 
amount  of  energy  which  has  been  liberated  in  their  consumption  in  the 
body."  The  loss  of  energy  represented  by  the  normal  incomplete  com- 
bustion of  the  proteids  may  amount  to  22  to  28  per  cent.  (Rubner).^ 
Finally,  it  may  be  added  that  when  a  portion  of  the  intake  is  anabohzed 

1  Tigerstedt  has  noted  as  a  general  rule  that  the  percentage  loss  of  calories  in 
the  feces  is  roughly  equal  to  the  figure  obtained  by  estimating  the  percentage 
relation  of  the  dry  solids  of  the  faeces  to  the  total  dry  solids  of  the  food  ingested. 


GENERAL  CONSIDERATIONS  OF  METABOLISM  653 

or  stored  in  the  body,  its  potential  energy  is  likewise  held  in  reserve; 
and  when  katabolism  of  the  tissues  proceeds  uncompensated  from  with- 
out, the  metabolism  of  energy  is  proportionate  to  the  yields  required  of 
the  particular  compound  (proteid,  fat,  glycogen),  which  is  burned  or 
spHt  up,  with  due  allowance  for  the  corrections  suggested  above. 

The  calorimetric  researches  of  Berthelot,  Stohmann,  Rubner,  Atwater, 
and  their  associates  have  given  us  a  large  number  of  data  relative  to  the 
potential  energy  or  fuel  value  of  many  compounds.  Relatively  few  figures 
apply  to  the  isolated  foodstuffs — the  proteids,  fats,  and  carbohydrates. 
A  few  typical  examples  are  given  below; 

Heats  of  Combustion  of  Organic  Substances. 

— per  gram — 

Other 
Proteids.  Calories.     Fats.  Calories.  Carbohydrates.  Calories,  organic  sub- 

stances.     Calories^ 

Beef .   5.65  Beef  fat 9.50  Pentoses 4.00  Urea 2.52 

Protein  of  meat.  ..  5.65  Mutton  fat  ....   9.51  Dextrose 3.75  Alcohol 7.07 

Egg  albumin 5.71   Lard 9.59  Cane  sugar 3.  96  Citric  acid 2.39 

Caseinofmilk    ....    5.78  Butter  fat 9.27  Milk  sugar 3.86  Creatin 4.27 

Gluten  of  wheat. . .    5.  95  Olive  oil 9.  47  Starch 4.  20  Uric  acid 2.  62 

Gelatin 5.27  Fat  of  cereals.  .   9.30  Dextrin 4.11  Leucin 6.  .53 

Vegetable    proteid  5.00  Glycogen 4.19  Fseces  (average)  6.20 

It  need  scarcely  be  pointed  out  that  such  figures,  by  themselves,  give 
little  idea  of  the  actual  fuel  value  or  available  energy  attributable  to  the 
nutrient  substances  as  they  are  ordinarily  consumed.  The  diet  of  man 
consists  of  foods  of  complex  composition,  rather  than  definite  chemical 
compounds;  and  it  is  only  under  experimental  conditions  that  the  pure 
foodstuffs  enter  into  consideration.  The  actual  amount  of  energy  which 
the  body  can  derive  from  a  given  diet  depends  upon  a  variety  of  factors, 
chief  among  which  are  the  quantities  and  chemical  energy  of  the  food- 
stuffs available  and  the  amount  of  incompletely  oxidized  material  re- 
jected in  the  excretions. 

Availability  of  Nutrients. — ^We  may  digress  here  to  discuss  what  is 
meant  by  the  expression  "available  foodstuffs"  or  "available  nutrients." 
If  the  ingesta  were  completely  digested,  absorbed,  and  utilized,  such  dis- 
tinctions would  be  unnecessary.  But  the  ordinary  make-up  of  the  diet  is 
such  that  the  nutrient  materials  are  in  part  either  undigested  or  indiges- 
tible, and  thus  represent  a  loss  to  the  body  in  relation  to  the  energy- 
yielding  compounds  ingested.  Strictly  speaking,  the  excreta  from  the 
alimentary  tract  represent  both  residues  of  metabolic  products  and  un- 
digested food  residues.  Atwater  has  suggested  the  term  "co-efficient  of 
digestibihty"  to  represent  the  factor  found  by  subtracting  the  undigested 
residues  from  the  food.  The  "co-efficients  of  availability"  are  found  by 
subtracting  the  total  excreta  from  the  total  food.  Commonly,  the  expres- 
sions digestibility  and  availability  are  used  synonymously  in  reference  to 
the  foodstuffs,  owing  to  the  practical  difficulty  of  distinguishing  between 
unutihzed  food  residues  and  true  metabolic  products  in  the  faeces.  From 
experiments  made  in  many  laboratories,  data  have  been  collected  in  the 
course  of  an  inquiry  regarding  the  nutrition  of  man,  carried  out  under 
authority  of  the  United  States  government,  and  co-efficients  have  been 
obtained  for  different  classes  of  materials.  From  the  data  thus  observed, 
factors  were  assumed  for  the  total  food  of  ordinary  mixed  diet,  and 
the  results  of  over  400  such  experiments  have  been  collated  and  the 


654  NUTRITION 

co-efficients  of  availability  of  the  foodstuffs  calculated.  The  proposed 
co-efficients  represent  very  nearly  the  actual  average  availability  (or 
digestibility)  of  the  nutrients  of  ordinary  mixed  diet,  as  will  be  seen  in  the 
appended  table   (Atwater) : 

Availability  of  Nutrients. 

Protein.  Fats.  Carbohydrates 

Proposed  factors 02.0  per  cent.      95.0  per  cent.      97.0  jjcr  cent. 

Factors  found  in  average  of 

411  experiments 91 . 1  iwv  cent.      94.8  per  cent.      96.8  per  cent. 

In  the  developing  infant,  Rubner  and  Ilcubner  have  found  a  utiliza- 
tion of  91  to  94  per  cent,  of  the  total  nutrients  under  normal  nutritive 
conditions. 

It  is  important  to  bear  in  mind  the  essential  fact  brought  out  by  these 
figures,  namely,  that  only  a  portion  of  the  materials  ingested  is  actually 
made  available  or  utilized  in  metabolism.  The  available  energy  of  the 
fats  and  carbohydrates  is  the  total  energy  of  their  available  material. 
In  the  case  of  the  proteids,  however,  the  digested  and  absorbed  material 
is  not  completely  broken  down  and  oxidized;  the  available  energy  of 
this  group  is  therefore  represented  by  the  difference  between  the  total 
and  that  of  the  excreta  which  escape  unoxidized.  Such  general  state- 
ments as  these  are  of  course  subject  to  minor  modifications,  the  discus- 
sion of  which  would  be  unprofitable  in  this  place.    The  table  on  page 

655  illustrates  the  differences  between  the  physical  and  physiological  fuel 
value  (Physiologischer  Nutzeft'ekt)  of  the  chief  components  of  an  ordi- 
nary diet. 

Twenty  years  ago  Rubner  proposed  a  series  of  factors  by  means  of 
which  the  energy-yielding  value  of  the  foodstuffs  could  be  calculated, 
namely : 

1  gram  of  proteid  yields  ....      4.1  Calories  (large). 

1  gram  of  fat 9.3  Calories. 

1  gram  of  carbohydrate 4.1  Calories. 

Since  that  time  the  heat  of  combustion  of  a  large  number  of  compounds 
has  been  determined,  the  proportions  of  the  foodstuffs  in  the  ordinary 
foods  of  man  have  been  ascertained  on  an  extensive  scale,  and  many 
digestion  and  absorption  experiments  have  been  added  to  the  literature. 
From  the  data  secui-ed  by  a  careful  review  and  compilation  of  the 
statistics  thereby  furnished,  Atwater  and  his  associates  have  proposed  a 
slightly  altered  series  of  factors,  as  shown  on  page  655. 

Outside  of  the  three  groups  included  above,  few  other  food  materials 
have  any  significant  interest.  Alcohol  and  a  few  compounds  of  the 
fatty  acid  series,  such  as  asparagin,  may  enter  into  the  diet  at  times; 
but  the  other  organic  substances  need  not  receive  serious  consideration 
as  sources  of  energy  or  matter  for  the  organism.  Some  of  them,  to  be 
sure,  liberate  energy  as  heat  when  they  are  burned  with  oxygen  in  the 
calorimeter.  In  the  body,  however,  they  cannot  serve  as  sources  of 
energy,  because  they  are  either  .ot  absorbed  or  fail  to  be  katabolized. 
To  this  group  belong  the  inorganic  salts  and  water,  which  furnish  no 
energy  to  the  organism,  however  indispensable  they  may  be  for  the  per- 
formance of  its  functior.s.  An  engine  requires  lubricants  even  though 
it  draws  it.  supply  of  energy  from  coal. 


GENERAL  CONSIDERATIONS  OF  METABOLISM 


655 


Factors  for  Heats   op  Combustion  and   Fuel   Values  of  Nutrients  in 
Different  Groups  of  Food  Materials  and  in  Mixed  ]Jiet.    (Atwater.) 


Nutrients    furnished 
by  each  group  per 
100  grams   total. 

Heat  of  combustion 
per  gram. 

Proportion    of    total 
nutrients   actually 
available. 

Total      energy      per 
gram   in  available 
nutrients. 

Fuel  Value. 

Kind  of  Food  Material. 

Per  gram 
available  nutri- 
ents. 

a      lb 
to       3 

o 

A 

B 

C 

D 

=  BXC 

E, 

F2 

Protein. 

Meats,  fish,  etc 

Eggs 

Dairy  products 

Grams. 

43.0 

6.0 

12.0 

Calories. 

5.65 
5.75 
5.65 

Per  Cent. 

97 
97 
97 

Calories. 

5.50 
5.60 
5.50 

Calories. 

4.40 
4.. 50 
4.40 

Calories. 

4.25 
4.35 
4.25 

Animal  food 

61.0 

31.0 
2.0 
5.5 
0.5 

5.65 

5.80 
5.70 
5.00 
5.20 

97 

85 
78 
83 
85 

5.50 

4.95 
4.45 
4.15 
4.40 

4.40 

4.55 
4.45 
3.75 
3.95 

4.25 
3.70 

3.20 

2.90 

Fruits 

3.15 

Vegetable  food . . . 
Total  food 

Fat. 

Meat  and  eggs 

Dairy  products 

39.0 
100.0 

60.0 
32.0 

5.65 
5.65 

9.50 
9.25 

85 
92 

95 
95 

4.80 
5.20 

9.00 
8.80 

4.40 
4.40 

9.50 
9.25 

3.55 
4.00 

9.00 
8.80 

Animal  food 

Vegetable  food . . . 

92.0 
8.0 

9.40 
9.30 

95 
90 

8.95 
8.35 

9.40 
9.30 

8.95 
8.35 

Total  food.....  .  . 

Carbohydrates. 

100.0 

5.0 
55.0 

1.0 
13.0 

5.0 
21.0 

9.40 

3.90 
4.20 
4.20 
4.20 
4.00 
3.95 

95 

98 
98 
97 
95 
90 
98 

8.90 

3.80 
4.10 
4.05 
4.00 
3  60 
3.85 

9.40 

3.90 
4.20 
4.20 
4.20 
4.00 
3.95 

8.90 
3.80 

4.10 

4.05 

4.00 

Fruits 

3.60 

3.85 

Vegetable  food. .  . 
Total  food 

95.0 
100.0 

4.15 
4.15 

97 

97 

4.00 
4.00 

4.15 
4.15 

4.00 
4.00 

Heat  of 
combus- 
tion 
per  gram. 

Avail- 
abihty. 

Fuel  Value. 

Kind  of  material. 

Referred  to 
available  nutrients. 

Referred  to 
total  nutrients. 

per  gram 

per  pound 

per  gram 

per  pound 

Calories 
(large). 

5.65 
9.40 
4.10 

Per  Cent. 

92 
95 
97 

Calories 
(large). 

4.4 
9.4 
4.1 

Calories 
(large). 

2000 
4260 
1860 

Calories 
(large). 

4.0 
8.9 
4.0 

Calories 

(large). 

1820 

Fats 

Carbohydrates 

4040 
1820 

1  Values  for  fats  and  carbohydrates,  same  as  corresponding  values  in  column  B.     Values  for 
protein,  same  as  corresponding  values  in  column  B  minus  1.25. 

2  Values  for  fats  and  carbohydrates,  same  as  corresponding  values  in  column  D.    Values  for 
protein,  same  as  corresponding  values  in  column  D  minus  1.25. 


656  NUTRITION 

From  the  tables  presented  above,  it  is  apparent  that  proteids  and  carbo- 
hydrates furnish  practically  the  same  yield  of  energy  in  metabolism,  in 
contrast  with  the  fats  which  afford  far  more  heat  per  miit  of  material. 
If  the  composition  of  the  ingesta,  with  reference  to  the  content  of  pro- 
teids, carbohydrates,  antl  fats  is  known,  the  fuel  value  of  the  mixed  food 
materials  can  readily  be  calculated,  and  approximate  corrections  made 
for  the  availability  of  the  tliffcrent  constituents.  Let  us  say,  for  example, 
that  an  individual  consumes  100  grams  of  protcid,  400  grams  of  carbo- 
hydrate and  100  grams  of  fat.  The  fuel  value  of  the  intake,  expressed 
in  large  calories  is  as  follows: 

100  grams  of   proteid  x  4 . 4  =      440  Calories. 

400  grams  of   carbohydrate x  4.1=    1,640 
100  grams  of   fat  x  9.4=      940 

3,020  Calories, 

During  the  past  few  years  our  knowledge  of  the  chemical  composition 
of  food  materials  has  been  added  to  largely,  through  the  efforts  of  the 
United  States  Department  of  Agriculture.  Quantitative  data  regarding 
the  make-up  of  a  large  number  of  products  have  been  compiled  from 
over  4,000  analyses  of  American  food  materials  alone,  and  in  many  in- 
stances the  fuel  value  has  been  determined  directly  with  the  calorimeter. 
Such  statistics  have  become  of  great  service  in  the  practical  study  of 
dietetics. 

With  this  introduction  to  the  consideration  of  the  transformation  of 
energy  in  the  living  body  and  with  the  foregoing  brief  reference  to  terms 
employed,  we  may  proceed  to  consider  some  of  its  phenomena  and  the 
laws  which  govern  them  in  their  application  to  metabolism.  No  adequate 
treatment  is  possible  without  a  thorough  understanding  of  the  principle 
of  the  conservation  of  energy.  A  knowledge  of  the  physical  relations 
which  this  involves  may  be  assumed  to  be  familiar.  The  circulation  of 
energy  is  intimately  associated  with  the  circulation  of  the  elements  in 
the  li^^ng  body  as  well  as  in  the  inorganic  world  about  us.  If  it  is  as 
impossible  to  destroy  energy  as  it  is  to  destroy  matter,  we  must  expect, 
when  the  chemical  potential  energy  of  the  food  or  the  body  tissues  is 
used  up,  to  find  an  equivalent  amount  of  other  forms  of  energy  appear- 
ing in  the  body.  Energy  itself  cannot  be  directly  observed  and  pursued; 
but  we  can  measure  it  by  its  manifestations  of  motion,  whether  it  be  a 
visible  motion  of  masses  of  matter  or  that  invisible  motion  of  infinitely 
smaller  particles  which  is  spoken  of  as  heat. 

In  accordance  with  this  statement,  it  is  to  be  noted  that  the  body  is 
continually  producing  heat,  and  furthermore  it  is  engaged  in  move- 
ment and  performing  work.  These  are  the  essential  manifestations  of  a 
transformation  of  energy.  It  has  frequently  been  suggested  that  in  the 
performance  of  psychical  functions  also,  chemical  potential  energy  must 
be  liberated.  We  are,  however,  unable  to  say  definitely  whether  the 
phenomena  of  consciousness  follow  the  law  of  the  conservation  of  energy. 
As  Bunge  has  well  expressed  it:  "There  is  probably,  in  the  afferent  and 
central  organs,  a  chain  of  processes  intervening  between  stimulation  and 
sensations,  as  there  is  between  will  and  muscular  action.  We  are  quite 
unable  to  decide  whether  the  last  form  of  motion,  which  reaches  the  brain 


GENERAL  CONSIDERATIONS  OF  METABOLISM  657 

as  the  result  of  stimulation,  is  converted  into  sensation,  or  only  serves  as 
an  impulse  originating  sensation,  possibly  from  chemical  potential  energy. 
It  is  conceivable  that  an  entirely  new  and  particular  kind  of  causal  con- 
nection may  be  at  work  in  this  case. 

"People  have  tried  to  prove  experimentally  that  intellectual  exertion 
has  an  influence  on  metabolism,  as  shown  by  the  amount  of  excretions. 
All  these  experiments  fail  on  account  of  the  impossibility  of  measuring 
intellectual  exertion,  or  of  even  deciding  whether  it  was  greater  or  less 
A  man  who  shuts  himself  up  in  a  dark  room,  with  the  intention  of  keep- 
ing his  mind  a  blank,  may  involuntarily  exercise  it  more  than  if  he  were 
to  sit  down  to  his  books  with  the  intention  of  exerting  all  his  intellectual 
faculties;  besides,  we  ought  to  take  into  consideration  the  emotions, 
which  probably  exceed  all  mental  exertions  in  the  expenditure  of  energy, 
and  which  we  cannot  call  into  play  or  dismiss  at  will. 

"We  must  consider  moreover  that  the  weight  of  the  brain  is  less  than 
two  per  cent,  of  the  weight  of  the  body,  and  that  only  a  portion  of  the 
brain  is  employed  in  mental  functions.  Even  if  the  metabolism  of  this 
organ  were,  by  higher  psychical  activity,  promoted  to  the  utmost,  we 
could  not  expect  to  recognize  this  fact  in  an  increase  in  the  total  metab- 
olism. Even  if  it  could  be  distinguished,  we  should  not  be  justified  in 
concluding  that  the  work  of  the  mind  was  converted  potential  energy. 
The  conversion  might  be  an  indirect  one." 

Finally,  there  is  no  evidence  in  man  and  the  higher  animals  that 
energy  is  liberated  in  the  form  of  light  or  electricity,  as  in  some  of  the  lower 
forms  of  life.  At  any  rate,  if  such  transformations  do  occur,  the  energy 
must  finally  leave  the  body  as  heat,  or  in  some  form  which  we  do  not  at 
present  recognize. 

Balance  of  Energy. — As  the  body  receives  its  energy  supply  solely 
in  the  form  of  chemical  compounds,  it  should  be  possible  to  determine 
experimentally  the  balance  of  energy  in  the  organism,  provided  that  the 
physical  and  chemical  changes  taking  place  occur  in  obedience  to  the 
laws  of  the  conservation  of  energy  and  matter.  The  essential  data  for 
comparison  are,  obviously,  the  income  and  outgo  of  energy.  The  former 
of  these  quantities,  the  income,  can  be  estimated  in  terms  of  calories  or 
heat  units  after  corrections  have  been  made  for  the  loss  of  potential 
energy  in  the  corresponding  incompletely  burned  metabolic  end-products. 
When  the  tissue  constituents  themselves  furnish  the  energy  liberated, 
the  quantitative  relations  can  be  established  by  ascertaining  the  exchange 
of  materials  which  has  ensued;  and  thus  the  energy  of  the  katabolized 
compounds  can  be  calculated. 

In  the  measurement  of  the  output  of  energy  from  the  body,  the  quan- 
tities to  be  ascertained  are  the  heat  given  off  from  the  body  and  the 
external  muscular  work,  which  can  in  turn  be  converted  into  terms  of  heat 
units.  The  muscular  work  of  the  internal  organs  is  transformed  into 
heat  before  it  leaves  the  body.  Briefly  reviewed,  the  factors  to  be  deter- 
mined in  preparing  the  balance-sheet  of  the  income  and  outgo  of  energy 
are:  (1)  Potential  energy  of  the  organic  compounds  of  food  and  drink; 
(2)  potential  energy  of  organic  compounds  of  fseces,  urine,  and  products 
of  perspiration  and  respiration;  kinetic  energy  given  off  as  heat  and 
external  muscular  work  (and  other  possible  forms). 

42 


658 


NUTRITION 


Since  the  study  of  tlie  balance  of  matter  gives  tlie  data  from  which 
the  gain  or  loss  of  proteid,  fat,  and  carbohytlrate  in  tlie  body  can  be 
estimated,  a  calculation  of  the  fuel  value  of  tlie  corresponding  foodstuffs 
can  readily  be  made.  Furthermore,  the  potential  energy  of  the  ingesta 
can  be  determined  directly  by  calorimetric  methods.  Thus  the  conditions 
are  given  for  comparing  the  energy  available  in  metabolized  materials 
■with  the  quantity  of  heat  generated  by  the  body.  Various  devices  have 
also  been  perfected  by  which  the  external  muscular  work  of  the  organism 
can  be  converted  into  heat  within  the  respiration  calorimeter  and  thus 
all  the  energy  transformed  (whether  as  heat  or  work)  determined  in 
heat  units.  Rubner  was  the  fir.st  to  show,  by  calorimetric  studies  on 
animals,  that  the  cpiantity  of  heat  given  off  by  the  body  is  almost  exactly 
equivalent  to  that  calculated  from  the  available  potential  energy  of  the 
foodstuffs  actually  metabolized,  vmder  various  conditions  of  diet.  Figures 
from  ills  experiments  are  quoted  below: 


Character  of 
diet. 

Number  of 
days. 

Heat  units 
calculated. 

Heat  units 
found. 

Percentage 
difference. 

No  Food. 

{i 

1,296.3 
1,091.2 

1,305.2 
1,056.6 

1 

-1.42 

F.\T 

2 

1,510.1 

1,495.3 

-0.97 

Mk.\t  .\Nn  F.\T 

{.1 

2,492.4 
3.985.4 

2,488.0 
3,958.4 

} 

-0.42 

Meat 

{? 

2,249.  8 
4,780.8 

2,276.9 
4,769.3 

1 

+  0.43 

Laulanie  has  likewise  found  a  correspondence  between  the  calculated 
chemical  energy  of  the  compounds  metabolized  and  the  heat  given  off 
in  the  case  of  small  animals  during  rest.  These  experiments  demon- 
strate almost  beyond  doubt  that  the  life  of  the  higher  animals  is  essen- 
tially a  process  of  combustion  and  that  the  law  of  the  conservation 
of  energy  is  strictly  applicable  to  the  living  body.  The  latter  controls 
no  permanent  sources  of  energy  other  than  those  furnished  by  the 
food.  More  recently  the  demonstration  of  this  fundamental  principle 
has  been  furnished  in  the  case  of  man  under  various  conditions  of  rest 
and  activity,  by  x\twater  and  his  associates  in  this  country.  The  results 
of  45  experiments  covering  one  hundred  and  forty-three  experi- 
mental days  are  summarized  in  the  table  on  page  659  (Atwater  and 
Benedict). 

The  remarkable  average  agreement  between  the  theoretical  and  actual 
changes  of  energy  in  the  human  body  evidenced  by  these  figures,  indicates 
that  the  law  of  the  conservation  of  energy  obtains  here  precisely  as 
d  priori  considerations  would  lead  us  to  expect.  The  actions  of  the 
organism  are  thereby  shown  to  be  clearly  within  the  domain  of  ordinary 
physical  and  chemical  laws.  It  is  cA-ident,  also,  that  in  the  study  of  metab- 
olism, the  caloi-imetric  method  is  capable  of  furnishing  data  quite 
comparable  in  value  with  the  facts  learned  by  study  of  the  purely  chem- 
ical changes.  We  are  enabled  to  ascertain  the  energy  transformations 
which  go  on. 


GENERAL  CONSIDERATIONS  OF  METABOLISM 


659 


Comparison  of  Income  and  Outgo  of  Enekgy  in  45  Metabolism  Experi- 
ments Covering  143  Experimental  Days — Average  Amounts  Per  Day. 


Subject  and  Kind  of  Experiment. 


Dura- 
tion. 


Net  income 
(potential 
energyof 
material 

oxidized  in 
the  body). 


Net  outgo 
(kinetic 

energy 
given  off 
from  the 

body). 


Difference  (in  terms  of 
net  income). 


Ordinary  diet. 
Rest  Experiments. 


'i   Experiments  with  E.  O 

1   Experiment  with  A.  W.  S 

3  Experiments  with  J.  E.  S 

1  Experiment  with  J.  C.  W 

Average  of  12  experiments  with  E.  O. 
A.  W.  S.,  J.  F.  S.,  and  J.  C.  W 


Work  Experiments. 


2  Experiments  with  E.  O 

4  Experiments  with  J.  F.  S 

14  Experiments  with  J.  C.  W 

Average  of  20  experiments  with  E.  O., 
J.  F,  S.,  and  J.  C.  W 

Average  of  all  rest  and  work  experi- 
ments (32)  with  ordinary  diet 


Special  diet. 

Rest  Experiments. 

6  Experiments  with  E.  O 

3  Experiments  with  A.  W.  S 

1   Experiment  with  J.  F.  S 

Average  of  10  experiments  with  E.  O 
A.  W.  S.,  and  J.  F.  S 

Work  Experiments. 

1  Experiment  with  E.  O 

2  Experiments  with  J.  F.  g 

Average  of  3  experiments  with  E.  O., 
and  J.  F.  S 

Average  of  all  rest  and  work  experi 
ments  (13)  with  special  diet 

Average  of  all  rest  and  work  experi 
ments  (45)  all  diets 


Days. 

25 
3 
9 

4 


12 
46 


66 


107 


17 
6 
3 


26 


36 


143 


Calories. 

2,268 
2,304 
2,118 
2,357 


2,246 


3,865 
3,539 
5,120 


4,682 


3,748 


2,313 
2,308 
2,124 


2,290 


3,922 
3,583 


3,719 


2,687 


3,481 


Calories. 

2,259 
2,279 
2,136 
2,397 


2,246 


3,829 
3,540 
5,120 


4,676 


3,745 


2,319 
2,356 
2,123 


2,305 


3,928 
3,552 


3,702 


2,695 


3,481 


Calories. 


-25 
+  18 
-f  40 


-36 

+    1 
0 


+  6 
+  48 
-    1 


+  15 


+    6 
-31 


•17 


Per  cent. 

-0.4 
-1.1 
+  0.8 

+  1.7 


0.0 


-0.9 
0.0 
0.0 


-0.1 


-0.1 


+  0.3 

+  2.1 

0.0 


+  0.7 


-0.2 
-0.9 


-0.5 


+  0.3 


0.0 


Ii  is  instructive  to  examine  the  relative  participation  of  different  paths 
in  the  discharge  of  energy  from  the  body.  The  significant  features  are 
plainly  indicated  in  the  summary  on  page  660,  prepared  from  the 
experiments  of  Atwater  and  Benedict. 

The  important  role  of  the  body  surfaces  in  the  dissipation  of  heat 
is  thus  made  apparent. 

Replacement  of  Nutrients. — The  conception  of  metabolism  as  a 
process  in  which  the  body  transforms  the  potential  energy  of  the  food  in 
accord  with  well-known  physical  and  chemical  laws,  suggests  the  pog- 


660  NUTRITION 

Percentaoe   of  Energy  Givex  Off  from   the   Body  in  Different  Ways. 


Path  of  Heat  Elimination 

Rest, 
fasting. 

Re.-^t, 
with  food. 

Work 
experiments. 

By  radiation  and  conduction 

73.4 

0.9 

25.7 

74.4 
1.4 

24.  2 

71.4 
0.6 

In  water  vaporized  from  lungs  \ 

18.4 

Heat     equivalent     of     external  j 

9.6 

100.0 

100.0 

100.0 

sibility  that  different  substances  might  replace  one  another,  as  nutrient 
materials,  in  proportion  to  their  energy-yielding  or  fuel  value.  This 
would  mean  that  these  different  materials  are  of  service  to  the  organism 
in  proportion  to  the  heat  and  work  which  they  can  develop,  despite 
any  dift'erences  in  the  chemical  transformations  by  which  they  are 
metabolized.  From  this  point  of  view,  the  content  of  energy  (as  ex- 
pressed in  the  available  heat  of  combustion)  becomes  the  crucial  factor 
in  estimating  the  importance  of  any  food;  the  demands  of  nutrition  are 
satisfied  by  supplying  energy  to  the  body.  Limitations  to  such  a  con- 
ception at  once  arise,  as,  for  example,  the  impossibility  of  maintaining 
life  unless  at  least  a  minimum  of  proteid  is  furnished  to  make  good  the 
continued  degradation  of  the  nitrogenous  tissues.  Yet  the  general  idea 
that  the  foodstuffs  can  replace  one  another  to  a  very  large,  if  not  an 
unlimited,  extent  in  metabolism  was  long  ago  suggested.  In  1883,  Rubner 
published  experimental  observations,  which  were  later  widely  extended, 
indicating  that  the  organic  nutrients  can  under  certain  conditions 
replace  each  other  in  proportion  to  the  energy  which  they  furnish 
outside  of  the  body,  corrections  being  made  for  the  availability  and  un- 
oxidized  fragments  of  the  typical  nutrients.  In  Rubner's  earlier  experi- 
ments, the  actual  quantities  of  various  substances  which  yielded  the 
same  amount  of  heat  as  100  grams  of  fat  were  determined  in  animal 
calorimetric  trials  and  compared  with  the  figures  derived  in  a  pre- 
\'ious  chapter  for  the  heat  values  of  compounds  as  deduced  and  cor- 
rected from  physical  measurements,  viz.: 


1  gram  of   protein 

1  gram  of   fat . . . .' 

1  gram  of   carbohydrate 


4. 1  large  calories. 
9.3  large  calories. 
4.1  large  calories. 


The  relatively  close  correspondence  of  the  observed  and  calculated 
values  is  shown  in  the  table  on  page  661. 

With  the  exception  of  the  slight  differences  in  the  case  of  the  proteids, 
these  experiments  show  a  satisfactory  equivalence  between  the  actual 
heat  production  and  the  computed  values.  From  this  we  may  conclude 
not  only  that  the  foodstuffs  yield  heat  in  the  body  in  proportion  to  their 
estimated  fuel  value,  but  that  the  nutrients  may  replace  each  other  in 
proportions  corresponding  to  their  heat  value.  By  the  latter  is  of  course 
here  understood  their  "available"  or  "physiological"  heat  value — 
"metabolizable  energy,"  as  expressed  by  Armsby.    The  quantities  which 


GENERAL  CONSIDERATIONS  OF  METABOLISM  GGl 

Equivalent  to  100  Grams  of  Fat.     (Ruhneh.) 


Substance. 

Found  in  animal 
experiments. 

Computed  from 
available  energy. 

Differences. 

Muscle  proteid 

Grama, 

225 
243 
232 
234 
250 

Grama. 

213 
235 
229 
235 
255 

Per  Cent. 

+  5.6 
+  4.3 

+  1.3 

0 

0 

thus  replace  each  other  are  said  to  be  isodijnamic.  Accordingly,  it  follows 
that  the  bodies  of  the  higher  animals  do  not  require  the  same  cjuantities 
of  different  foods  for  the  purposes  of  metabolism;  but  they  obey  a  law 
of  isodynamic  replacement  according  to  which  the  foodstuffs  may  be 
substituted  for  one  another  in  inverse  proportion  to  their  available 
energy. 

These  observations  and  deductions  which  place  food  values  in  a  new 
light  and  emphasize  the  energetics  of  metabolism  so  strikingly,  have 
received  wide  acceptance.  Renewed  investigation  has,  however,  demon- 
strated that  the  foodstuffs  are  strictly  isodynamic  only  within  certain 
narrow  limits  and  under  definite  conditions.  The  animal  body  is  by  no 
means  a  machine  so  simple  that  it  transforms  energy  with  such 
indifference  toward  the  kifids  of  materials  metabolized.  Whenever 
transformations  go  on,  the  yield  of  heat  is  strictly  proportional  to  the 
energy-content  of  the  materials  metabolized;  but  the  regulation  of  the 
kind  of  food  or  body  constituents  burned  up  is  apparently  far  more  com- 
plex than  was  formerly  assumed.  A  slight  departure  from  theoretical 
conditions  has  already  been  noted  incidentally  in  the  case  of  the  proteids. 
Rubner  has,  indeed,  gradually  modified  his  earlier  conception  of  the 
isodynamic  replacement  of  the  foods  to  apply  strictly  only  to  small 
amounts  of  the  latter  under  conditions  approaching  the  maintenance 
ration,  i.  e.,  conditions  of  nutritive  equilibrium.  With  these  reservations 
the  general  idea  expressed  above  still  forms  an  important  part  of  the 
current  theories  of  nutrition,  and  is  capable  of  at  least  partial  demon- 
stration. The  chief  practical  value  of  the  law  of  isodynamic  values  lies  in 
the  application  of  the  idea  that  food  is  a  source  of  energy,  and  in  the 
interpretation  of  the  relative  significance  of  different  diets. 

We  cannot  undertake  here  to  review  in  detail  the  criticism  and  changes 
which  the  preceding  ideas  have  experienced  since  they  were  first  promul- 
gated. A  difference  between  the  effects  of  small  and  large  amounts  of 
food  was  early  discovered.  Moreover,  the  work  of  digestion  and  assimi- 
lation varies  widely  with  different  types  of  food,  and  introduces  a  new 
source  of  heat.  In  some  cases  the  heat  thus  produced  is  utilized  to  warm 
the  body,  and  less  energy  is  withdrawn  from  that  stored  in  the  tissues  At 
other  times,  however,  the  excess  of  heat  arising  from  the  work  of  digestion 
cannot  thus  be  compensated  for.  Furthermore,  environmental  conditions 
as  well  as  feeding  play  a  role  in  the  adjustment.  In  a  general  way 
it  may  be  pointed  out  that  materials  containing  the  same  amount  of  total 
energy  may  require  the  expenditure  of  very  unequal  amounts  of  energy  for 
their  digestion  and  utilization;  and  although  the  general  laws  of  energy 


662  NUTRITION 

naturally  support  the  theory  of  isodynamic  replacement,  the  discrepancies 
largely  hinge  upon  the  factors  which  determine  the  net  available  energy  in 
each  case.  The  facts  may  also  be  expressed  by  saying  that  when  large, 
but  isodynamic,  quantities  of  different  foodstuffs  are  compared,  they  exert 
unequal  energy  transformations.  Proteids  arc  especially  peculiar  in  this 
respect,  in  stimulating  heat  })roduction.  Without  attributing  it  specially 
to  the  work  of  the  digestive  or  other  glands,  Rubner  has  lately  a|)plied  to 
this  function  the  expression  .specific  dynamic  action.  The  isodynamic 
values  of  fats  and  carbohydrates  show  a  tendency  to  be  maintained;  but 
"when  the  proteids  are  exhibited  in  excess  they  exert  a  specific  dynamic 
action  in  provoking  a  disproportionate  transformation  of  energy  with  lib- 
eration of  heat.  A  further  example  of  an  apparently  similar  specific 
action  is  seen  when  alcohol  is  administered.  The  possibility  of  its  com- 
bustion and  an  isoydnamic  replacement  of  ordinary  nutrients  seems  to 
depend  upon  conditions  which  involve  both  the  individual  and  the  quanti- 
ties administered.  "In  the  transformation  of  energy,  there  is,  in  addition 
to  the  diet,  a  quite  different  factor  which  is  of  potent  influence,  namely,  the 
condition  of  the  body  and  its  dependence  on  the  thermal  environment. 
.  .  .  Amid  a  diversity  of  conditions  of  life  and  nature  we  are  too  prone  to 
regard  the  body  as  something  fixed  (Einheit) ;  whereas  in  fact,  w^hen  the 
conditions  about  and  within  us  are  considered,  it  is  an  extremely  change- 
able organism."  Accordingly,  when  we  consider  the  needs  of  the  body 
from  the  standpoint  of  the  changes  of  energy  going  on  within  it,  too  much 
emphasis  must  not  be  placed  upon  absolute  figures  or  fixed  proportions. 
Despite  the  tendency  toward  isodynamic  utilization  of  materials,  thermal 
conditions,  individuality,  age,  etc.,  in  addition  to  the  relative  cpiantities  of 
dift'erent  nutrients  offered,  must  be  reckoned  Avith.  As  elsewhere  in  physi- 
ology, so  in  the  study  of  metabolism,  adaptation  processes  are  met  with. 
The  specific-dynamic  action  of  proteids,  in  inaugurating  a  liberation  of 
energy  far  greater  than  the  small  plus  of  digestive  w^ork  entailed  by  them 
can  account  for,  applies  broadly  only  to  the  adult.  In  the  young  and 
growing  organism,  a  different  disposition  of  proteids  is  made.  We  are 
dealing,  in  the  case  of  the  animal  body,  wdth  a  complicated  apparatus  the 
workings  of  which  cannot  be  expressed  in  simple  laws. 

Mechanical  Efficiency  of  the  Body.— Before  leaving  the  considera- 
tion of  the  body  as  an  energy-transforming  mechanism,  we  may  refer  to 
its  efficiency  and  capacity  for  w^ork.  Part  of  the  energy  stored  within 
the  organism  is  expended  in  maintaining  physiological  functions  and  in 
the  case  of  the  heart  the  work  done  can  readily  be  calculated.  The 
energy  involved  in  these  processes  is,  however,  ultimately  transformed 
into  heat,  in  wdiich  form  it  leaves  the  body.  In  speaking  of  the  work- 
ing capacity  of  the  body  we  ordinarily  refer  to  external  muscular  work. 
It  is  a  familiar  fact  that  in  the  performance  of  an  ordinary  steam-engine 
a  relatively  small  fraction  of  the  energy  furnished  in  the  form  of  fuel  can 
be  transformed  into  mechanical  energy,  the  greater  portion  being  dissi- 
pated as  heat.  The  average  efficiency  of  such  engines,  that  is,  the  pro- 
portion of  the  expended  energy  which  appears  as  work  done,  is  under 
15  per  cent.  The  determination  of  this  ratio  in  man  is  attended  with 
considerable  difficulty.  The  necessary  data  are  derived  by  comparing  the 
excess  of  energy  transformad  when  w^ork  is  done  with  the  heat  equivalent 
of  the  external  muscular  work  done.     The  latter  can  be  measured  on  such 


GENERAL  CONSIDERATIONS  OF  METABOLISM  663 

apparatus  as  an  ergometer,  while  the  entire  exeess  of  energy  katabolized 
forworking  purposes  can  be  ascertained  through  comparison  between  the 
energy  metabolism  in  days  of  rest  and  (measured)  activity  in  the  same 
individual.  Experiments  by  Atwater  and  Benedict,  on  a  bicycle  rider, 
gave  19.6  as  the  efficiency  percentage. 

Other  experiments  in  which  the  necessary  data  have  been  accurately 
determined  have  given  efficiency  figures  of  a  similar  order.  There  is  no 
evidence  at  present  to  indicate  that  mental  "work"  is  attended  by  any 
liberation  of  energy  peculiar  to  it,  or  that  mental  excitement  per  se  induces 
any  noticeable  metabolism.  The  results  may  be  expressed  in  a  general 
way  by  saying  that  "for  every  calorie  which  was  transformed  into  external 
muscular  work,  four  calories  or  more  were  transformed  into  heat,  and  left 
the  body  in  that  form.  Whether  the  same  ratio  of  efficiency  applies  to 
the  muscular  work  of  the  internal  organs  has  not  yet  been  ascertained. 
Calculations  of  the  total  energy  metabolized  and  the  external  work  done 
during  prolonged  and  severe  muscular  work  by  trained  athletes  (bicycle 
riders)  indicate  a  far  larger  efficiency;  but  the  results  are  attended  with 
too  great  a  degree  of  uncertainty  to  receive  serious  consideration  without 
further  corroboratory  experimental  evidence."  There  is  little  doubt 
that  the  utilization  of  energy  in  doing  work  is  favorably  affected  by 
training. 

Heat  Production. — Finally,  the  subject  of  the  metabolism  of  energy 
requires  a  brief  mention  of  its  relation  to  heat  production.  To  what  extent 
heat  is  produced  for  its  own  sake,  i.  e.,  to  maintain  a  definite  temperature 
in  the  body,  or  whether  it  is  to  be  looked  upon  solely  as  a  waste  product 
arising  incidental  to  the  metabolism  occasioned  by  other  physiological  func- 
tions like  muscular  and  glandular  activity,  is  still  a  debated  question.  The 
temperature  of  man  being  approximately  uniform,  obviously  changes  in 
the  thermal  environment  must  affect  the  rate  of  dissipation  of  heat  from 
the  body  or  its  production,  or  both.  Changes  in  metabolism  must 
thereby  arise.  Voit  attempted  to  ascertain  the  extent  of  such  changes 
many  years  ago  by  measuring  the  carbon  dioxide  production  in  a  man  of  70 
kilograms  body  weight  kept  at  different  temperatures.  The  figures 
(per  hour)  found  are  given  here: 

Temperature,  COo  in  Grams. 

4.5  °C 35.1 

6.5          34.3 

9.0          32.0 

14.3          25.8 

16.2          26.4 

23.7          27.4 

24.2          27.6 

26.7          : 26.6 

30.0          28.3 

It  will  be  observed  that  a  "regulation"  of  metabolism  in  the  sense  of 
increased  metabolism  takes  place  only  at  the  lower  temperatures.  At 
higher  ranges,  a  "physical"  regulation  takes  the  place  of  the  "chemical" 
or  metabolic  adaptation.  At  lower  temperatures,  it  is  by  no  means  un- 
likely that  the  demand  for  heat  is  satisfied  by  direct  combustion  of  body 
material — that  is,  a  metabolism  of  energy, — ^whereas  at  ordinary  tempera- 


664  NUTRITION 

tures,  the  heat  liberated  in  connection  witli  tlie  usual  metabolic  changes 
more  than  suffices  to  maintain  the  body  temperature.  The  views  on 
these  points  are  somewhat  divergent  but  the  evidence  seems  favorable  to 
the  idea  that,  ordinarily,  heat  production  is  incidental  to  the  metabolic 
processes  and  is  sufficient  to  maintain  the  temperature  of  the  individual 
above  that  of  his  surrountlings.  Whatever  excess  of  heat  may  be  pro- 
duced is  gotten  rid  of  in  various  ways;  for  there  is  no  evidence  of  dimin- 
ished metabolism  (and  diminished  generation  of  heat)  with  increase 
of  external  temjierature.  Heat  is  produced  in  excess.  On  the  other 
hand,  when  external  conditions  are  given  in  which  this  excess  changes 
to  a  deficit,  metabolic  processes  are  provoked.  At  low  temperatures, 
accordingly,  a  "chemical"  regulation  is  inaugurated,  not  through 
direct  intermediation  of  the  food,  but  by  increased  protoplasmic 
activity. 

On  the  basis  of  such  views  as  have  just  been  advanced,  writers  like  Kas- 
sowitz  maintain  that  substances  such  as  alcohol,  glycerine,  lactic  acid,  etc., 
which  are  burned  in  the  body  without  entering  directly  into  the  structure 
of  the  protoplasm,  merely  add  to  the  heat  already  produced  in  excess,  with- 
out doing  any  physiological  work.  They  thus  distinguish  between  the 
oxidative  metabolism  of  integral  tissue  components  and  the  combustion  of 
unorganized  compoimds,  holding  that  the  latter  are  of  use  only  under  the 
relatively  mi  common  conditions  where  the  heat  production  in  the  ordinary 
course  of  metabolism  is  insufficient.  Such  views  have,  however,  been 
strongly  combated. 

The  removal  of  the  "waste  heat"  of  metabolism  is  affected  by  a  number 
of  factors,  such  as  the  condition  of  the  atmosphere,  insolation,  relative  hu- 
midity, etc.,  which  are  subject  to  great  variations.  As  Rubner  has  pointed 
out,  the  process  of  ci\ilization  has  tended  to  eliminate,  moderate,  or  equal- 
ize to  some  degree  these  external  changes.  There  has  thereby  resulted  a 
disposition  on  the  part  of  the  body  of  civilized  man  to  lose  some  of  the 
regulatory  responses  which  primitively  belong  to  him.  It  seems  that 
increasing  intelligence  in  respect  to  this  department  of  hygiene  will  lead 
to  noteworthy  improvements  in  our  modes  of  dress,  and  in  the  heating  and 
ventilation  of  our  habitations.  The  maintenance  of  heat  eciuilibrium 
in  relation  to  the  mass  of  tissue  involved  and  the  size  of  the  surface 
exposed — variations  corresponding  to  large  and  small  individuals — is 
apparently  due  to  a  nice  adjustment  of  metabolism. 


MODIFICATIONS  OF  METABOLISM. 

Metabolism  During  Hunger. — The  problems  of  metabolism  are 
reduced  to  somewhat  simpler  terms  when  the  behavior  of  the  body 
during  inanition  is  considered.  The  extreme  case  would  be  that 
in  which  all  intake  (of  food  and  drink)  is  excluded,  the  respired 
oxygen  being  the  only  contribution  brought  to  the  organism  from  with- 
out. The  features  of  hunger  under  less  rigid  conditions,  e.  g.,  where 
water  is  taken,  closely  resemble  the  preceding  ones  in  general  character. 
For  the  physician  and  pathologist  the  subject  possesses  additional  prac- 
tical interest,  in  view  of  the  fact  that  the  essential  derangements  in  many 
cases  of  under  nourishment  are  quahtatively  comparable  with  those  noted 


GENERAL  CONSIDERATIONS  OF  METABOLISM 


G05 


during  complete  starvation,  the  dili'erence.s  being  of  degree  only.  Von 
Noorden  has  well  said  that  it  is  impossible  to  obtain  a  clear  under- 
standing of  the  metabolic  changes  which  characterize  or  accompany 
disease,  unless  we  can  form  some  estimate  of  the  implication  of  inani- 
tion in  such  changes.  From  this  standpoint  extreme  hunger  may, 
under  certain  relations,  form  the  most  extreme  type  of  malnutrition. 

In  starvation,  the  body  is  living  on  its  own  tissues, — that  is,  katabolizing 
body  constituents  to  liberate  the  energy  requisite  for  the  necessary  bodily 
functions.  As  might  be  expected,  the  character  of  metabolism  in  inani- 
tion depends  in  no  small  degree  upon  the  previous  nutritive  condition.  It 
is  necessary  to  bear  in  mind  that  a  well-nourished  organism  with  an  abun- 
dant reserve  supply  of  fat,  glycogen,  and  proteid,  may  experience  a 
response  to  the  demands  for  energy  somewhat  different  from  that  called 
forth  amid  less  bountiful  stores.  Most  of  our  information  on  this  subject 
has  been  derived  from  experiments  on  animals;  a  few  investigations 
on  healthy  men  fasting  over  a  considerable  period  of  time  will,  however,  be 
called  upon  to  yield  data  for  our  consideration. 

A  question  which  early  presents  itself  is  this :  How  great  are  the  losses 
which  the  body  can  sustain  during  hunger  without  serious  impairment  of 
function  ?  The  losses  in  body  weight  ascertained  in  the  most  carefully 
conducted  researches  on  starving  men  are  collected  in  the  table  below 
(Weber): 


Subject  and  Observer. 

Duration 

OF  FAST. 

Body  weight. 

Percentage  loss  of 
body  weight. 

At  beginning. 

At  end. 

Total. 

Per  day. 

Days. 

10 

6 
30 

5 

Kilograms. 

57.0 
60.0 
63.2 
67.8 

Kilogram,s. 

50.6 
56.4 
51.8 
62.8 

11.2 

6.0 

19.0 

7.4 

1    \ 

Breithaupt  (Senator  et  al.)    . . 

Succi  (Luoiani) 

Swede  (Johannsen) 

1.0 
0.6 
1.5 

These  figures  give  no  adequate  idea  of  the  losses  undergone  in  more  pro- 
longed fasting,  or  of  the  resources  of  the  body  under  such  a  trial.  Kuma- 
gawa  starved  a  bitch  for  ninety-eight  days,  during  which  time  she  suffered 
a  loss  of  65  per  cent,  in  body  weight  (17  to  5.96  kilograms).  The  distri- 
bution of  this  loss  varies  somewhat  with  the  amount  of  fat  available.  In 
the  table  on  page  667  the  changes  in  individual  organs  are  calculated  on 
100  parts  of  the /a^-/?-ee  tissues.   (E.  Voit.) 

These  figures  indicate  the  unequal  disintegration  of  different  organs. 
The  adipose  tissue  suffers  the  earliest  and  greatest  diminution.  Among 
the  residual  (fat -free)  organs,  the  glands  will  be  noted  to  undergo  a  propor- 
tionately large  loss,  others — especially  skin,  central  nervous  system,  and 
heart — experiencing  less  change.  It  has  often  been  pointed  out  in  this 
connection  that  the  tissues  suffering  the  relatively  smaller  losses  include 
those  whose  function  is  of  greatest  importance  for  the  continuance  of  life. 
Glycogen  disappears  from  the  body  with  varying  readiness  in  starvation. 
The  loss  of  proteid  is  extremely  variable  and  in  animals  starved  until  death 


660 


NUTRITION 


the  diminution  of  their  proteid-content  ranged,  in  E.  Voit's  ex|-)enmcnts, 
between  22  and  49  per  cent.  These  variations  are  attributable  to  the  thf- 
ferent  fat  reserves  of  the  animals.  Those  which  experienced  the  smaller 
losses  (22  to  26  per  cent.)  showed  a  considerable  su})ply  of  fat  even  after 


Organs. 

100  PARTS  OF  THE  FAT-FREE  ANIMAL  CONTAIN 

100   PARTS  FRESH  FAT- 
FREE  ORGANS  LOSE 

In  good  nutritive 
condition. 

After- 
starvation. 

After  24  days' 
starvation. 

14.87 
10.30 
53.77 
0.94 
0.11 
0.54 
7.14 
0.39 
3.98 
0.33 
0.66 
0.30 
5.81 
0.89 

21.50 
11.29 
48.39 
1.11 
0.16 
0.69 
5.69 
0.26 
3.05 
0.19 
0.45 
0.23 
6.02 
0.97 

5 

Skin 

28 

42 

Brain  and    cord 

Eves 

22 
3 

Heart 

16 

Blood 

48 

Spleen 

Liver 

Pancreas 

Kidneys 

Genitalia 

Alimentary  canal 

Lungs 

57 
50 
62 
55 
49 
32 
29 

death.  They  suffered  from  proteid  starvation ;  that  is,  certain  essential 
organs  must  have  experienced  a  loss  of  proteid  greater  than  they  could 
withstand.  Presumably,  these  must  have  been  specific  essential  organs, 
since  mostof  thetissuescan  withstand  a  far  greater  loss— even  50  percent. — 
than  is  here  indicated.  In  those  animals  where  a  larger  loss  (49  per 
cent.)  of  proteid  was  noted,  the  fat  had  been  reduced  to  a  minimum; 
and  the  animals  must  have  satisfied  the  demands  for  energy  during  the 
later  days  of  starvation  almost  entirely  with  proteid.  Here,  then,  we  have 
both  fat  and  proteid  starvation.  From  a  practical  standpoint,  it  may 
be  emphasized  that  all  organs  do  not  suffer  the  same  degree  of  loss  in 
under-nourishment;  that  some  of  them  are  able  to  protect  themselves  from 
extensive  losses  at  the  expense  of  other  organs;  and  that  the  character  of 
the  losses  is  in  no  small  degree  variable  with  the  previous  nutritive  con- 
dition. 

Some  of  the  characteristic  features  of  metabolism  in  hunger  are  illus- 
trated in  the  study  of  proteid  metabolism — the  aspect  of  starvation  which 
has  been  most  frequently  investigated.  The  output  of  nitrogenous  kata- 
bolic  products  tends  to  diminish  after  the  earlier  days  of  starvation,  ulti- 
mately reaching  a  fairly  constant  level.  This  would  seem  to  indicate  that 
proteid  katabolism  is  stimulated  during  the  first  two  or  three  days;  and 
the  increased  output  of  nitrogenous  products  during  this  period  seems  to 
vary  somewhat  in  proportion  to  the  richness  of  the  previous  diet  in  proteid. 
It  is  certainly  unlikely  that  the  high  values  for  urinary  nitrogen  found  in 
the  earlier  period  of  starvation  are  due  to  a  liberation  of  retained  excretory 
products  which  are  suddenly  swept  out  of  the  system  under  the  altered 
nutritive  conditions.  In  seeking  to  explain  this  repeatedly  observed  in- 
crease in  proteid  katabolism,  Voit  was  led  to  make  his  well-known  distinc- 
tion between  "circulating"  and  "morphotic"  or  "tissue"  proteid  in  the 
body.     The  morphotic  proteid  is  disintegrated  only  to  a  small  extent  in 


CtBNERAL  CONSIDERATIONS  OF  METABOLISM  667 

the  ordinary  course  of  metabolism;  that  is,  it  represents  the  relatively 
stable  nitrogenous  component  of  the  cells.  The  more  readily  metabo- 
lized circulating  proteid,  the  supj)ly  of  which  is  largely  dependent  on  pre- 
ceding conditions  of  nutrition,  is  used  up  during  the  early  days  of  inanition. 
In  this  way  the  early  high  nitrogen  output  is  explained  by  the  Voit  school. 
The  succeeding  fall  in  nitrogen  excretion  represents  a  stage  in  which  other 
tissue  components  are  destroyed  in  place  of  the  residual  and  more  stable 
morphotic  proteid.  Fat  and  glycogen  now  afford  a  part  of  the  energy 
required.  This  explanation  has,  however,  not  received  universal  accept- 
ance. In  the  few  experiments  made  on  man,  this  temporary  increase  in 
the  rate  of  nitrogen  katabolism  has  not  always  been  as  marked  as  in  the 
experiments  on  animals.  Among  other  explanations  of  the  phenomenon 
a  few  deserve  mention,  especially  because  they  illustrate  what  a  wide 
range  of  complicating  factors  may  influence  the  behavior  of  the  body  in 
metabolism.  Thus,  the  "nutritive  plane"  of  the  individual  has  been 
called  upon  to  account  for  the  relatively  high  or  low  nitrogen  output  in  the 
early  periods  of  starvation.  When  the  intake  of  nitrogenous  food  is  sud- 
denly cut  off  in  young  individuals  accustomed  to  a  high  proteid  metabo- 
lism, the  cells  do  not  at  once  adapt  themselves  to  the  new  conditions,  and 
the  high  rate  of  proteid  katabolism  is  continued  until  new  relations  are 
gradually  established.  Again,  a  larger  or  smaller  intake  of  water  in  star- 
vation is  effective,  according  to  both  Munk  and  Heilner,  in  increasing  the 
output  of  nitrogenous  compounds,  although  this  is  not  usually  the  case 
when  food  is  given.  Finally,  most  of  the  prolonged  starvation  experi- 
ments on  man  have  been  undertaken  with  individuals  in  whom  the  reserve 
store  of  non-nitrogenous  nutrients  was  relatively  low  This,  too,  may 
help  to  account  for  the  high  output  of  nitrogen 

In  brief  periods  of  starvation  some  observers,  notably  Prausnitz,  have 
regularly  found  a  higher  output  of  nitrogen  on  the  second  day  than  on  the 
first.  This  is  referred  to  the  rapid  consumption  of  glycogen  during  the 
early  period  of  hunger,  with  a  consequent  protection  of  the  proteid  from 
decomposition.  In  animals  a  prolonged  period  in  which  the  extent  of 
nitrogen  katabolism  is  fairly  low  and  constant  indicates  a  uniform  pro- 
gress of  the  decompositions  in  the  body — a  feature  to  which  other  facts 
likewise  point.  Finally,  a  period  is  reached  in  which  the  disintegration 
of  body  proteid  rapidly  increases,  indicated  by  a  twofold  or  threefold 
increase  in  the  nitrogenous  compounds  eliminated.  This  "premortal" 
rise  in  nitrogenous  output  is  the  sign  of  impending  death.  By  most 
investigators  it  has  been  referred  to  the  exhaustion  of  the  glycogen  and  fat 
depots  of  the  body.  When  the  latter  are  no  longer  available,  the  proteid 
resources  become  severely  taxed  and  the  tissues  rapidly  disintegrate  to 
furnish  the  energy  requisite  for  the  bodily  functions.  Death  is  thus 
attributable  to  the  lack  of  available  nutrients  in  the  tissues.  The  sudden 
premortal  rise  in  nitrogen  elimination  has  been  ascribed  by  others  to  a 
sudden  widespread  disintegration  of  body  cells  due  to  the  improper 
nutritive  conditions  to  which  they  are  finally  subjected.  The  amount 
of  materials  available  in  the  starving  body  before  death  intervenes  may 
be  very  great — ^in  animals  as  much  as  70  per  cent,  of  the  original  store 
of  energy. 

During  starvation,  heat  production  remains  remarkably  constant,  and 
the  body  temperature  is  maintained  until  near  the  end,  or  the  period  where 


668 


NUTRITION 


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The  actual  extent  of  proteid  katabolism  during  starvation  is  indicated 
by  these  data  from  experiments  by  Munk  and  by  Van  Hoogenhuyze 
and  Verploegh. 


GENERAL  CONSIDERATIONS  OF  METABOLISM  669 

profound  metabolic  changes  give  evidence  of  themselves  in  the  sudden  and 
rapid  increase  in  nitrogen  output.  So  far  as  has  been  exp(!rimentally  ob- 
served the  oxidative  processes  maintained  during  hunger  do  not  decrease 
in  extent  below  the  values  noted  in  the  same  individual  under  comparable 
conditions  when  food  is  not  denied.  This  is  apparently  true  not  only  in 
periods  of  rest,  but  likewise  during  work.  The  essential  difference  be- 
tween the  starving  man  and  one  in  good  nutritive  condition  (but  tempo- 
rarily without  food)  lies  in  the  earlier  onset  of  fatigue  in  the  former.  That 
is,  "the  muscles  of  the  man  are  still  capable  of  accomplishing  practically 
as  much  in  a  single  contraction  during  starvation  as  before;  but  they 
become  exhausted  more  speedily.  An  important  factor  in  this  lapid  fa- 
tigue is  found  in  the  extreme  irritabihty  and  slight  working  capacity  of  the 
heart.'' 

The  metabolism  of  the  elements  other  than  nitrogen  during  prolonged 
starvation  has  not  been  extensively  studied  in  man  except  in  a  few 
instances.  The  output  of  sulphur  appears  to  run  closely  parallel  to  that 
of  nitrogen,  indicating  a  common  source  of  the  two  elements  in  the  dis- 
integration of  proteid.  The  elimination  of  phosphorus  has  been  found 
to  be  increased  both  absolutely  and  relatively  with  respect  to  nitrogen. 
If  the  phosphorus  excreted  in  starvation  is  likewise  derived  from  pro- 
teids  it  should  obviously  bear  the  same  relation  to  the  nitrogen  excreted  as 
the  two  bear  to  each  other  in  the  body.  This  has  not  usually  been  the  case. 
In  addition  to  the  high  output  of  phosphorus,  an  increased  elimination  of 
calcium  and  magnesium,  too  great  to  be  attributed  to  the  disintegration 
of  muscle  tissue,  has  also  been  found.  These  facts,  taken  together,  leave 
little  doubt,  that  the  bones,  which  are  so  rich  in  phosphates  of  the  alkali 
earths,  suffer  loss. 

Since  the  chlorides  of  the  urine  are  primarily  derived  from  the  chlorides 
(chiefly  NaCl)  taken  with  the  food,  a  rapid  fall  in  the  output  of  chlorides 
during  starvation  is  naturally  to  be  expected,  and  has  repeatedly  been  ob- 
served. The  writers  have  seen  it  sink  to  a  small  fraction  of  a  gram  in  the 
early  days  of  starvation  in  man,  and  continue  at  that  level  throughout  a 
five-day  hunger  period.  The  excretion  of  potassium  considerably  ex- 
ceeds that  of  sodium,  quite  the  reverse  of  ordinary  conditions.  This 
observation  adds  another  to  the  many  evidences,  during  starvation,  of  the 
disintegration  of  the  tissue  elements  (structures)  in  which  potassium  salts 
greatly  preponderate. 

So  far  as  published  experiments  indicate,  the  formationof  the  f ffices  does 
not  cease  during  prolonged  starvation,  although  the  quantities  are  greatly 
diminished.  The  composition  of  the  "hunger  faeces,"  viz.,  the  relatively 
high  content  of  nitrogen  (6  to  8  per  cent.),  fat,  and  inorganic  salts,  recalls 
the  fseces  discharged  after  an  easily  digestible  diet,  free  from  cellulose. 
This  close  resemblance  has  contributed  largely  to  the  prevailing  \dew  that 
the  fseces  are  not  to  be  considered  as  the  undigested  residue  from  food  to 
any  great  extent  under  satisfactory  conditions  of  diet,  but  rather  as  con- 
sisting in  large  part  of  secretory  products  from  the  alimentary  tract. 

We  cannot  attempt  to  follow  the  fate  of  the  many  other  katabolic 
products  arising  during  hunger,  nor  designate  the  specific  changes 
produced  in  individual  organs.  One  is  impressed,  however,  by  the 
slight  extent  of  the  variations  from  the  normal  which  are  met  vAih.  The 
differences  between  fasting  and  normal  individuals   are  quantitative 


670  NUTRITION 

rather  than  qualitative,  at  least  during  the  earlier  stages  of  starvation. 
Experiments  of  Abderhalden  and  otliers  have  demonstrated  that  the 
chemical  make-up  of  the  tissues  -svliich  remain  unused  in  a  starving 
animal  is  not  noticeably  altered.  The  proportions  of  nitrogenous  decom- 
position products  obtainable  are  entirely  comparable  with  those  yielded 
by  a  well-fed  animal  of  the  same  species.  It  is  interesting  to  note  that  the 
fat  content  of  the  blOotl  may  be  foimd  notably  higher  during  the  early 
days  of  starvation.  This  corresponds  with  what  might  be  expected  if  fat 
is  transported  during  hunger  from  its  storehouses  in  the  body  to  the 
places  where  the  oxitlations  take  place. 

With  reference  to  the  actual  nutritive  condition  of  the  cells  and  their 
metabolic  ca{)acity  in  hunger,  experiments  by  Schondorlf  (1893)  have 
given  some  evidence.  He  perfused  the  hind  extremities  of  well-nourished 
and  starving  dogs  with  the  blood  of  starving  and  normal  animals,  and  esti- 
mated the  metabolic  power  of  the  surviving  body  cells  by  the  percentages 
of  urea  found  in  the  blood.  It  was  found  that  even  when  normal  blood 
was  perfused  through  the  "hunger"  limb,  the  proportion  of  katabohc 
products  was  smaller  than  that  yielded  by  the  well-nourished  muscles.  We 
may  reasonably  conclude  from  this  that  the  metabolic  activities  of  the  cells 
are  dependent  upon  their  inherent  nutritive  conditions,  as  well  as  upon  the 
character  of  the  blood  which  supplies  them.  The  extent  to  which  indi- 
vidual organs  may  be  impaired  is  seen  in  the  case  of  milk  secretion  during 
hunger.  Barbera  (1900)  saw  the  daily  yield  decrease  under  these  con- 
ditions to  one-seventh  of  its  original  volume  in  the  course  of  fourteen  days, 
all  the  constituents  being  involved  in  the  change,  although  the  yield  of  fat 
diminished  most  slowly.  Lusk  (1901)  had  a  similar  experience  with  a 
goat  in  which  the  output  of  milk  could  be  diminished  to  far  greater  extent 
by  a  few  days'  starvation. 

Closely  related  to  the  conditions  pertaining  in  complete  inanition  or 
"acute"  starvation,  are  those  found  in  the  more  chronic  forms  of  deficient 
nutrition  ("Unterernahrung")  or  malnutrition.  Unfortunately  we  have 
few  accurate  experimental  data  on  this  subject — one  highly  important  for 
the  physician,  within  w^hose  province  it  distinctly  falls.  The  cases  in 
which  deficient  nutrition  may  arise  are  nvmierous,  and  in  all  we  have  to 
deal  with  physiological  conditions  not  markedly  different  from  those 
discussed  under  complete  hunger.  It  is  possible  that  the  organism  adapts 
itself  to  the  deficiency  in  intake  by  a  more  economical  utilization  of  its 
resources,  so  that  the  body  can  maintain  its  nutritive  equilibrium  with 
a  smaller  expenditure  of  energy.  Accurate  data  are  not  yet  available 
in  this  direction,  while  evidence  to  the  contrary  is  not  wanting.  Von 
Noorden  believes  that  even  after  prolonged  deficient  nutrition  an  intake 
of  30  large  calories  per  kilo  of  body-weight  is  required  to  maintain  equi- 
librium. Practical  experience,  however,  has  shown  that  under  poor 
nutritive  conditions,  persons  may  make  gains  on  diets  Avhich  are  barely 
sufficient  for  the  well-nourished  individual.  A  careful  study  of  this 
subject  is  important ;  for  in  conditions  (such  as  gastric  ulcer)  where 
larger  quantities  of  food  cannot  be  consumed  without  danger,  a  knowl- 
edge of  body  needs,  as  demonstrated  by  actual  experience,  becomes 
invaluable. 

In  connection  with  the  phenomena  of  metabolism  pecuhar  to  starva- 
tion, it  is  perhaps  appropriate  to  mention  the  marked  retention  of 


GENERAL  CONSIDERATIONS  OF  METABOLISM 


671 


ingested  materials  which  characterize  what  has  been  termed  "re-alimen- 
tation"; that  is,  the  return  , to  normal  conditions  when  food  ingestion  is 
resumed.  In  accordance  with  the  general  protection  which  the  body 
aifords  in  starvation  to  the  organs  most  important  for  its  survival,  it 
has  been  noted  that  even  prolonged  starvation  does  not  destroy  the  neuro- 
secretory apparatus.  When  food  is  again  given,  the  digestive  changes 
go  on  as  usual.  The  glycogen  content  of  the  liver  is  rapidly  reestablished 
and  a  decided  gain  is  noted  in  the  balance-sheet  of  intake  and  output 
of  materials.  This  is  especially  true  in  the  case  of  the  inorganic  salts 
as  well  as  the  nitrogenous  intake.  At  present  no  extensive  data  appli- 
cable to  inan  are  available  on  this  subject.  An  interesting  illustration 
of  the  extent  to  which  nitrogen  may  be  retained  is  afforded  by  observa- 
tions of  Fr.  Miiller  on  a  patient  whose  body-weight  had  fallen  to  31 
kilos  during  insufficient  nutrition  following  stenosis  of  the  oesophagus. 
After  four  days  of  absolute  starvation  with  a  daily  loss  of  4.28  grams  of 
nitrogen,  it  became  possible  to  increase  the  intake  of  food.  During  the 
following  twenty-six  days  of  feeding,  the  nitrogen  balance  was  as  given 
below : 


Daily  intake  of 
nitrogen. 

Daily  intake  of 
food. 

Daily  output  of 

nitrogen  in  urine 

and  faeces. 

Nitrogen  retention 
per  day. 

5  days 

7  days 

8  days 

6  days 

Grams. 

7.60 

8.99 

11.77 

13.67 

Calories  (large). 

765 

881 
1000 
1100 

Grams. 

5.91 
7.04 
8.18 
8.83 

Grams. 

1.69 
1.95 
3.59 

4.84 

26  days 

42.  03 

29.96 

With  every  gain  in  proteid  intake,  a  proportionately  larger  retention 
of  nitrogen  was  noted.  This  is  characteristic  of  convalescence  from 
wasting  disease,  in  which  the  katabolic  processes  preponderate.  A 
similar  retention  of  nitrogen  is  not  readily  brought  about  in  the  well- 
nourished  organism  in  which  nitrogenous  equilibrium  tends  to  be  es- 
tablished very  speedily. 

Metabolism  During  Feeding-.— Observations  during  conditions  of 
starvation  might,  perhaps,  be  expected  to  furnish  a  satisfactory  basis 
upon  which  to  estimate  the  actual  nutritive  needs  of  the  organism.  In 
hunger,  where  one  group  of  factors — ^the  intake— can  be  entirely  elimi- 
nated, it  might  appear  that  we  are  dealing  with  the  simplest  state  of 
metabolic  changes  possible  and  that  the  data  obtained  would  be  broadly 
applicable.  This,  however,  is  only  partly  the  case.  For  example,  the 
relative  quantities  of  proteid  or  fat  decomposed  per  day  in  a  starving  indi- 
vidual are  not  necessarily  indicative  of  the  most  advantageous  utiliza- 
tion of  materials,  as  the  organism  is  compelled  to  employ  the  resources 
which  are  most  easily  available.  It  becomes  important,  therefore,  to 
learn  how  the  metabolic  processes  are  modified  when  food  substances 
are  ingested. 


672  NUTRITIoy 

Influence  of  Proteids  on  Metabolism. — The  unique  importance  of 
proteids  in  nutrition,  owing  to  their  content  of  nitrogen,  has  ah'cady  been 
mentioned.  Since  the  body  is  unable  to  utihze  other  tyj)es  of  nitrogenous 
compounds  in  the  entire  absence  of  true  proteids,  except  perhaps  the 
immediate  decomposition  products  of  the  latter,  prolonged  proteid  hunger 
becomes  as  serious  in  its  consequences  as  does  the  comj^lete  absence  of 
food.  Under  suitable  conditions  a  carnivorous  animal  like  the  dog 
can  be  kept  in  nutritive  equilibrium  on  an  exclusive  meat  diet.  To 
accomplish  this  the  animal  must  eat  three  to  four  times  as  much  proteid 
as  is  decomposed  during  hunger.  It  has  thus  far  been  imj)ossible  to 
maintain  similar  equilibrium  in  man  on  an  exclusive  ])roteid  diet.  The 
failure  to  do  so  is  associated,  in  part  at  least,  with  the  inability  to  digest 
properly  the  enormous  quantities  of  i)r()teid  requisite.  It  will  be  recalled 
that  the  net  available  energy  of  the  proteids  is  smaller  than  their  heat  of 
combustion  woukl  indicate,  owing  to  the  incompletely  oxidized  products 
which  are  liberated  from  them.  The  digestive  work  which  they  entail 
is  also  not  inconsiderable.  The  fundamental  observations  noted  show 
that  every  increase  in  the  amount  of  proteid  fed  tends  to  increase  the 
katabolism  of  proteid.  By  virtue  of  the  tendency  of  the  body  to  adapt 
its  nitrogenous  katabolism  to  the  proteid  intake,  it  becomes  possible  to 
attain  nitrogenous  equilibrium  with  widely  varying  quantities  of  proteid. 
In  all  of  these  cases  it  is  understood  that  the  total  intake  of  food  must  be 
sufficient  to  cover  the  demands  of  the  body  for  energy.  In  the  fasting 
condition  the  latter  may  amount,  in  the  case  of  a  man  of  average  body 
weight,  to  somewhat  over  2,000  calories  per  day,  or  30  large  calories 
per  kilo  of  body  weight.  When  food  is  taken,  and  no  external  work  of 
any  consequence  is  performed,  the  metabolism  of  energy  is  slightly  in- 
creased over  the  fasting  figure,  perhaps  to  32  to  33  large  calories  per 
kilo  per  day;  while  under  conditions  of  muscular  activity  the  demand 
for  energy  may  be  increased  under  extraordinary  circumstances  to  100 
large  calories  per  kilo  per  day  or  over. 

Provided  that  these  nutritive  demands  are  satisfied,  the  absolute 
quantity  of  proteid  required  to  prevent  a  loss  of  body  proteid  will  depend 
somewhat  on  the  proportion  of  non-proteid  foods  ingested  and  absorbed. 
A  determination  of  the  maximum  quantity  of  proteid  which  can  be 
utilized  is  scarcely  feasible  in  the  case  of  man,  since  it  is  practically  im- 
possible to  exceed  200  grams  in  the  intake  without  eliciting  unpleasant 
symptoms.  While  it  is  true  that  most  experiments  in  this  direction  have 
been  carried  out  with  meat  as  the  chief  source  of  the  proteid,  and  that 
the  extractive  substances  (such  as  lactic-acid  salts,  creatin,  potassium 
salts,  etc.)  cannot  be  regarded  as  physiologically  inert  and  non-toxic, 
yet  there  is  no  reason  to  believe  that  larger  quantities  of  pure  proteids 
of  animal  or  vegetable  origin  could  be  consumed  with  relish  for  any 
length  of  time.  Finally,  certain  considerations  make  it  unlikely  that  a 
nutritive  equilibrium  could  ever  be  established  in  man  on  an  exclusive 
proteid  diet. 

While  an  increase  of  the  proteids  in  the  diet  tends  to  augment  proteid 
katabolism  and  leads  to  a  greater  elimination  of  nitrogen  in  proportion 
to  the  supply  of  proteids  offered,  an  increase  in  the  fat  or  carbohydrate 
constituents  of  the  food  tends  to  diminish  proteid  katabolism,  although 
the  latter  cannot  be  completely  stopped  under  any  combination  of  diets. 


GENERAL  CONSIDERATIONS  OF  METABOLISM  673 

An  animal  which  receives  a  nitrogcn-frec  diet  of  either  fat  or  carbohy- 
drate or  both,  will  not  succumb  as  soon  as  a  starving  animal.  Neverthe- 
less, the  continued  nitrogen  losses  during  nitrogen  (or  proteid)  hunger 
lead  to  a  fatal  result  as  inevitably  as  does  complete  inanition.  More 
recent  experimental  work  has,  however,  shown  that  in  proteid  starvation 
the  loss  of  body  proteid  may  become  far  smaller  than  the  earlier  investi- 
gators found.  The  essential  feature  in  maintaining  a  lower  plane  of 
proteid  metaboKsm  in  these  cases  consists  in  the  administration  of  suffi- 
cient non-proteid  nutrients  to  cover  more  nearly  the  demands  of  the 
organism  for  energy.  This  is  well  illustrated  in  experiments  made  by 
Fohn  on  man.  On  a  diet  consisting  of  400  grams  of  pure  arrow-root 
starch  and  300  cc.  of  cream  containing  15  to  25  per  cent,  of  fat,  together 
with  a  few  grams  of  salt,  the  daily  output  of  nitrogen  was  reduced  to 
between  three  and  four  grams  in  all  the  individuals  under  observation 
over  a  period  of  several  days.  This  effect  appears  to  be  common  to  both 
fats  and  carbohydrates,  although  in  different  degree. 

Effects  of  Non-Nitrogenous  Nutrients  on  Proteid  Metabolism. — The 
effect  of  carbohydrate  and  fat  on  the  metabolism  of  proteids  under  con- 
ditions in  which  the  total  nutritive  demands  are  more  nearly  satisfied  is 
deserving  of  closer  attention.  Although  these  non-nitrogenous  nutrients 
cannot  check  the  katabolism  of  body  proteid  in  proteid  hunger,  they  are 
capable  of  exerting  a  definite  and  important  influence  in  diminishing  the 
extent  of  proteid  katabolism.  This  is  usually  spoken  of  as  the  proieid- 
sparing  action  of  fats  and  carbohydrates.  Most  of  the  data  in  demon- 
stration of  this  have  been  collected  from  experiments  on  animals.  The 
following  experiment  by  von  Noorden  and  Dieters  illustrates  the  proteid- 
sparing  action  of  carbohydrates  in  man.  The  daily  nitrogen  intake  dur- 
ing a  period  of  four  days  amounted  to  12.6  grams,  with  a  daily  output, 
in  the  urine,  of  10.4  grams  of  nitrogen.  When,  on  the  fifth  day,  200  grams 
of  cane-sugar  were  added  to  the  diet  the  urinary  nitrogen  fell  to  9  grams. 
According  to  this,  1.4  grams  of  nitrogen  (equivalent  to  13  per  cent,  of  the 
previous  output)  had  been  spared  in  the  form  of  proteid.  Similar  pro- 
teid-sparing  effects  have  been  obtained  with  fat.  The  experience  of  all 
observers  agrees  in  indicating  the  superiority  of  carbohydrates  over  fats 
in  this  respect.  Voit  found  an  average  decrease  in  proteid  metabolism 
of  about  7  per  cent,  with  fats  and  about  9  per  cent,  with  carbohydrates. 
A  comparison  which  Kayser  instituted  upon  himself  is  interesting:  with 
an  intake  of  (in  round  numbers)  132  grams  of  proteid,  70  grams  of  fat 
and  340  grams  of  carbohydrate,  having  a  fuel  value  of  2,600  large  calor- 
ies, he  was  able  to  maintain  nitrogenous  equilibrium.  The  replacement 
of  carbohydrate  in  the  food  by  an  "isodynamic"  amount  of  fat  (140 
grams)  caused  an  increase  in  the  output  of  urinary  nitrogen  and  a  con- 
sequent negative  balance,  in  contrast  with  the  preceding  slight  gain.  It 
should  be  noted,  however,  that  possible  differences  in  the  relative  avail- 
ability of  the  supposedly  "isodynamic"  quantities  of  fat  and  carbohy- 
drate have  not  been  drawn  into  consideration  by  most  investigators. 

The  methods  of  estimating  the  protective  power  which  the  different 
foodstuffs  exert  upon  tissue  constituents,  other  than  proteids,  are  indirect 
and  too  complicated  to  be  referred  to  here.  Marked  differences  in  the 
role  of  the  fats  and  carbohydrates  of  the  food  in  sparing  body -fat  have 
not  been  made  out.    The  preceding  discussion  of  the  relations  of  metab- 

43 


674  NUTRITION 

olism  to  the  food  suj)ply  lias  iiulicatetl  the  "flexibiUty  in  the  anhiuil 
organism  as  regards  the  nature  of  the  material  consumed  in  its  vital 
processes,"  Armsby  has  well  summarized  the  range  of  choice  by  the 
organism  and  the  mutual  replacement  of  nutrients.  "The  amount  of 
proteid  material  necessarily  required  for  the  metabolism  of  the  mature 
animal,  we  have  seen  to  be  relatively  small.  Aside  from  this  minimum, 
the  metabolic  activities  of  the  body  may  be  supported,  now  at  the  expense 
of  the  body-fat,  now  by  the  body  ])roteids,  and  again  by  the  proteid,", 
the  fats,  or  the  carl)t)liydrates  of  the  food.  AYhatever  may  1k>  true  econoni- 
ically,  physiologically  the  welfare  of  the  matiwe  animal  is  not  con- 
ditioned upon  any  fixed  relation  between  the  classes  of  nutrients  in  its 
food  supply,  apart  from  the  minimum  requirement  for  proteids.  The 
possibility  of  a  mutual  reiilacement  of  the  several  classes  of  nutrients 
in  the  food  follows  almost  necessarily  from  the  power  of  the  organism 
to  utilize  them  all  indifferently  (in  a  quahtative  sense  at  least)." 

It  is  appropriate  to  consider  the  influence  exerted  upon  metabolism 
by  a  number  of  substances  which  cannot  properly  be  classed  among 
the  typical,  foodstuffs,  but  nevertheless  may  enter  to  an  important  extent 
into  the  make-up  of  the  diet.  Among  the  nitrogenous  compounds,  gelatin 
stands  foremost.  Although  closely  related  to  the  true  proteids,  gelatin 
is  sufficiently  characteristic  and  peculiar  in  its  chemical  make-u})  to  be 
classed  in  the  groupof  albuminoids  (proteoids,scleroproteins).  Chemically 
it  differs  from  proteids  in  the  absence  of  the  tyrosin-  and  tryptophan- 
yielding  groups,  the  small  content  of  sulphur-containing  radicals,  and  the 
peculiar  quantitative  distribution  of  its  constituent  organic  complexes. 
Experiments  both  on  man  and  on  animals  have  demonstrated  the  failure  of 
gelatin  to  prevent  loss  of  body  proteid  when  it  is  the  sole  nitrogenous 
compound  fed.  It  can,  however,  replace  proteid  to  a  very  large  extent, 
and  it  acts  conspicuously  in  sparing  both  proteid  and  fat  in  the  body. 
In  the  absence  of  other  forms  of  nitrogenous  substances,  animals  fed 
on  gelatin  with  non-nitrogenous  nutrients  succumb  within  a  few  weeks. 
Careful  experiments  by  Murlin,  in  Lusk's  laboratory,  have  suggested 
the  following  conclusions:  A  mixed  diet,  more  than  covering  the  energy 
requirement  of  the  organism,  and  containing  two-thirds  of  the  starvation 
minimum  of  nitrogen  in  the  form  of  gelatin,  and  one-third  in  the  form 
of  proteid,  will  maintain  nitrogenous  equilibrium  for  a  few  days  at  least. 
In  other  words,  the  proteid  requirement  under  the  combined  sparing 
action  of  gelatin,  fat,  and  carbohydrate  falls  to  one-third  the  starvation 
requirement.  Experimental  data  obtained  on  animals  by  C.  Voit  and 
by  I.  Munk  show  that  100  grams  of  gelatin  will  protect  about  the  same 
quantity  of  proteid  as  is  spared  by  200  grams  of  carbohydrate.  Body- 
fat,  likewise,  can  be  protected  by  gelatin  feeding.  As  might  be  expected, 
the  gelatigenous  tissues  (tendons  and  cartilage)  exert  a  similar  proteid- 
and  fat-sparing  action  to  the  extent  to  which  they  are  digested  and  con- 
verted into  gelatin  in  the  alimentary  tract. 

The  influence  of  other  nitrogenous  compounds,  such  as  proteoses, 
peptones,  amino-acids,  and  amides,  upon  proteid  metabolism,  has  not 
been  studied  in  man.  Undoubtedly  these  substances,  especially  the  im- 
mediate derivatives  of  the  proteids,  can  replace  the  latter  to  a  certain 
extent;  but  under  ordinary  circumstances  they  are  unim]5ortant.  Among 
the  non-nitrogenous  ingesta,  cellulose,  owing  to  its  indigestibility,  plays 


GENERAL  CONSIDERATIONS  OF  METABOLISM  675 

little  if  any  part,  further  than  to  increase  the  nitrogenous  waste  leav- 
ing the  body  when  large  portions  of  indigestible  foods  are  fed.  The 
few  data  available  on  the  action  of  pentoses — the  five-carbon  sugars 
like  arabinose,  xylose,  and  rhamnose — upon  proteid  metaboHsm  dis- 
close no  marked  effects.  The  fatty  acids  have  been  found  to  exert  a 
proteid-sparing  influence  quite  comparable  with  that  of  the  fats  from 
which  they  are  derived;  while  the  remaining  component  of  the  latter, 
the  glycerin,  appears  to  be  negligible  in  this  regard  when  equivalent 
doses  are  used. 

Alcohol. — Among  the  substances  which  may  influence  proteid  metabo- 
lism, alcohol  deserves  mention  because  of  its  widespread  use.  The  views 
regarding  its  value  as  a  food  and  its  influence  on  metabolism  are 
somewhat  divergent,  and  some  of  the  testimony  has  not  always  been  free 
from  bias.  That  it  is  in  large  measure  burned  in  the  body  seems  reason- 
ably certain,  at  least  as  far  as  this  applies  to  moderate  quantities.  We 
must,  however,  distinguish  carefully  between  large  doses  which  have  an  un- 
mistakable toxic  action,  and  smaller  doses  in  which  the  alcohol  appears 
to  exert  a  protective  action  on  proteid  and  fat.  Neubauer  has  observed 
that  in  severe  diabetes  administration  of  alcohol  may  check  the  output 
of  acetone  much  as  carbohydrates  do.  In  careful  metabohsm  experi- 
ments by  Atwater  and  Benedict,  results  with  ordinary  diet  were  compared 
with  those  in  which  part  of  the  fats  and  carbohydrates  of  the  food  were 
replaced  by  the  isodynamic  amount,  about  72  grams  (2 J  ounces),  of 
absolute  alcohol.  This  is  about  as  much  as  would  be  suppHed  in  a 
bottle  of  claret,  or  6  ounces  of  whisky,  or  5  ounces  of  brandy.  The 
quantities  of  alcohol  eliminated  by  the  lungs,  skin,  and  kidneys,  varied 
from  0.7  to  2.7  grams,  and  averaged  1.3  grams  per  day.  Over  98  per 
cent,  of  the  ingested  alcohol  was  oxidized  in  the  body,  and  one  gram  of 
alcohol  was  calculated  to  be  isodynamic  with  1.73  grams  carbohydrate 
or  0.78  gram  of  fats  of  ordinary  food  materials.  The  proportions  of 
food  and  of  the  several  kinds  of  nutrients  made  available  for  use  in  the 
body  were  practically  the  same  in  the  experiments  with  and  those  with- 
out alcohol  in  the  diet.  The  potential  energy  of  the  alcohol  was  trans- 
formed into  kinetic  energy  in  the  body  as  completely  as  that  of  ordinary 
nutrients.  The  efficiency  of  alcohol  in  the  protection  of  body  fat  from 
consumption  was  very  evident.  The  losses  of  fat  were  no  larger  and  the 
gains  no  smaller  with  alcohol  in  the  diet  than  with  the  corresponding 
diet  without  alcohol.  In  this  respect  there  was  no  indication  of  any 
considerable  difference  between  the  alcohol  and  the  nearly  isodynamic 
amounts  of  fats  and  carbohydrates  which  it  replaced.  The  efficiency  of 
alcohol  in  protecting  body  protein  was  evident,  but  not  fully  equal  in 
this  respect  to  the  isodynamic  amounts  of  the  ordinary  nutrients,  the 
result  depending  somewhat  on  the  extent  to  which  the  individual  was 
accustomed  to  the  use  of  alcohol.  We  may  repeat  with  Atwater  and 
Benedict,  "that  there  is  a  very  essential  diiference  between  the  trans- 
formation of  the  potential  energy  of  the  alcohol  into  the  kinetic  energy 
of  heat,  or  of  either  internal  or  external  muscular  work,  and  the  useful- 
ness or  harmfulness  of  alcohol  as  a  part  of  ordinary  diet." 

It  would  be  a  mistake,  however,  to  assume  that  alcohol  can  be  rated 
as  a  true  non-nitrogenous  food  in  the  sense  in  which  fats  and  carbo- 
hydrates are  foods.    For  experiments  have  shown  that  alcohol  prior  to 


676  NUTRITION 

its  combustion  in  the  body  exerts  a  noticeable  influence  upon  the  meta- 
bolic processes  in  the  liver,  and  possibly  in  other  organs,  whereby  a 
marked  effect  is  produced  upon  the  output  of  uric  acid.  In  other  words, 
alcohol,  and  especially  alcoholic  drinks,  when  taken  with  purin-contain- 
ing  foodstuffs,  exert  a  direct  influence  upon  the  metabolism  of  those 
compounds  which  give  rise  to  exogenous  uric  acid,  increasing  largely 
the  amount  of  uric"  acid  excreted  (Beebc).  Whisky,  for  example,  may 
be  given  with  impunity  when  the  patient — as  in  typhoid  fever — is  on  a 
light  or  ])urin-free  diet,  without  materially  influencing  the  ])roduction 
or  output  of  uric  acid;  but  when  the  alcoholic  fluid  is  taken  with  a  hearty 
meat  diet,  or  with  any  diet  containing  free  or  combined  purin  com- 
pounds, the  system  is  at  once  liable  to  show  the  eft'ects  of  the  excess  of 
uric  acid.  In  this  respect  alcohol  behaves  quite  differently  from  an 
ordinary  non-nitrogenous  food. 

The  literature  abounds  in  studies  regarding  the  influence  of  a  large 
variety  of  substances,  both  organic  and  inorganic,  upon  metabolism. 
Some  of  these,  like  the  drugs,  cannot  be  considered  here;  others,  like 
tea,  coft'ee,  and  various  dietary  accessories,  exert  no  profound  action  on 
the  organism  in  moderate  dietetic  quantities.  In  recent  years  food  pre- 
servatives, such  as  borax  and  boric  acid,  sulphites,  benzoic  and  salic3'lic 
acids,  formaldehyde  and  fluorides,  have  received  special  consideration 
in  view  of  their  increasing  and  widespread  use.  At  the  present  time  it 
would  be  unprofitable  to  generalize  from  these  studies. 

Role  of  Inorganic  Salts.— The  inorganic  constituents  of  the  diet  possess 
a  significance  in  no  degree  commensurate  with  their  lack  of  energy- 
yielding  qualities.  The  elements  which  they  include  are  essentially 
sodium,  potassium,  calcium,  magnesium,  iron,  phosphorus,  sulphur, 
chlorine,  and  silicon — which  are  distributed  in  widely  varying  propor- 
tions in  different  parts  of  the  body,  about  S3  per  cent,  belonging  to  the 
skeleton  and  the  remaining  17  per  cent,  to  the  soft  parts.  The  quan- 
titative relationship  is  shown  in  the  following  table  summarized  from 
Soldner's  analyses  of  the  bodies  of  infants: 

Grams  per  Kilogram  of  Body  Weight. 

K,0 1.87  AlA 0.03         SO, 0.54 

Na.0 2.04  Fe..d.; 0.22        CI 1.76 

CaO 10.12  Mn.A 0.007       SiO., 0.02 

MgO 0.38  PA 10.01         COj' 0.14 

That  a  growing  organism  must  be  supplied  with  the  inorganic  con- 
stituents necessary  for  the  proper  development  and  organization  of  the 
tissues  is  self-evident.  It  is  interesting  to  note  that  in  milk,  nature  has 
supplied  the  infant  with  an  admirable  diet  in  resjject  to  the  needs  for 
inorganic  constituents.  Milk  is  richer  in  calcium,  so  essential  to  the 
development  of  the  skeleton,  than  any  other  common  dietary  article 
except  the  egg,  which  in  turn  is  the  storehouse  of  materials  furnished  to 
those  young  which  have  an  extra-uterine  development.  The  splendid 
adaptation  to  the  relative  needs  of  growing  young,  which  Bunge  has 
called  attention  to  in  the  case  of  the  milk  of  diff'erent  species,  is  well 
worthy  of  careful  study.  His  investigations  have  shown  that  the  rapidity 
of  growth  of  man  and  the  domestic  animals  during  lactation  is  propor- 


GENERAL  CONSWERATIONS  OF  METABOLISM 


677 


tional  to  the  composition  of  the  milk.     As  regards  calcium  and  phos- 
phorus, two  elements  especially  concerned,  this  feature  is  striking. 


Time  in  which  the  body-weight 

of  the  new-born  animal  was 

doubled  (in  days). 


One  hundred  parts  of  milk  contain 


Proteid. 


Ash. 


Calcium. 


Phosphoric  acid. 


Man.  . 180 

Horse 60 

Cow.  .  . 47 

Goat 19 

Pig... 18 

Sheep 10 

Dog. 8 

Cat 7 


1.6 
2.0 
3.5 
4.3 
5.9 
6.5 
7.1 
9.5 


0.2 
0.4 
0.7 
0.8 

6!9 
1.3 


0.328 
1.24 
1.60 
2.10 


2.72 
4.53 


0.  473 
1.31 
1.97 
3.22 

4!  12' 

4.93 


The  effects  of  a  lack  of  certain  of  the  inorganic  salts  in  the  diet  have 
long  been  familiar  in  the  case  of  the  adult,  as  well  as  the  growing  young. 
A  deficiency  of  calcium  giving  rise  to  rachitic  conditions  in  the  child  has 
its  analogue  in  the  osteoporosis  of  the  adult.  We  have  taken  occasion 
to  refer  to  these  facts,  because  they  illustrate  the  important  role  of  inor- 
ganic compounds  in  the  metabolism  of  growth  and  direct  attention  to 
similar  functions  of  these  compounds  in  adult  life.  In  health,  the  adult 
is  continually  losing  inorganic  salts,  not  only  so  long  as  they  are  contrib- 
uted to  the  body  with  the  diet,  but  equally  well  when  there  is  a  deficiency 
of  them  in  the  intake.  Experimental  observation  shows  that  with  ade- 
quate nutrition  there  is,  in  the  full-grown  individual,  a  tendency  toward 
"salt  equilibrium."  The  latter  condition  is  apparently  subject  to  far 
more  extensive  fluctuations  than  is  the  case  with  the  organic  foodstuffs; 
but  it  is  as  yet  impossible  to  frame  any  general  laws  bearing  on  the  in- 
direct influences  of  the  inorganic  food  constituents  on  the  metabolism 
of  the  energy-yielding  compounds.  There  is  here  a  broad  field  for  fruit- 
ful research.  Sufficient  facts  are  at  hand  to  indicate  the  promising 
character  of  such  studies.  For  example,  lack  of  sodium  chloride  m  the 
food  soon  leads  to  deficient  secretion  of  hydrochloric  acid  in  the  gastric 
juice.  Animals  fed  for  long  periods  of  time  on  foods  deficient  in  cal- 
cium, but  rich  in  organic  nutrients,  are  extremely  susceptible  to  intoxi- 
cation with  organic  acids,  like  lactic  or  oxalic  acid.  Since  the  latter 
may  be  formed  at  times  in  the  intermediary  metabolism  of  carbohydrates, 
in  certain  perversions  of  metabolism  their  toxic  action  may  be  traced 
directly  to  the  lack  of  neutrahzing  or  "antitodal"  (disintoxi eating)  inor- 
ganic bases  in  the  diet. 

The  profound  osmotic  effects  which  the  inorganic  salts  of  the  body 
fluids  are  concerned  in;  the  phenomena  of  saline  diuresis  and  accelera- 
tion of  lymph-flow;  the  imique  types  of  salt  glycosuria;  the  marked 
effects  on  the  muscular  and  nervous  structures;  and  the  peculiar  antagon- 
istic relations  of  differentiations  such  as  sodium,  potassium,  and  calcium, 
leave  no  doubt  of  the  importance  of  the  inorganic  foods  in  modif}-ing 
metabolic  processes.  At  present  we  can  scarcely  go  beyond  the  realm 
of  interesting  speculations.  We  need  further  to  be  instructed  not  only 
regarding  the  quantitative  needs  of  the  animal  body  in  the  case  of  the 
individual  elements,  but  also  regarding  the  forms  (or  types  of  compoimds) 


678  NUTRITION 

in  which  these  are  best  rendered  available.  Many  of  the  elements 
exist  in  nature  in  organic  combinations,  conspicuous  in  the  case  of  cer- 
tain foods. 

The  determination  of  the  nutritive  requirements  of  the  body  for  these 
inorganic  compounds  properly  belongs  to  the  subject  of  dietetics.  One 
of  the  difHcultics  in  arriving  at  a  correct  understanding  of  the  metab- 
olism of  the  inorganic  salts  has  arisen  from  a  lack  of  knowledge  regard- 
ing the  channels  by  which  they  leave  the  body.  Iron  furnishes  a  good 
illustration  of  some  of  the  errors  formerly  encountered.  The  failure  to 
recognize  the  intestinal  epithelium  as  a  factor  concerned  in  the  removal 
of  iron  naturally  allowed  a  false  interpretation  to  be  placed  on  the  occur- 
rence of  this  clement  in  the  faeces.  To  the  earlier  observers,  iron  in  the 
stools  was  a  direct  indication  of  lack  of  iron-absorption,  particularly  in 
view  of  the  extremely  scanty  elimination  of  ferric  salts  usually  noted  in 
the  urine  during  the  same  period.  But  the  establishment  of  the  fact 
that  the  gut  may  be  directly  concerned  in  the  excretion  as  well  as  in  the 
absorption  of  iron  compounds,  made  possible  a  new  interpretation  of  the 
earlier  observations.  Iron  might  be  present  in  the  alimentary  canal, 
either  owing  to  failure  to  be  absorbed,  or  ecpially  well  because  it  had  been 
discharged  into  this  channel,  through  the  epithelial  walls.  It  became 
necessary  to  follow  the  paths  of  elimination  when  the  introduction  of 
this  element  directly  into  the  alimentary  canal  w^as  avoided.  Since  it 
has  been  found  that  iron  may  be  introduced  subcutaneously  or  even 
directly  into  the  blood  current,  without  producing  any  marked  increase 
in  the  output  through  the  urine,  while  the  faeces  may  contain  noticeable 
quantities,  the  significance  of  the  intestine  with  reference  to  the  elimi- 
nation of  such  elements  becomes  apparent. 

The  part  which  the  inorganic  salts  may  play  is  thus  manifold  and 
difficult  of  interpretation.  No  energy  is  set  free  in  their  oxidation;  yet 
they  may  exert  most  subtle  influences,  if  such  examples  as  the  assumed 
profound  physiological  function  of  the  iodine  present  to  the  extent  of 
a  few  milligrams  in  the  thyroid  glands  are  to  be  trusted.  So  far  as  can 
be  judged  at  present,  Liebig  was  cjuite  correct  in  pointing  out  that  the 
inorganic  salts  are  not  an  accidental  contamination  of  living  matter,  but 
rather  of  fundamental  importance. 

Work  and  Metabolism. — Among  the  influences  which  affect  metab- 
olism, muscle-work  is  perhaps  of  even  greater  significance  than  the  food 
intake.  The  effects  are  immediate  and  the  extent  of  the  change  produced 
is  far  greater  than  the  mere  measure  of  the  work  done  would  seemingly 
indicate;  for  the  most  part,  the  skeletal  (voluntary)  muscles  outrank  the 
non-striated  (involuntary)  ones  in  the  extent  to  which  they  participate 
in  these  effects.  When  a  muscle  contracts,  heat  is  liberated,  and  work 
is  done.  The  relative  distribution  of  the  energy  between  these  two 
effects  varies  somewhat  with  the  conditions  under  which  the  contrac- 
tion is  carried  out.  Within  certain  limits,  as  Fick  demonstrated,  the 
working  capacity  increases  with  the  demand  made  upon  the  muscle. 
For  example,  a  muscle  which  under  slight  stimulation  transformed 
6  per  cent,  of  the  energy  used  into  work  done,  performed  work  up  to 
29  per  cent,  of  the  total  used  when  its  most  vigorous  efforts  were  called 
out. 


GENERAL  CONSIDERATIONS  OF  METABOLISM  679 

The  law  of  the  conservation  of  energy,  which  we  have  seen  to  hold 
for  the  body,  teaches  that  the  various  manifestations  of  energy,  such  as 
heat,  work,  etc.,  can  be  expressed  in  common  terms;  and  the  relation 
between  heat  and  mechanical  work  is  shown  in  the  equation,  1  large 
calorie  =  425  kilogrammeters.  On  this  basis,  the  potential  energy  of 
the  foodstuffs  can  be  expressed  in  terms  of  the  maximum  work  which 
they  can  afford,  approximately  as  follows: 

1  gram  of  proteid  yields 1,700  kilogrammeters. 

1  gram  of  fat  yields 4,000  kilogrammeters. 

1  gram  of  carbohydrate  yields 1,700  kilogrammeters. 

Actually,  however,  much  larger  quantities  of  the  foodstuffs  must  be  katab- 
olized  to  yield  mechanical  work  in  this  amount;  roughly,  about  one- 
fifth  to  one-quarter  of  the  total  energy  is  thus  convertible.  The  extent 
to  which  metabolism  may  be  increased  by  work  under  normal  conditions 
is  best  illustrated  by  actual  figures.  In  experiments  covering  forty-nine 
days  on  healthy  adults,  the  average  total  energy  given  off  per  day  during 
rest,  with  food,  was  2,262  large  calories;  during  work  in  the  same  in- 
dividuals, over  sixty-six  days,  the  daily  average  was  4,676  large  calories. 
Of  this  twofold  increase  (2,400  calories),  450  calories  were  equivalent 
to  the  extra  muscular  work  done.  Rubner  has  calculated  the  total  metab- 
olism of  a  large  number  of  individuals,  on  the  basis  of  an  average  body 
weight  of  70  kilos,  and  expressed  the  results  in  heat  units  (kilocalories), 
thus: 

During  rest 2,303  calories  =32.9  calories  per  kilo. 

Slight  bodily  work  "1  2,442  calories  =34.9  calories  per  kilo  =  6%  increase, 
(physicians,  etc.)      j       '  s^  /u 

^1:soYSers,°ete  )  "^"'^  }  ^'^^^  ''^^°"^'  =^^  "^  '^^°"^'  P^'  ^^"^  =  ^4%  increase. 
(  firh'  '  i  tp  1  I  3,362  calories  =48.0  calories  per  kilo  =  45%  increase, 
Cminers'^etc  ")  I    4,790  calories  =68.4  calories  per  kilo   =  108%  increase. 

The  influence  of  muscular  work  on  metabolism  is  speedily  made  evident 
by  an  increased  consumption  of  oxygen  and  output  of  carbon  dioxide. 
The  relation  between  the  oxygen  inspired  and  the  carbon  dioxide  expired, 
i.  e.,  ~  is  known  as  the  respiratory  quotient;  normally  this  is  less 
than  1 .  Not  all  of  the  oxygen  reappears  again  in  the  eliminated  carbon 
dioxide,  since  some  of  it  is  used  in  the  oxidation  of  other  elements  to 
form  water,  sulphuric  acid,  and  other  bodies.  In  the  combustion  of 
pure  carbon,  one  volume  of  oxygen  yields  one  volume  of  carbon  dioxide. 
The  ratio  -^  in  this  case  is  unity.  In  the  body,  however,  the  magnitude 
of  the  respiratory  quotient  depends  on  the  nature  of  the  katabolized 
substances.  For  the  combustion  of  carbohydrates  it  is  approximately  1; 
in  the  katabolism  of  proteids  it  is  about  t^b;  and  for  fats  the  ratio  falls 
to  To.  The  respiratory  quotient  will  accordingly  vary  in  accordance  -^^th 
the  relations  here  expressed,  and  may  afford  important  information  re- 
garding the  nature  of  the  katabolic  processes.  Experience  has  sho\\Ti 
that  the  consumption  of  oxygen  by  the  tissues  is  independent,  within  wide 


680  NUTRITION 

limits,  of  the  oxygen  supply,  but  varies  directly  with  the  demands  of  the 
tissues.  In  view  of  this,  the  extent  of  oxygen  consum})tion  may  be  taken 
as  a  measure  of  the  action  of  different  influences  on  the  rate  of  metab- 
olism. Studies  have  been  made  on  the  effects  of  walking,  marching, 
swimming,  mountain  climbing,  etc.,  upon  respiratory  metabolism.  Zuntz 
and  Katzenstein  have  estimated  the  intensity  of  the  metabolic  changes 
which  work  brings  about  in  man.  Expressed  in  the  consumption  of 
oxygen  per  minute,  in  contrast  with  the  conditions  prevailing  during  rest, 
they  found:  During  rest  263  cc,  walking  on  level  763  cc,  walking  up 
hill  1,253  cc.  These  arerjuite  comi)arable  with  the  observations  made 
by  Zuntz  and  Schumburg  on  soldiers  at  rest,  and  marching  with  and 
without  accoutrements.  The  total  change  in  the  daily  excretion  of  car- 
bon dioxide  resulting  from  work  is  shown  in  experiments  on  a  man  of 
twenty-three  years  of  age.  During  the  periods  of  ordinary  work,  the 
heat  equivalent  of  the  external  muscular  work  amounted  to  about  11 
per  cent,  of  the  total  energy  metabolized. 

D-ULY  Elimination  of  Carbon  Dioxide  in  the  Same  Individual. 
(From  experiments  by  Atwater  and  Benedict.) 

Rest,  without  food 676  grams 

Rest,  with  food 812  grams 

Work,  with  carbohydrate  in  diet 1,820  grams 

Work,  with  fat  in  diet 1,665  grams 

Extra  severe  work,  with  fat  in  diet.  .  .  3,073  grams 

Higley  and  Bowen  have  made  a  study  of  the  immediate  changes  in 
the  excretion  of  carbon  dioxide  incidental  to  muscular  work  in  bicycling. 
The  results  agree  with  those  of  previous  workers  in  indicating  a  uniform 
output  of  carbon  dioxide  during  uniform  work.  The  changes  which 
give  rise  to  this  katabolic  product  in  the  muscle  may  be  pictured  as 
beginning  instantly  with  the  commencement  of  the  work.  Since  the  gas 
must  first  diffuse  into  the  blood  and  then  be  carried  to  the  lungs,  there 
should  be  a  latent  period  of  a  little  more  than  half  the  time  required  for 
a  complete  circuit  of  the  blood  before  the  first  waste  product  formed 
during  work  can  be  exhaled.  A  variation  of  several  seconds  may  reason- 
ably be  expected,  dependent  upon  the  rapidity  of  the  circulation.  The 
latent  period  of  increase  in  the  output  of  carbon  dioxide  from  the  lungs 
in  case  of  beginning  work  is  nearly  twenty  seconds,  the  increase  reaching 
its  maximum  in  about  two  minutes.  Upon  cessation  of  work,  the  output 
decreases  again  to  the  normal  amount  in  about  the  time  occupied  by  its 
increase  and  after  a  like  latent  period. 

In  view  of  the  rapid  adjustment  of  the  carbon  dioxide  output  to  the 
muscular  metabolism  occurring,  it  might  be  expected  that  the  extra 
elimination  during  work  would  be  confined  almost  entirely  to  the  day 
time  when  the  work  is  done.  This  is  actually  the  case;  and  during  the 
night  periods  it  is  only  a  little  larger  in  the  work  experiments  than  in 
the  rest  experiments. 

The  proportions  of  carbon  dioxide,  water,  and  heat,  eliminated  during 
the  different  periods  of  the  day  in  the  same  individual  at  rest  and  at  work, 
with  and  without  food,  are  shown  on  page  681  (Atwater  and  Benedict). 

It  is  well  known  that  a  given  amount  of  mechanical  work  is  not  always 
done  at  the  same  cost  of  materials  metabolized.    Training  and  fatigue 


GENERAL  CONSIDERATIONS  OF  METABOLISM 


681 


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682  NUTRITION 

are  important  factors  in  considering  the  expenditure  which  a  given  mus- 
cular task  calls  for.  In  general,  the  trained  and  untired  muscle  is  the 
more  economical;  that  is,  it  transforms  less  material  in  doing  a  given 
amount  of  work  than  docs  the  untrained  or  fatigued  muscle.  Other 
circumstances,  among  which  are  atmospheric  conditions  (oppressive 
heat,  humidity,  etc.),  the  relative  strain  on  specific  muscular  parts,  the 
absolute  amount  of  work  to  be  done,  as  well  as  personal  factors — all 
influence  the  capacity  for  work  and  the  relative  expenditure  of  energy. 
The  importance  of  an  adequate  knowledge  of  the  factoVs  which  influence 
the  capacity  for  work  has  been  cmj)hasized  by  the  study  of  Zuntz  and 
Schumburg  on  soldiers  during  marching.  Apj^arently  minor  considera- 
tions, such  as  comfortable  or  uncomfortable  adjustment  of  the  knap- 
sack, irritation  of  the  skin,  improper  clothing,  and  overweighting,  may 
be  sufficient  to  occasion  an  increased  expenditure  of  energy  entirely  dis- 
proportionate to  the  work  done.  Again,  in  bicycling,  the  influence  of  the 
speed  on  the  energy  utilized  per  kilo  of  body  weight  and  1,000  meters 
distance  covered  were  found  by  Leo  Zuntz  to  vary  as  follows: 

At  a  speed  of  60  meters  per  min.,  40 . 3  cal.  =  552  cal.  per  kilo,  per  1,000  meters. 
At  a  speed  of  100  meters  per  min.,  47 . 2  cal.  =  647  cal.  per  kilo,  per  1,000  meters. 
At  a  speed  of  143  meters  per  min.,  78 . 5  cal.  =  1,075  cal.  per  kilo,  per  1,000  meters. 

The  increased  expenditure  of  energy  which  is  called  forth  by  those 
exertions  which  ordinarily  pass  unnoticed  may  be  not  inconsiderable. 
The  mere  maintaining  of  the  body  in  an  upright  position  calls  for  a  con- 
sumption of  10  to  20  per  cent,  more  oxygen  than  is  used  in  quiet  repose. 
The  varied  activity  of  the  hands  and  arms  makes  corresponding  demands 
on  the  energy  supply.  Wolpert  has  estimated  the  increase  of  CO2  output 
in  people  engaged  in  various  occupations  over  the  quantities  observed 
for  the  same  individuals  at  rest,  as  follows: 

In  a  seamstress  the  increase  was  13  per  cent. 
In  a  bookkeeper  the  increase  was  17  per  cent. 
In  a  tailor  the  increase  was  22  per  cent. 
In  a  shoemaker  the  increase  was  47  per  cent. 

These  differences  are  obviously  attributable  to  the  different  degree  to 
which  the  hands  and  arms  are  employed,  the  general  (sitting)  posture 
being  maintained  in  each  case.  In  sleep  we  have  the  extreme  contrast 
to  muscular  activity  in  work;  and  although  the  consumption  of  oxygen 
and  the  output  of  carbon  dioxide,  for  example,  fall  to  about  three-fourths 
of  the  figure  quoted  in  the  waking  state,  it  is  scarcely  less  than  what  can 
be  attained  by  complete  relaxation  during  waking  hours.  Johansson  ob- 
served an  hourly  CO2  elimination  of  22  grams  during  sleep;  of  31  grams 
during  waking  rest.  In  general,  we  may  say  that  there  is  an  increase  of 
about  40  to  45  per  cent,  in  carbon  dioxide  output  during  waking  rest 
over  absolute  relaxation;  a  figure  which  illustrates  the  physiological 
significance  of  repose  in  therapeutics.  With  a  patient  reduced  to  a 
minimum  of  strength  and  store  of  surplus  energy,  rest  (in  the  sense  of 
complete  relaxation)  can  well  be  advised  as  an  important  protective 
measure,  on  the  basis  of  sound  physiological  evidence. 

In  addition  to  external  muscular  work,  we  may  also  call  attention  to 
another  form  of  activity  parity  muscular,  which  is  associated  with  diges- 


GENERAL  CONSIDERATIONS  OF  METABOLISM  683 

tion.  The  following  figures,  calculated  from  experiments  made  in  Zuntz's 
laboratory,  indicate  the  relation  of  the  digestive  work  accomplished  to 
the  heightened  metabolism,  in  terms  of  the  percentage  increase  in  carbon 
dioxide  excreted  and  oxygen  consumed  (in  daily  averages) : 

Heat  value  of  the  Increase  in  carbon  Increase  in  oxygen 

food  absorbed.  dioxide  produced.  consumed. 

Calories.  Per  cent.  Per  cent. 

2,233  16.3  12.2 

The  same  facts  may  be  expressed  from  another  standpoint,  by  noting 
that  in  rest  the  amount  of  energy  expended  when  fasting  is  only  about 
10  per  cent,  less  than  with  food. 

We  have  reserved  any  discussion  of  the  influence  of  muscular  work 
upon  nitrogenous  metabolism  for  this  place,  because  it  bears  directly 
upon  the  question  of  the  source  of  the  energy  transformed  in  this  condi- 
tion of  bodily  activity.  Is  work  done  at  the  expense  of  proteids,  fats, 
carbohydrates,  or  two  or  more  of  these  body  constituents?  With  respect 
to  the  proteids,  the  problem  admits  of  a  ready  experimental  answer.  If 
an  individual  is  maintained  in  nitrogenous  equilibrium  upon  an  adequate 
mixed  diet,  the  effect  of  muscular  activity  ought  to  manifest  itself  in  a 
distortion  of  the  nitrogen  balance  if  proteids  are  katabolized  to  supply 
energy  for  work.  It  seems  obvious  that  if  an  individual  is  fed  over  long 
periods  on  a  ration  largely  or  exclusively  composed  of  proteids,  the 
source  of  muscular  work  must  be  found  in  increased  proteid  katabolism. 
Similarly  when  the  supply  of  non-nitrogenous  food  is  inadequate  to  fur- 
nish all  the  energy  needed,  the  conclusion  is  inevitable  that  nitrogenous 
compounds  will  be  disintegrated  to  supply  the  demands.  In  accordance 
with  this,  it  has  been  observed  that  animals  fed  over  long  periods  of 
time  on  lean  meat  alone  are  capable  of  performing  severe  muscular 
labor.  Although  the  nitrogenous  excretion  has  been  observed  to  be 
increased  under  such  conditions,  the  proteid  katabolized  was  too  small 
to  account  for  the  energy  expended  in  the  work;  such  experiments,  how- 
ever, give  no  sufficient  reason  for  concluding  that  the  body  performs 
work  preferably  at  the  expense  of  proteid  material.  What  do  observa- 
tions made  under  other  conditions  of  diet  teach? 

It  may  be  profitable  to  review  the  history  of  physiological  views  on 
the  sources  of  muscular  energy.  Liebig  early  assumed  that  proteids 
are  decomposed  in  the  body  to  yield  the  energy  of  mechanical  work — 
a  view  which  is,  in  a  certain  sense,  still  shared  by  Pfliiger.  Observations 
by  Pettenkofer  and  Voit  soon  made  such  a  position  appear  untenable; 
for  they  failed  to  find  the  increase  in  urea  excretion  which  might  have 
been  expected  during  increased  muscular  exertion.  Further,  the  experi- 
ments made  it  clear  that  the  non-nitrogenous  nutrients  must  be  the 
sources  of  the  energy  available  under  these  conditions  The  classic 
experiment  of  Fick  and  Wislicenus  (1866)  w^as,  perhaps,  the  first  satis= 
factory  attempt  to  compare  the  energy  expended  during  work  T^dth  that 
rendered  available  by  the  proteid  disintegrated.  They  calculated  that 
the  quantity  of  proteids  katabolized  during  an  ascent  of  the  Swiss  Faul- 
horn  (6^500  feet),  and  measured  by  the  urea  excreted,  was  insufficient 


684 


NUTRITION 


to  account  for  more  than  a  .small  fraction  of  the  energy  required  to  raise 
their  bodies  to  the  height  of  the  mountain,  not  to  mention  the  energy 
expended  in  the  work  of  the  internal  organs  and  muscular  movements 
not  directly  involved  in  the  ascent. 

Contrary  to  these  results,  various  investigators  have  found  more  or 
less  increase  in  proteid  metaholism  after  muscular  work.  In  those  in- 
stances, it  has  usually  been  found  that  the  diet  selected  was  insufficient 
for  the  demands  made  upon  the  body.  Where  the  food  suj)ply  has  been 
in  excess  of  the  amount  required  for  maintenance,  any  material  increase 
in  the  nitrogen  excretion  as  the  result  of  the  work  done  has  usually  been 
overlooked.  As  an  illustration  of  conditions  where  daily  losses  of  nitrogen 
amounting  to  5  to  8  grams  were  noted  during  severe  muscular  work,  we 
may  quote  the  observations  of  Atwater  and  Sherman  on  bicycle  riders 
in  six-day  races.  Analyses  of  food,  urine  and  fteces  are  summarized 
below,  in  terms  of  daily  averages: 


Rider. 

Nitrogen. 

Equivalent 

LOSS  OF 
BODY    PROTEIN. 

In  food. 

In  fspces. 

In  urine. 

Loss. 

Miller 

Albert 

Pilkington.. .  . 

Grams. 

29.4 
29.  1 
36.0 

Grams. 

1.8 
2.5 
2.2 

Grams. 

30.2 
33.7 
38.9 

Grams. 

8.6 
7.1 
5.1 

Grams. 

53.8 
44.4 
31.9 

The  exertion  in  these  races  Avas  very  severe,  the  riders  averaging 
eighteen  and  a  half  to  twenty  hours  of  work  and  a  distance  of  over  300 
miles  a  day.  There  was,  unquestionably,  a  deficiency  of  non-nitrogen- 
ous nutrients  in  the  diet  which  was  evidently  poorly  selected  and  inade- 
quate, and  it  is  quite  conceivable  that  equally  severe  and  prolonged 
exertion  might  be  undergone  without  increased  metabolism  of  nitrogen, 
provided  the  supply  of  non-nitrogenous  fuel  material  Avas  abundant. 

In  the  studies  of  Zuntz  and  Schum})urg  on  soldiers  during  marching, 
an  increased  elimination  of  nitrogen  was  observed  on  the  marching  days 
and  the  rest  days  immediately  succeeding  them.  It  was  noted  that 
the  increased  katabolism  of  proteid  would  account  for  not  more  than 
6  to  7  per  cent,  of  the  extra  work  accomplished;  furthermore,  the 
increase  in  nitrogenous  waste  was  in  no  way  proportional  to  the 
absolute  amount  of  work  done,  but  was  essentially  influenced  by  the 
severe  heat  and  other  oppressive  atmospheric  conditions.  Further,  there 
was  no  change  in  the  distribution  of  the  nitrogen  in  the  various  types  of 
urinary  constituents  during  work.  One  feature  during  work  deserves 
mention,  namely,  the  noticeable  increase  in  nitrogen  eliminated  in  the 
perspiration.  Under  conditions  of  profuse  sweating  during  active  exer- 
tion, the  daily  output  through  this  channel  may,  according  to  Benedict, 
become  as  high  as  0.22  gram  per  hour — a  quantity  by  no  means  negli- 
gible in  accurate  balance  experiments. 

The  increase  in  the  excretion  of  nitrogenous  waste  during  extreme 
activity  may  reasonably  be  attributed  to  a  decomposition  of  tissue  pro- 
toplasm, incited  perhaps  by  fatigue  or  deficient  respiration  in  individual 


GENERAL  CONSIDERATIONS  OF  METABOLISM  685 

groups  of  muscles,  as  Speck  has  maintained.  In  many  experiments  made 
in  this  country,  under  the  auspices  of  the  Department  of  Agriculture,  no 
similar  influence  has  been  found;  and  no  evidence  whatever  has  been 
obtained  to  indicate  that  proteids  are  the  sole  source  of  energy  in  mus- 
cular work.    Armsby  has  well  summarized  the  evidence  now  available: 

"1.  The  non-nitrogenous  ingredients  of  the  food  or  of  the  tissues  are 
the  chief  source  of  muscular  energy.  In  by  far  the  greater  number,  if 
not  all,  of  the  experiments  upon  this  subject  the  amount  of  protcid  metab- 
olized, as  measured  by  the  nitrogen  excretion,  was  insufficient  to  fur- 
nish energy  equivalent  to  the  work  done,  the  deficiency  being  in  many 
cases  very  great.  This  statement,  it  will  be  observed,  does  not  assert 
that  the  proteids  are  not  concerned  in  the  production  of  this  energy.  We 
may  regard  it  as  very  probable  that  the  non-nitrogenous  matter  metab- 
olized has  first  entered  into  the  structure  of  the  muscular  protoplasm, 
which,  as  we  know,  consists  largely  of  proteids;  but  in  a  contraction  it 
is  largely,  if  not  wholly,  the  non-nitrogenous  groups  contained  in  the 
protoplasm  which  are  metabolized  rather  than  the  nitrogenous  groups. 

"2.  With  insufficient  food  there  may  be  a  considerable  increase  in  the 
proteid  metabolism,  as  a  result  of  muscular  exertion,  especially  when 
pushed  to  exhaustion. 

"3.  This  increase  is  far  from  sufficient  to  supply  energy  for  the  work 
actually  done,  is  not  proportional  to  it,  and  seems  dependent  to  a  con- 
siderable degree  upon  accompanying  conditions. 

"4.  With  sufficient  food  the  increase  of  the  total  proteid  metabolism 
consequent  upon  muscular  exertion  is  at  the  most  slight  and  possibly 
equal  to  zero. 

"5.  In  some  cases  a  storage  of  proteids  has  been  observed  to  result 
from  the  performance  of  work." 

It  would  be  a  mistake  to  conclude  that  the  proteids  of  the  body  play 
no  part  in  the  work  of  its  muscles.  The  muscle  protoplasm  is  built  up 
of  both  nitrogenous  and  non-nitrogenous  components;  and  while  the 
readjustments  which  take  place  during  the  contractile  processes  involve 
a  destruction  of  the  non-nitrogenous  constituents,  perhaps  in  the  form 
of  sugar  or  glycogen,  both  components  appear  to  be  requisite  for  the 
proper  maintenance  of  an  active  working  apparatus.  It  is  thus  quite 
conceivable  that  with  an  inappropriate  proteid  supply  muscular  power 
might  be  impaired  seriously,  even  though  the  liberation  of  energy  in 
the  actual  contractile  changes  goes  on  at  the  expense  of  the  carbohydrate 
groups  of  the  protoplasm.  We  may  picture  the  latter  as  a  labile  substance 
when  the  easily  detached  non-nitrogenous  groups  are  joined  to  it.  Mus- 
cular activity  would  accordingly  involve  a  change  in  the  stabiUty  of 
the  protoplasm,  which  in  turn  would  resume  its  original  condition  of 
irritability  by  becoming  regenerated  through  the  addition  of  fresh  carbo- 
hydrate groups.  Several  experimental  observations  are  more  easily  inter- 
preted from  this  point  of  view.  For  example,  it  becomes  evident  that 
proteid  alone  will  not  accomplish  the  regeneration  of  the  contractile 
substance  in  a  satisfactory  degree,  although  in  its  disintegration  it  may 
furnish  a  considerable  proportion  of  non-nitrogenous  groups — the  so- 
called  "carbon  moiety"  of  the  proteid  molecule.  Again,  if  the  proteids 
form  a  semi-passive  agent,  as  it  were,  in  the  development  of  muscular 
power,  it  is  plain  why  the  muscles  may  be  more  capable  of  retaining  pro- 


686  NUTRITION 

teid  when  they  are  active,  than  is  the  case  with  inactive  or  less  ^^go^ously 
working  musck>s.  Herein  hes  the  expUmation  of  the  phenomena  of 
muscular  hypertrophy;  and  experiments  have  indicated  a  greater  ten- 
dency for  the  body  to  gain  proteid  during  hght  work  and  abundant  diet, 
than  is  observed  in  a  less  active  condition.  We  have  here  indicated  the 
distinction  between  "putting  on  flesh"  (growth  of  muscle),  and  storing 
up  foodstuifs.  The  bearing  of  this  reciprocal  relation  between  exercise 
and  muscular  growth  and  its  connection  with  the  metabolism  of  muscle, 
is  not  without  })hysiological  imjiortance.  We  must  distinguish  between 
the  development  of  a  well-organized  muscular  system  calling  for  a  liberal 
proteid  supply,  and  the  nuiintenance  and  working  demands  of  such 
organs — i.  e.,  between  the  construction  of  the  machine  and  its  energy 
requirement.  Finally,  the  participation  of  the  body  proteids  may 
apparently  be  provoked  by  unfavorable  conditions  for  muscular  work,  to 
some  of  which  reference  has  already  been  made  and  among  which  oxygen 
starvation  is  a  conspicuous  example.  Thus,  in  the  muscular  exertion  of 
dyspnoea  the  increased  proteid  decomposition  seems  to  be  attributable 
to  local  conditions  in  the  muscles  involved.  The  katabolic  processes  in 
these  organs  are  qualitatively  altered  and  fatigue  products  are  more 
speedily  formed.  That  proteids  are  not  the  only  components  affected 
in  this  perverted  function,  is  seen  by  the  disturbances  evoked  in  the  carbo- 
hydrate constituents  of  the  muscles,  whereby  such  compounds  as  lactic 
acid  may  arise  in  considerable  quantities. 

At  present,  it  is  practically  impossible  to  ascertain  with  certainty  what 
choice,  if  any,  the  body  exercises  between  fats  and  carbohydrates  in  the 
decomposition  of  non-nitrogenous  compoimds  in  muscular  work;  nor 
can  we  say  that  the  fats  are  transformed  into  sugar  or  glycogen  before 
they  become  available  for  the  immediate  work  of  the  contractile  tissues. 
The  more  recent  studies  upon  isolated  muscles,  especially  the  heart,  are 
very  suggestive.  These  show  that  such  organs  can  maintain  active  con- 
tractions for  many  hours,  when  they  are  supplied  by  perfusion  with  an 
oxygen-laden  isotonic  solution  of  inorganic  salts  and  dextrose.  Blood 
serum  or  proteid  solutions  are  not  more  effective  than  solutions  of  com- 
mon salt — all  of  which  are  decidedly  inferior  in  sustaining  power  to 
Ringer's  solution  with  sugar.  It  would  seem  from  this  that  the  sugar 
solution  is  effective  not  so  much  in  washing  away  fatigue  products — 
the  muscle  waste — as  in  supplying  a  nutrient  group.  Otherv;ise,  we 
should  expect  equally  efi'ective  results  from  simple  saline  perfusion. 
Within  the  body  as  a  whole,  it  is  not  so  easy  to  analyze  the  function  of 
the  individual  non-nitrogenous  nutrients  in  muscular  work.  To  be  sure, 
numerous  ergographic  experiments  seem  to  demonstrate  the  effective  use 
of  carbohydrates ;  but  the  results  afforded  are  not  very  trustworthy.  We 
have  seen  that  the  respiratory  quotient  varies  for  the  different  kinds  of 
materials  consumed  in  the  body.  A  review  of  the  literature  suggests 
that  when  the  body  is  well  supplied  with  carbohydrates  the  respiratory 
quotient  remains  high  during  work,  indicating  a  large  utilization  of  carbo- 
hydrates. The  latter  are  thus  readily  used  when  they  are  available  for 
the  cells  of  the  body;  and  accordingly  the  store  of  glycogen  in  the  mus- 
cles is  seen  to  diminish  with  severe  work.  On  the  other  hand,  metab- 
olism experiments  on  man  fail  to  indicate  any  difference  in  the  way 
the  body  utilizes  the  kinetic  energy  arising  from  oxidation  of  the  different 


GENERAL  CONSIDERATIONS  OF  METABOLISM  687 

nutrients  Atwater  and  Benedict  have  tested  the  relative  efficiency  of 
fats  and  carbohydrates  by  ascertaining  whether  it  costs  more  energy  to 
do  the  same  work  with  fats  than  with  isodynamic  amounts  of  carbo- 
hydrates. In  directly  comparable  work  experiments  a  somewhat  higher 
efficiency  for  the  carbohydrate  than  for  the  fat -diet  was  observed. 

In  other  experiments  not  so  comparable,  less  pronounced  differences 
appeared.  The  general  conclusion  of  the  investigators  is  "that  in  these 
experiments  the  fats  were  slightly  inferior  to  isodynamic  amounts  of 
carbohydrates  as  a  part  of  a  ration  for  muscular  work.  But  while  the 
natural  inference  is  that  calorie  for  calorie  the  carbohydrates  were  slightly 
superior  to  the  fats  as  sources  of  muscular  energy,  the  difference  observed 
was  very  small  and  may  have  been  due  to  some  individual  peculiarity  of 
the  subject  with  which  the  more  directly  comparable  experiments  were 
made,  rather  than  to  any  inherent  capacity  of  the  materials  to  yield 
energy  for  external  muscular  work."  Regarding  the  immediate  sources 
of  muscular  energy  and  the  character  of  the  substances  actually  metab- 
olized in  the  muscles,  these  experiments  give  no  answer;  nor  is  the 
solution  apparent  in  the  lack  of  more  extensive  information  respecting 
the  intermediary  changes  in  metabolism. 

Other  Influences  on  Metabolism. — Regarding  other  influences  which 
may  be  brought  to  bear  upon  metabolism  aside  from  the  intake  of  food 
and  muscular  exertion,  the  time  has  not  yet  come  for  any  comprehensive 
summary.  The  influence  of  growth  deserves  careful  investigation,  and 
a  study  of  the  nutritive  changes  in  the  young  is  certain  to  afford  an 
abundance  of  practical  suggestions.  The  available  data  indicate  a  fairly 
good  absorption  of  the  foodstuffs  in  young  infants,  the  figures  for  the 
total  available  energy  varying  from  90  to  96  per  cent,  of  the  total  intake. 
Sugar  absorption  appears  to  be  by  far  the  most  perfect.  Oppenheimer 
first  called  attention  to  the  fact  that  the  gain  in  weight  of  infants  is 
directly  proportional  to  the  quantity  (or  calories)  of  milk  ingested. 
Thus  two  different  children  during  the  second  month  of  their  lives 
gained  191.2  and  201.1  gm.  for  each  kilogram  of  milk  given;  in  the 
third  month,  120.3  and  138.5  gm.;  in  the  fourth  month,  102.6  and 
103.3  gm. 

It  is  noteworthy  that  the  appetite  determines  the  regular  ingestion  of 
sufficient  energy  for  the  life  processes,  plus  a  small  but  fixed  extra  per- 
centage necessary  for  growth.  Lusk  has  formulated  a  law  of  growth, 
that  in  the  development  of  the  normal  young  of  the  same  age  and  species, 
a  definite  percentage  of  the  energy  content  of  the  food  is  retained  for 
growth  irrespective  of  the  size  of  the  individual.  According  to  Heubner, 
vigorous  growth  in 'infants  demands  an  intake  of  energy  amounting  to 
100  to  120  large  calories.  That  growth  itself  is  attended  with  an  active 
chemical  exchange  is  shown  by  studies  on  the  respiration  of  the  embryo, 
in  which  the  gas  metabolism  has  been  found  to  be  as  active  as  that  of 
adults.  The  metabolism  of  the  young  appears  to  be  somewhat  more 
iactive  than  that  of  the  adult,  as  far  as  can  be  judged  from  the  data  on 
page  688  which  the  authors  have  compiled  from  various  sources. 

Although  it  appears  as  if  the  metabolic  processes  are  less  extensive  in 
old  age,  it  must  be  remembered  that  the  activity  of  the  individual  is 
greatly  diminished,  and  our  conclusions  are  based  upon  the  dietetic 
habits  of  the  old  rather  than  on  actual  metabolism  experiments.     It 


688  NUTRITION 

seems  doubtful  if  any  specific  influence  of  old  age  aside  from  diminished 
muscular  exertion  can  be  demonstrated. 


Age  of  Subject. 

CO2  output  per  kilogram, 
and  per  hour. 

Urea  output  per  kilogram, 
and  per  day. 

35  years. 

20   years. 

15  years. 
9-13  years. 
3-  7   years. 

Grama. 

0.51 
0.53 
0.00 
0.90 
1 .  20 

Grama. 

0.5 
0.5 
0.5 

0.6 

0.7 

There  is  no  evidence  that  the  psychical  processes,  as  exemplified  in 
nervous  excitement,  specifically  influence  metabolism.  During  sexual 
changes  modifying  influences  are  doubtless  at  work,  but  they  lack  ex- 
perimental verification. 

More  conspicuous  than  the  preceding  are  the  effects  which  external 
climatic  and  hygienic  conditions  impose  upon  metabolism.  The  explana- 
tion for  many  of  these  undoubted  effects  is  not  yet  forthcoming.  In 
some  cases,  problems  of  temperature  regulation  seem  to  be  concerned; 
for  the  temperature,  relative  humidity  of  the  air,  and  its  rate  of  move- 
ment modify  the  "physical"  regulation  of  the  body  temperature  so  long 
as  an  excess  of  heat  is  produced  in  metabolism.  But  below  the  so-called 
"critical  temperature"  (about  37°  C.  for  naked  man,  according  to  Rub- 
ner,  and  15°  C.  in  ordinary  clothing)  the  incidental  heat  production  no 
longer  suffices  to  maintain  the  normal  temperature  of  the  body,  and  addi- 
tional body  material  must  be  oxidized  for  this  special  purpose.  Under 
ordinary  circumstances  this  is  avoided  by  the  devices  used  to  keep  our 
immediate  surroundings  above  the  point  where  a  "chemical"  or  meta- 
bohc  regulation  of  temperature  is  called  into  play.  Herein  lies  the  in- 
direct influence  of  cloihing  on  metabolism.  Materials  which  prevent 
radiation  and  conduction  of  heat,  as  well  as  modes  of  dress  which  fail 
in  a  cold  environment  to  conserve  the  heat  produced  by  the  body,  exert 
an  influence  on  the  chemical  changes  going  on  in  the  organism  concerned. 
We  are  accustomed  to  dress  ourselves  in  such  a  manner  as  to  make  the 
loss  of  heat  equivalent  to  that  which  the  naked  body  would  undergo  at 
about  33°  C.  The  cold  hath,  rapidly  removing  heat  from  the  body, 
stimulates  katabolism.  From  calorimetric  observations,  Rubner  has 
calculated  the  effects  of  an  hour's  bath  at  various  temperatures  in  terms 
of  additioyial  fat  katabolized,  as  follows: 

Bath  at  15°  C Katabolism  of  fat  =  52     grams. 

Bath  at  20°  C Katabolism  of  fat  =37     grams. 

Bath  at  25°  C Katabolism  of  fat  =  22     grams. 

Bath  at  30°  C Katabolism  of  fat  =   9     grams. 

Bath  at  35°  C Katabolism  of  fat  =   0.7  grams. 

Lately,  the  action  of  high  and  low  altitudes  has  received  considerable 
attention  in  connection  with  climatotherapy.  It  appears  that  both  moun- 
tain- and  sea-air  may  exert  a  stimulating  influence  upon  metabolism  in 
those  unaccustomed  to  the  climatic  condition  selected.  This  is  made 
evident  in  the  increased  consumption  of  oxygen  and  output  of  carbon 


GENERAL  CONSIDERATIONS  OF  METABOLISM  689 

dioxide  at  rest  without  food.  It  has  become  quite  certain  that  other 
climatic  factors  than  the  diminished  barometric  pressure  are  eifective 
in  the  case  of  mountain  experiences  and  similar  subtle  influences  appear 
to  come  into  evidence  at  the  seashore.  Doubtless  the  direct  insolation 
plays  some  part  in  the  action  of  climate  at  high  altitudes;  in  illustration 
of  this  we  quote  from  Rubner  the  observation  that  at  Davos,  on  sunshiny 
days  without  winds,  one  can  remain  quietly  seated  in  the  open  air  at 
— 1°  C.  without  wearing  heavy  clothes.  The  vacuum  thermometer  indi- 
cating the  degree  of  insolation  may  rise  to  +43°  C.  at  the  same  time.  It 
is  not  impossible  that  increase  in  the  radio-activity  of  the  air  in  mountain 
regions  may  exert  a  physiological  influence.  In  saying  this,  however, 
we  are  still  within  the  realm  of  conjecture. 


FATE  OF  THE  INGE  ST  A  AND  ORIGIN  OF  THE  EXCRETA. 

No  review  of  this  subject  would  be  complete  without  some  considera- 
tion of  the  changes  which  the  digested  compounds  experience  in  becom- 
ing incorporated  with  the  tissues  and  fluids  or  transformed  into  materials 
for  the  purposes  of  movement  and  vitality  and  finally  altered  into  pro- 
ducts ready  for  excretion.  This  intermediary  metabolism  still  remains  a 
most  obscure  chapter;  and  the  progress  of  physiological  chemistry  has 
helped  to  make  the  subject  more  complex.  Thus,  in  speaking  of  the 
albuminous  substances  we  are  now  prepared  to  distinguish  between  the 
various  members  of  a  great  group  of  organic  compounds  related  in  many 
chemical  and  physical  features  and  yet  sufficiently  different  in  structure 
and  physiological  behavior  to  demand  a  special  interpretation  for  their 
roles  in  metabolism  in  many  instances.  In  this  way,  for  example,  a 
familiarity  with  the  specific  metabolism  of  the  nucleoproteids,  with  their 
phosphorus,  carbohydrate,  purin,  and  pyrimidin  complexes,  has  been 
obtained;  and  little  by  little  the  independent  origin  of  the  different 
nitrogenous  excretives  has  been  unraveled.  The  source  of  the  katabolites, 
urea,  uric  acid,  and  oxalic  acid,  has  been  traced  to  different  members 
of  the  proteid  family;  whereas  at  one  time  they  were  attributed  to  a 
common  source  which  was  assumed  to  give  rise  to  diverse  end-products 
by  obscure  variations  in  the  metabolic  processes  of  the  organism,  now 
yielding  one,  now  another  of  them.  Similarly,  the  physiologist  is  able 
at  present  to  distinguish  between  the  metabolic  fate  of  proteids  which 
convey  phosphorus  to  the  organism  and  those  which  do  not;  or,  looking 
from  another  point  of  view,  to  refer  eliminated  phosphorus  to  a  variety 
of  possible  origins — the  phosphates  ingested,  or  the  phosphorus  of  gland 
nucleoproteids,  lecithins,  or  disintegrating  leukocytes,  as  the  circum- 
stances may  direct.  In  this  way  he  aims  to  obtain  a  deeper  insight  into 
the  chain  of  events  which  constitute  intermediary  metabolism — what 
Foster  has  termed  the  "gaps  and  guesses"  of  nutrition.  There  is  so 
much  which  is  uncertain  and  the  subject  of  controversy  that  we  shall 
aim  to  recount  briefly  only  such  facts  and  theories  as  have  received  more 
general  acceptance,  or  are,  in  our  opinion,  deserving  of  special  recognition. 

Metabolism  of  Carbohydrates.— Carbohydrates  apparently  experi- 
ence the  best  utilization  of  all  the  types  of  foodstuffs  commonly  ingested. 
In  the  healthy  infant,  which  receives  these  nutrients  in  the  form  of  milk- 
44 


690  NUTRITION 

sugar,  no  trace  of  sugar  ordinarily  escapes  with  the  stools,  and  in  the 
adult  the  record  is  scarcely  less  satisfactory  for  the  digestible  carbohy- 
drates. They  are,  of  course,  not  all  absorbed  in  the  form  in  which  they 
are  ingested.  Experimental  evidence  indicates  that  the  monosaccharides 
(hexoses  and  pentoses)  are  the  "physiological"  sugars  and  that  the 
digestible  carbohydrates  are  converted  into  this  form  before  they  are 
absorbed  and  utilized.  The  ]>ossibility  of  functional  adaptations  of  the 
digestive  glands  to  the  materia-ls  upon  which  their  secretions  are  required 
to  act  has  been  suggested  in  recent  years.  The  experimental  evidence 
thus  far  presented  is,  however,  unconvincing.  To  what  extent,  if  at  all, 
such  functional  adaptations  may  involve  an  inter-relation  between  the 
diet  and  certain  nutritive  factors  important  in  practical  experience  re- 
mains to  be  learned. 

AYhen  soluble  carbohydrates  enter  the  circulation  without  intervention 
of  the  alimentary  digestive  processes  they  are  only  retained  in  part,  de- 
pending on  the  nature  of  the  compound  introduced.  The  monosaccha- 
rides, dextrose  and  levulose  in  particular,  are  not  excreted  at  once;  but 
such  carbohydrates  as  cane-sugar,  milk-sugar,  glycogen,  or  dextrins,  re- 
appear to  a  considerable  extent  in  the  urine  when  they  enter  the  blood 
as  such.  Maltose  (malt-sugar)  appears  to  afford  an  exception  in  this 
respect,  presumably  owing  to  the  presence  of  a  maltase,  or  maltose- 
inverting  enzyme  in  the  blood  itself.  Dextrose  may  be  introduced  into 
the  circulation  by  a  variety  of  channels  and  is  in  every  case  largely  re- 
tained unless  the  quantity  and  rate  of  introduction  are  excessive.  Under 
ordinary  circumstances  in  man,  the  monosaccharide  products  of  diges- 
tion are  carried  in  the  portal  blood-stream  to  the  liver,  and  doubtless  go 
to  form  the  glycogen  store  of  this  and  other  tissues.  So  far  as  is  known, 
the  glycogen  from  different  sources  is  chemically  the  same. 

Aside  from  glycogen,  another  important  carbohydrate  constituent  of 
the  body  is  the  blood-sugar.  This  has  repeatedly  been  identified  as  dex- 
trose. Whether  it  exists  there  in  the  free  state  or  in  combination  with 
other  organic  groups  like  the  lecithins,  or  both,  has  not  been  answered 
to  the  satisfaction  of  all  physiologists.  The  most  recent  experimental 
evidence  speaks  against  the  idea  of  a  combination.  Two  facts  deserve 
emphasis  in  considering  the  intermediary  metabolism  of  the  carbohy- 
drates; namely,  the  relatively  wide  distribution  and  noteworthy  quantities 
of  glycogen  which  may  be  present  in  the  body  at  one  time,  and  the  appar- 
ent constancy  of  the  sugar-content  of  the  blood.  It  seems  to  be  demon- 
strated  that  there  is  no  pronounced  diminution  of  the  percentage  oi 
sugar  in  the  blood  during  starvation,  although  it  is  doubtless  continually 
being  requisitioned  for  the  needs  of  the  functioning  tissues.  Neither 
does  work  or  rest  detectably  affect  the  sugar-content  of  the  circulation 
as  a  whole;  and  any  condition  in  which  hyper-  or  hypoglycfemia  arises 
partakes  at  once  of  the  nature  of  disease.  It  is  therefore  apparent  that 
some  regulatory  mechanism  must  be  at  work  in  the  organism  serving  to 
maintain  the  constant  level  of  the  blood-sugar  content. 

We  ask  ourselves:  How  is  this  constancy  maintained?  How,  on  the 
one  hand,  is  the  surplus  which  the  digestive  processes  furnish  retnined; 
and  how,  despite  continued  utilization,  is  the  blood  replenished  with 
dextrose  ?  Under  ordinary  circumstances  of  health,  the  blood  contains 
about  1  per  mille  of  dextrose.    Whenever  sugar  tends  to  increase  to 


GENERAL  CONSIDERATIONS  OF  METABOLISM  691 

any  considerable  extent  beyond  this  and  excecKls  tlie  limit  of  about  3 
per  mille,  dextrose  is  eliminated  by  the  kidneys.  Indeed,  it  is  not  unlikely 
that  the  intestine  may  act  as  an  excretory  organ  at  times  when  the  sugar- 
content  of  the  blood  becomes  physiologically  excessive  and  the  kidneys 
are  insufficient.  These  processes  are  normally  not  called  into  play; 
for  the  excess  of  carbohydrate  is  taken  care  of  and  retained  in  the  organ- 
ism or  immediately  burned  up.  But  when  this  fails  to  be  effected  com- 
pletely, an  excretion  of  sugar  may  follow  the  intake  of  relatively  large 
quantities  of  carbohydrate,  giving  rise  to  the  condition  spoken  of  as 
"aUmentary  glycosuria."  The  failure  to  retain  or  destroy  the  sugar 
intake  may  be  a  relative  one  in  this  case  and  depend  upon  the  quantity 
poured  into  the  circulation  at  one  time;  thus,  100  grams  of  dextrose 
ingested  in  a  single  dose  can  ordinarily  be  retained  by  a  healthy  individual, 
and  the  failure  in  this  respect  is  generally  regarded  as  an  approach  to  a 
pathological  condition. 

When,  however,  the  monosaccharide  sugar  is  retained  in  the  organism 
it  is  not  always  burned  at  once.  There  can  be  no  question  regarding 
the  increase  of  glycogen  in  the  liver  following  the  introduction  of  some 
carbohydrates  at  least.  Whatever  discussion  the  glycogenic  function  of 
the  liver  has  aroused  has  been  directed  at  the  theory  of  glycogen  deposi- 
tion. The  anhydride  theory  assumes  a  chemical  re-arrangement  and 
alteration  of  the  sugar  molecule  when  it  reaches  the  liver,  together  with 
a  polymerization  by  which  the  relatively  insoluble  glycogen  is  retained 
in  the  hepatic  cells,  ready  to  be  dispensed  in  ways  which  will  be  consid- 
ered later.  A  few  physiologists  have  believed  that  the  glycogen  is  not 
derived  from  the  carbohydrates  ingested;  the  latter  are  supposed  to 
be  burned  up  directly,  thus  sparing  the  glycogen  which  they  believe  is 
formed  from  proteid.  This  is  the  spariiig  theory.  Neither  of  these 
theories  is  satisfactory  in  explaining  the  facts  of  experiment.  Nor  can 
the  newer  metabolic  theory  be  said  to  answer  all  objections.  According 
to  this  view,  the  food-sugars  are  not  converted  directly  into  glycogen, 
but  are  first  synthesized  into  the  living  protoplasm  from  which  in  turn 
glycogen  is  split  off — secreted  as  it  were.  The  most  important  feature 
of  such  a  theory  lies  in  the  necessity  for  proteid  in  the  construction  of 
a  glycogen-yielding  protoplasm.  It  makes  clear  why  more  glycogen  is 
apparently  stored  when  both  proteid  and  sugar  are  furnished,  and  how 
hexose  sugars,  with  such  different  configurations  as  dextrose,  levulose, 
and  galactose  afford,  can  yield  a  carbohydrate  of  constant  chemical 
structure.  The  function  of  glycogen-formation  thus  becomes  a  property 
of  the  living  protoplasm-constructing  cell,  and  the  deposition  of  gly- 
cogen in  so  many  tissues  of  the  body  as  well  as  in  such  vegetable  cells 
as  yeast  can  more  readily  be  understood. 

Again,  the  metabolic  theory  of  glycogen-formation  makes  it  somewhat 
easier  to  appreciate  how  substances  like  glycerin  or  even  inorganic  salts 
like  ammonium  carbonate  cause  an  increase  of  glycogen  in  the  liver. 
These  compounds  afford  both  glycogen  and  urea,  by  inciting  a  katab- 
olism  of  the  liver  protoplasm,  which  results  in  the  liberation  of  carbo- 
hydrate on  the  one  hand,  and  nitrogenous  groups  on  the  other.  The 
glycerin  or  ammonium  salt  accordingly  need  not  be  considered  as  directly 
entering  into  the  glycogen-yielding  process  and  itself  participating  in  its 
construction.    The  metabolic  theory  also  lends  probability  to  the  power 


692  »  NUTRITION 

of  many,  if  not  all,  cellular  tissues  to  produce  glycogen  as  well  as  the 
liver,  so  that  the  muscles  need  not  be  assumed  to  owe  their  store  to  the 
supply  transmitted  from  the  liver.    The  living  protoplasm  can  rebuild 
glycogen  in  any  organ;    and  we  can  understand  how  starving  animals 
can  in  part  renew  the  glycogcn-content  of  their  tissues,  and  why  even 
in  prolonged  hunger,  as  Pfliiger  has  shown,  the  tissues  may  still  contain 
a  noticeable  ]iroportion  of  the  carbohydrate.     Pfliiger,  to  be  sure,  is  un- 
willing to  admit  the  formation  of  glycogen  from  proteid,  and  assumes 
in  the  case  of  the  starving  organism  that  the  glycogen  is  only  slowly  used 
up.     Is  it  not  more  likely  that  the  proteids  incorporated  in  the  indefinite 
substance  called  protoplasm  may  take  part,  as  indicated  above,  in  the  re- 
newal of  the  glycogen  in  the  cell  ?     And  with  the  necessity  of  both  nitrog- 
enous and  non-nitrogenous  groups  admitted  for  protoplasmic  anabolism, 
it  becomes  clear  that  with  the  lack  of  cHher  of  these  constructive  materials 
glycogen  can  be  manufactured  only  at  the  expense  of  ready  formed  proto- 
plasm, involving  in  turn  increased  katabolism  of  nitrogenous  material. 
We  might  expect  in  this  event  that  proteid  and  carbohydrate  katabolism 
should  run  parallel,  or,  in  case  of  a  failure  to  use  the  carbohydrate,  its 
excretion  in  quantities  strictly  proportional  to  the  nitrogenous  waste — as 
it  is  observed  in  certain  pathological  conditions — could  more  easily  be 
understood.     For  no  conclusive  evidence  of  a  direct  conversion  of  food 
proteid  into  carbohydrate  has  yet  been  advanced.     Whatever  our  view 
regarding  the  origin  of  glycogen  may  be,  whether  we  admit  its  formation 
from  proteid  or  sugar  alone  or  from  both,  directly  or  indirectly,  or  even 
from  fat — for  which  there  is  much  less  evidence — the  important  role  of 
glycogen  as  a  carbohydrate  reserve  in  the  body  must  generally  be  admitted. 
Returning  to  a  consideration  of  the  fate  of  the  ingested  carbohydrates 
in  metabolism,  we  have  followed  them  until,  in  pathological  conditions, 
they  are  excreted  unused  and  unchanged  or  disappear  from  the  circulating 
media.     There  remains  the  second  inquiry:     How  is  the  sugar-content 
of  the  blood  maintained  and  the  losses  to  the  tissues  made  good  ?   Without 
discussing  this  point  we  incline  to  the  view  that  it  arises  from  glycogen, 
notably  in  the  liver.     The  blood-sugar  rapidly  sinks  in  quantity  when  the 
liver  is  cut  out  of  the  circulation;   and  it  becomes  difficult,  if  not  impos- 
sible, to  produce  any  typical  hyperglycsemia  by  experimental  means,  when 
the  glycogen-content  of  the  liver  has  previously  been  greatly  reduced.     In 
the  conversion  of  glycogen  into  sugar,  enzymes  are  doubtless  concerned  to 
an  important  extent.   Soluble  ferments  capable  of  inducing  such  changes  are 
known  to  exist,  and  there  is  no  good  ground  for  denying  that  the  processes 
which  can  be  observed  postmortem  in  the  liver  go  on  during  life,  though 
perhaps  at  a  greatly  altered  rate.     A  reaction  of  this  type  is,  furthermore, 
quite  in  accord  with  prevailing  views  regarding  the  importance  of  enzyrnes 
for  the  chemical  organization  of  living  cells.     And  in  attributing  the  vital 
process  of  sugar-formation  to  enzyme  activity,  it  is  unnecessary  to  postu- 
late any  extra-cellular  secretion  of  the  active  agent;   the  modem  view 
merely  attempts  to  define  more  precisely  the  character  of  the  chemical 
reaction  involved  by  classifying  it  with  those  transformations  known  as 
enzymatic.     The  relation  of  the  nervous  system  to  these  manifold  pro- 
cesses is  at  present  ill-defined  and  only  partly  understood,  although  its 
physiological  bearing  must  be  manifest.     Finally,  it  seems  likely  that 
glycogen  is  not  used  directly,  but  is  previously  transformed  into  sugar. 


GENERAL  CONSIDERATIONS  OF  METABOLISM  693 

To  be  of  use  to  the  organism  in  furnishing  energy,  the  carbohydrate 
must  be  burned  up.  From  the  standpoint  of  energy  transformations  it 
makes  little  difference  whether  it  is  consumed  rai)idly  and  at  once,  or 
whether  the  decomposition  goes  on  more  slowly  and  in  successive  stages,  as 
is  the  case  in  the  living  organism.  To  the  physiologist,  however,  these 
intermediary  processes  are  of  no  little  concern;  and  for  the  physician  they 
attain  due  significance  in  the  light  which  appreciation  of  them  throws  upon 
many  obscure  pathological  states.  Experimentally,  glycolysis,  or  sugar 
destruction,  has  been  found  to  be  characteristic  of  various  tissues  as  well  as 
of  the  blood.  Undoubtedly,  such  destructive  changes  go  on  in  the  muscle 
during  activity;  but  whether  the  glycolytic  power  of  the  muscular  tissue 
is  reinforced  by  contributions  from  other  organs,  such  as  an  internal 
secretion  of  the  pancreas,  and  whether  the  chemical  reaction  involved  de- 
pends on  the  presence  or  absence  of  sufficient  oxygen,  cannot  be  foretold  at 
the  present  moment.  Some  investigators  believe  that  the  process  of  car- 
bohydrate utilization  in  the  body  is  comparable  with  typical  fermentation 
changes  as  exhibited  in  the  destruction  of  sugar  by  yeast  or  its  zymase; 
for  others  the  intermediation  of  oxygen  in  this  internal  respiration  seems 
more  important.  Regarding  the  nature  of  the  products  actually  formed, 
little  is  definitely  known  at  present;  carbon  dioxide  is  undoubtedly  pro- 
duced and  various  organic  acids  appear  to  arise  in  an  intermediate  stage. 
Perhaps  we  have  in  this  the  explanation  of  the  tendency  of  an  active  tissue 
to  become  more  acid  when  the  circulation  and  oxygen  supply  are  deficient. 
We  regard  it  as  extremely  probable  that  the  paralactic  acid  found  in  the 
animal  organism  has  its  origin  in  carbohydrates.  Ordinarily  it  is  further 
burned  up;  but  when  there  is  a  lack  of  oxygen  we  have  to  deal  with  an 
incomplete  combustion  of  the  lactic  acid  derived  by  cleavage  from  sugar, 
without  denying  the  possibility  of  a  similar  production  from  proteids. 

In  accordance  with  this  view,  a  considerable  excretion  of  lactic  acid  and 
sugar  is  found  in  poisoning  with  carbon  monoxide,  in  which  an  oxygen 
deficiency  is  always  manifested;  and  simultaneously  with  the  formation 
of  lactic  acid  a  decrease  in  the  glycogen  reserve  is  noted.  Another  evi- 
dence of  the  inter-relationship  between  lactic  acid  and  carbohydrate 
katabolism  has  been  offered  in  cases  of  phosphorus  poisoning.  Here 
the  urine  contains  paralactic  acid;  but  when  artificial  diabetes  is  produced 
by  means  of  phlorizin  during  phosphorus  poisoning,  the  lactic  acid  dis- 
appears from  the  blood  and  urine  with  the  appearance  of  the  sugar  pro- 
duced by  the  phlorizin.  According  to  Mandel  and  Lusk,  this  indicates 
that  "lactic  acid  produced  from  the  cleavage  and  denitrogenization  of  pro- 
teid,  whether  this  occurs  in  the  intestinal  wall  or  in  the  liver  or  elsewhere, 
is  first  synthesized  to  dextrose  within  the  organism  (liver)  before  further 
distribution  to  the  tissues.  In  the  case  of  simple  phosphorus  poisoning 
this  distribution  of  dextrose  takes  place  with  resultant  anaerobic  cleavage, 
leading  to  a  second  production  of  lactic  acid."  Following  the  view  of 
Hoppe-Seyler,  the  formation  of  lactic  acid  from  carbohydrates  and  its 
elimination  may  be  regarded  as  an  abnormal  process,  occurring  only  under 
the  imperfect  physiological  conditions  attending  an  insuflScient  supply  of 
oxygen. 

Another  compound  which  doubtless  owes  its  origin  to  the  intermediary 
metabolism  of  the  carbohydrates  is  glycuronic  acid 

CHO.  HCOH.  HCOH.  HCOH.  HCOH.  COOH. 


694  XUTRITIO.y 

This  is  readily  obtained  in  the  urine  paired  with  camphor,  thymol, 
menthol,  and  a  large  number  of  other  compounds  when  the  latter  or 
related  antecedents  are  introduced  into  the  body.  Conjup;ated  g'lycuro- 
nates  are  found  in  traces  in  the  blood  and  liver;  and  the  normal  urine 
is  said  to  contain  very  small  cjuantities  in  combination  with  phenol,  cresol, 
indoxyl  and  sk-atoxyl.  The  possibility  of  a  formation  of  glycuronic 
acid  from  proteids  cannot  be  denied  at  present  and  the  problem  is  asso- 
ciated with  the  broader  question  of  sugar  formation  from  proteids.  But 
the  available  evidence  points  to  carbohydrates  as  the  chief,  if  not  the 
only,  source  of  this  agent  with  ^\•hich  toxic  compounds  become  conjugated 
and  excreted  in  less  harmful  forms.  Animals  which  have  been  starved 
sufficiently  long  to  diminish  to  a  minimum  their  carbohydrate  reserve  (gly- 
cogen) yield  little,  if  any,  glycuronate  after  ingestion  of  camphor.  Re- 
versely, the  toxic  action  of  some  of  the  conjugated  compounds  can  be 
greatly  diminished  by  feeding  carbohydrates  which  yield  glycogen  or  dex- 
trose in  metabolism. 

The  glycuronic  acid  conjugation  appears  to  take  place  in  the  liver,  and 
the  primary  significance  of  its  formation,  therefore,  probably  lies  in  its  anti- 
toxic action.  This  is  a  well-known  function  of  metabolic  products  of  the 
proteids  as  we  see  it  exemplified  in  the  formation  of  ethereal  sulphates.  In 
cases  such  as  profound  cocaine  intoxication,  where  dyspnoeic  conditions 
arise,  glycuronates  have  been  found  in  increased  c[uantity  in  the  urine. 
P.  Mayer  believes  that,  normally,  the  oxidation  of  dextrose  in  the  body 
proceeds  through  the  stage  of  glycuronic  acid,  and  that  Avhen  further  katab- 
olism  is  checked  the  imperfectly  oxidized  carbohydrate  is  eliminated  in 
part  in  this  form.  Corresponding  with  this  view,  a  simultaneous  elimina- 
tion of  both  glycuronates  and  sugar  is  observed  under  pathological  con- 
ditions in  which  circulatory  and  respiratory  disturbances  play  a  part.  A 
further  step  in  the  oxidative  degradation  of  sugar  is  oxalic  acid,  which  may 
likewise  escape  unburned  under  certain  conditions.  It  is  not  uncommon 
to  find  oxaluria  and  glycuronic  acid  elimination  associated  in  diabetes. 

Considering  the  preceding  facts,  it  would  appear  as  if  carbohydrates 
may  undergo  fermentative  decompositions  in  the  body,  or  be  decomposed 
through  a  succession  of  oxidative  changes.  Under  conditions  of  imper- 
fect oxidation  one  or  more  of  these  ijitennediate 'products  may  escape  from 
the  body.  Glycosuria  is  thus  only  one  evidence  of  a  defective  interme- 
diary metabolism  of  the  sugars.  Glycuronic  acid,  saccharic  acid,  oxalic 
acid,  lactic  acid,  and,  perhaps,  other  organic  acids  primarily  associated 
with  diabetes  are  referable  to  the  same  source.  Such  a  view  may  at  any 
rate  serve  toward  the  construction  of  a  tentative  theory  of  intermediary 
carbohydrate  metabolism . 

Reference  may  be  made  to  other  less  frequent  anomalies  of  carbo- 
nydrate  metabolism,  such  as  pentosuria,  levulosuria,  lactosuria,  and 
galactosuria.  The  excretion  of  lactose  (milk-sugar),  during  and  after 
pregnancy,  is  a  temporary  disturbance  referable  to  an  escape  of  the 
carbohydrates  from  the  active  mammary  glands  into  the  circulation. 
When  these  glands  are  extirpated,  lactosuria  is  never  observed.  The 
excretion  of  levulose  has  been  frequently  reported  and  seems  to  occur  in 
conjunction  with  dextrose  elimination  in  many  diabetics.  The  fact  that 
dextrose  can  be  converted  in  part  into  levulose  in  alkaline  media  makes 
this  less  difficult  of  interpretation.     Galactose  has  been  found  in  the 


GENERAL  CONSIDERATIONS  OF  METABOLISM  695 

urine  of  Infants  suffering  with  gastro-intestinal  disorders.  (Langstein 
and  Steinitz.)  It  represents  an  unutilized  inversion  product  of  milk- 
sugar  absorbed  from  the  intestine  of  milk-fed  individuals.  In  explana- 
tion of  the  phenomena  of  pentosuria  little  can  be  said  at  present.  The 
ordinary  diet  of  man  contains  pentosans,  which  yield  five-carbon  sugars 
(C5H10O5),  such  as  xylose  and  arabinose,  on  hydrolysis.  When  pentoses 
are  fed  they  are  in  part  oxidized.  It  is  unlikely,  however,  that  the  sugar 
eliminated  in  chronic  pentosuria  is  derived  from  the  food,  since  the 
elimination  continues  even  during  starvation.  The  nucleoproteids  such 
as  are  found  in  the  pancreas  also  yield  pentose;  but  the  latter  is  1-xylose, 
whereas  the  urine  pentose  appears  to  be  r-arabinose.  Ordinarily,  there 
is  no  interference  with  the  oxidation  of  the  hexoses  in  pentosuria ;  and  the 
condition  may  persist  for  years  without  exhibiting  any  other  untoward 
symptoms.  For  the  present,  pentosuria  is  of  interest  chiefly  as  an 
illustration  of  a  curious  and  unexplained  anomaly  of  carbohydrate  metab- 
olism. 

Metabolism  of  Fats. — In  presenting  a  review  of  the  present 
knowledge  regarding  the  metabolism  of  fats,  we  shall  be  obliged  to  touch 
upon  many  topics  Avhicli  are  still  the  subject  of  controversy.  The  views 
expressed  are  not  to  be  interpreted  too  rigidly,  for  dogmatic  statements 
should  not  be  expected  in  a  department  of  study  which  is  at  present 
being  pursued  by  many  investigators.  An  adult  man  can  digest  300 
grams  of  fat  per  day,  provided  that  it  is  offered  in  suitable  form.  What 
becomes  of  this  after  it  leaves  the  alimentary  tract  ?  Furthermore  we  may 
inquire  whether  the  tissue  fat  is  derived  directly  from  the  ingesta  or 
synthesized  in  indirect  ways,  and  what  are  the  chemical  processes  which 
inaugurate  these  transformations? 

At  the  outset,  the  radical  changes  which  prevalent  ideas  of  fat  digestion 
and  absorption  have  experienced  should  be  mentioned.  A  few  years  ago 
it  was  thought  that  fats  were  absorbed  in  the  form  of  an  emulsion,  the  un- 
dissolved and  finely  divided  particles  passing  through  the  epithelial  cells 
in  some  mysterious  manner.  This  view  has  been  altered  more  recently; 
for  we  have  learned  of  the  more  extensive  distribution  of  lipolytic  enzymes 
in  the  alimentary  tract,  the  process  of  fat  cleavage  apparently  having  a 
beginning  in  the  stomach  itself.  Fatty  acids  and  soluble  soaps  are  formed 
in  not  inconsiderable  quantities  in  the  digestive  tube.  Furthermore, 
bile  affords  a  medium  for  the  solution  of  large  quantities  of  free  fatty  acids 
at  the  temperature  of  the  body.  It  is  difficult  to  obtain  indisputable  e^^- 
dence  of  the  absorption  of  unchanged  fat,  except  by  histological  methods 
which  are  perhaps  not  wholly  reliable.  Certainly  other  insoluble  sub- 
stances (such  as  fluid  paraffin)  are  not  absorbed  even  when  they  are  finely 
emulsified,  but  are  recovered  in  toto  in  the  faeces.  While  it  is  perhaps  too 
soon  to  say  that  fats  must  be  completely  transformed  by  digestive  change 
to  soluble  forms  before  they  can  be  absorbed,  it  seems  certain  that  such  a 
preliminary  cleavage  or  saponification  does  take  place  to  a  degree  not  for- 
merly appreciated.  Once  beyond  the  lumen  of  the  gut,  the  fragments 
are  again  synthesized  to  neutral  fats.  Foreign  esters  of  the  fatty  acids 
reappear  as  glyceryl  esters.  There  is  some  evidence  that  the  Ij^Tuphatic 
tissue-elements  are  concerned  in  these  synthetic  transformations. 

When  fats  reach  the  blood-stream  through  the  lymph  channels,  they  are 
exposed  to  a  peculiar  metamorphosis  which  is  still  little  understood.    The 


696  NUTRITION 

suspended  particles  of  the  minute  emulsion  of  the  blood-fats  may  become 
changed  into  soluble  and  diffusible  substance.  Perhaps  it  is  in  this  inter- 
mediary soluble  form  that  fats  arc  transported  to  the  tissues,  as  we  know 
carbohydrates  to  be.  Regarding  the  nature  of  the  processes  a  few  defi- 
nite statements  may  be  ventured.  The  transformation  is  inaugurated  by 
some  constituent  element  of  the  erythrocytes  which  is  destroyed  by  high 
temperatures;  thus  the  change  partakes  of  the  nature  of  an  enzyme  reac- 
tion. It  does  not  go  on  in  the  absence  of  oxygen,  yet  the  chemical  change 
certainly  is  not  one  of  complete  oxidation.  The  resultant  product,  unlike 
the  original  fat,  is  insoluble  in  ether  and  soluble  in  water.  Neither  is  this 
fat  metamorphosis  a  lipolytic  change  of  the  usual  digestive  type,  compar- 
able with  the  cleavage  produced  by  ordinary  lipases.  The  latter  appear 
to  be  almost  completely  wanting  in  the  blood;  the  various  body  tissues  are, 
on  the  other  hand,  supplied  with  more  or  less  lipolytic  power,  so  that  we 
may  postulate  a  widespread  distribution  of  lipase  in  the  animal  body.  The 
reversible  action  of  fat-splitting  enzymes,  i.  e.,  the  capacity  of  the  same 
enzyme  solution  to  synthesize  neutral  fats  from  fatty  acids  and  alcohols,  as 
well  as  to  effect  a  corresponding  cleavage  of  neutral  fats,  has  directed 
attention  to  the  probable  important  role  of  lipases  in  the  tissue  metab- 
olism of  fats.  It  is  not  unlikely,  therefore,  that  the  reserve  supply  of  tissue 
fats  is  in  some  way  transformed  into  more  soluble  forms  by  enzymes  pre- 
cisely as  the  storage  glycogen  may  be,  and  thus  transported  from  the  tissue 
cells;  while  the  deposition  of  transported  fat  components  is  perhaps 
accomplished  by  a  synthesis  in  which  enzymes  are  likewise  effective 
agents.  Other  esters  are  similarly  attacked  by  tissue  lipases.  Enough 
has  been  said  to  indicate  the  actual  occurrence  of  synthetic,  lipolytic,  and 
solvent  enzymes  for  the  fats.  Connstein  has  offered  the  following  tenta- 
tive description  of  the  immediate  fate  of  food-fats.  When  ingested  in  the 
form  of  an  emulsion,  they  may  be  in  part  hydrolyzed  in  the  stomach; 
otherwise  the  lipolysis  begins  in  the  intestine.  The  cleavage  products  are 
absorbed  and  incidentally  resynthesized  to  neutral  fat,  wdiich  reaches  the 
blood  through  the  chyle.  In  the  circulation,  the  fat  is  transformed  into 
an  (at  present  unknown)  soluble  and  diffusible  modification  which  can 
readily  pass  through  the  capillaries,  and  thus  gain  direct  access  to  the 
tissues  themselves  where  a  regeneration  of  fat  goes  on.  AVhen  the  fat 
depots  in  the  tissues  are  drawn  upon,  lipolysis  again  takes  place.  Before 
accepting  this  it  remains  to  be  seen  whether  the  emulsified  particles  of  fat 
cannot  pass  through  the  walls  of  the  capillary  vessels  in  other  than  water 
soluble  forms.  The  possible  fat-dissolving  power  of  the  lipoids  (lecithins, 
etc.)  present  in  all  cells  is  not  to  be  overlooked  in  this  connection.  The 
inadequacy  of  our  present  knowledge  in  only  too  patent. 

The  fat  which  enters  the  circulation  is  not  imlikely  in  part  involved  very 
soon  in  the  combustions  continually  going  on.  \Yhere  this  katabolic 
change  occurs  can  only  be  surmised;  the  liver  is  suggested,  although  the 
evidence  is  somewhat  indirect.  In  greater  part,  the  fat  is  undoubtedly 
first  deposited,  the  most  important  depots  being  the  subcutaneous  connec- 
tive tissue,  the  liver,  and  the  folds  of  the  peritoneum.  The  panniculus 
adiposus  is  of  foremost  importance  in  fat  deposition,  the  other  storage 
places  being  utilized  prominently  only  when  the  former  has  already  been 
well  taxed.  The  liver  may  become  the  seat  of  transitory  or  temporary 
storage.    There  exists  in  the  liver  a  kind  of  antagonistic  relation  between 


GENERAL  CONSIDERATIONS  OF  METABOLISM  697 

glycogen  and  fat,  as  the  result  of  which  fat  fails  to  accumulate  in  the  liver 
so  long  as  glycogen  is  abundantly  formed  there  and  the  other  fat  depots  are 
available.  Thus  it  happens,  as  Rosenfeld  has  pointed  out,  that  the  livers 
of  fattened  pigs  are  frequently  poor  in  fat,  owing  to  their  richness  in  glyco- 
gen; whereas  those  animals  like  fishes,  which  live  on  diets  poor  in  carbo- 
hydrates (glycogen-formers)  store  up  enormous  quantities  of  fat  in  their 
hepatic  cells.  In  man,  with  whom  a  mixed  diet  is  customary,  fatty  liver 
is  normally  not  observed  for  reasons  just  advanced.  Lusk  has  pictured 
conditions  when,  owing  to  diabetes,  or  activity  of  the  mammary  gland  in 
utilizing  dextrose  to  form  milk-sugar,  the  cells  affected  become  "sugar- 
hungry  cells, "  which  attract  fat  in  greater  quantity  than  they  can  burn  it 
(fat  infiltration). 

The  preceding  remarks  involve  the  assumption  that  tissue-fats  may  owe 
their  origin  directly  to  the  food-fat,  and  lead  to  the  broad  question  of  fat- 
formation  in  the  animal  body.  Such  an  assumption  is  more  easily  made 
in  the  case  of  fats  because  they  are  believed  to  undergo  less  radical  changes 
in  the  process  of  digestion  than  do  carbohydrates  or  proteids,  and  the  re- 
synthesis  occurs  in  the  passage  through  the  absorbing  cells.  Kassowitz  has 
modified  the  point  of  view  somewhat  by  regarding  the  chyle-fat  as  a  pro- 
duct of  the  internal  secretion  of  the  intestinal  epithelial  cells.  From  his 
standpoint  the  make-up  of  the  circulating  fat  which  is  able  to  gain  its  way 
to  the  fat  depots  is  dependent  upon  the  protoplasmic  activity  of  these  living 
cells,  a  view  which  implies  a  somewhat  indirect  deposition  of  the  fat  in- 
gested. Such  distinctions,  however,  are  verbal  rather  than  real.  The  im- 
portant facts  are,  firstly,  that  when  foreign  fats  possessing  recognizable 
chemical  and  physical  characteristics  are  fed,  the  constituent  fatty-acid 
group  which  lends  peculiar  character  to  them  can  be  detected  in  the  tissue- 
fats.  The  subject  has  attained  importance  in  agriculture  where  the 
quality  of  the  fat  in  animals  is  a  matter  of  serious  commercial  moment. 
In  the  second  place,  it  is  noteworthy  that  despite  variations  in  the  char- 
acter of  the  fat  fed,  there  is  an  inherent  tendency  to  maintain  a  typical  con- 
stancy for  the  species  and  the  particular  depot  under  consideration. 
Mutton-fat  differs  from  the  fat  of  cattle  even  under  somewhat  similar 
conditions  of  diet;  and  in  the  same  animal  the  fat  has  not  the  same  com- 
position in  different  parts  of  the  body.  These  facts  mean  that  various 
factors  are  at  work  in  determining  the  make-up  of  the  adipose  tissue, 
and  especially  suggest  other  sources  for  body-fat  besides  the  fat  in- 
gested. Among  these,  carbohydrates  are  without  question  the  most 
important.  The  feeding  of  a  diet  rich  in  carbohydrate  is  a  familiar 
method  of  fattening  animals.  It  does  not,  however,  afford  rigorous  proof 
of  the  origin  of  the  fat  produced,  since  every  dietary  of  this  sort  usually 
contains  an  abundance  of  proteid.  In  the  formation  of  milk-fat  we  have 
a  specific  illustration  of  the  relation  of  carbohydrates  to  fat  formation. 
Jordan  fed  a  cow  during  ninety-five  days  on  a  ration  frOm  w^hich  the  fats 
had  been  nearly  all  extracted,  and  the  animal  continued  to  secrete  milk 
similar  to  that  produced  when  she  was  fed  on  the  same  kinds  of  grain  and 
hay  in  their  normal  condition.  The  yield  of  milk-fat  during  the  ninety- 
five  days  was  62.9  pounds.     The  food-fat  eaten  during  this  time  was 

11.6  pounds,  of  which  only  5.7  were  absorbed;    consequently  at  least 

52.7  pounds  of  the  milk-fat  must  have  had  some  source  other  than  the 
food-fat. 


698  NUTRITION 

Tlic  milk-fat  in  tlic  above  experiment  could  not  have  come  from  pre- 
viously stored  body-fat.  This  is  supported  by  three  considerations:  (1) 
The  cow's  botly  could  have  contained  scarcely  more  than  GO  pounds  of 
fat  at  the  beginning  of  the  experiment;  (2)  she  gained  47  pounds  in 
Aveight  during  this  jieriod  of  time  with  no  increase  of  body  nitrogen,  and 
Avas  judged  to  be  a  much  fatter  cow  at  the  end;  (3)  the  formation  of  this 
quantity  of  milk-fat  from  the  body-fat  would  have  caused  a  marked  con- 
dition of  emaciation,  which,  because  of  an  increase  in  the  body  weight, 
would  have  required  the  improbable  increase  in  the  body  of  104  pounds  of 
water  and  intestinal  contents.  During  fifty-nine  consecutive  days,  38.8 
])ounds  of  milk-fat  were  secreted  and  the  urine  nitrogen  was  ecpiivalent  to 
33.3  pounds  of  protein.  According  to  any  acce])ted  method  of  interpreta- 
tion, not  over  17  pomids  of  fat  could  have  l)een  produced  from  this 
amount  of  assimilated  protein.  From  these  considerations,  it  is  concluded 
that  the  milk-fat  was  produced  in  part  at  least  from  carbohydrates,  as  we 
know  to  be  the  case  with  body-fat. 

The  determination  of  the  place  where  the  conversion  of  carbohydrate  to 
fat  occurs  is  not  easy.  One  is  tempted  to  refer  it  to  those  places  where 
carbohydrates  accumulate,  viz.,  the  liver  and  muscles.  But  it  is  not  less 
likely  to  be  ])erfected  in  those  locations  where  fat  is  deposited — in  the  cells 
of  the  subcutaneous  adipose  tissue,  for  example. 

With  reference  to  proteids  as  fat -forming  elements,  it  is  impossible  to 
make  any  conclusive  statement  at  present;  the  evidence  is  by  no  means 
convincing  and  there  is  a  growing  tendency  to  regard  such  a  process  as  un^ 
likely,  if  not  impossible.  In  this  respect,  the  theory  of  fat -formation  has 
been  seriously  modified  in  recent  years,  as  the  outcome  of  the  controversy 
between  the  adherents  of  Voit  and  of  Pfliiger.  Even  pathological  fat- 
formation,  typically  described  as  "fatty  degeneration " is  now  for  the  most 
part  explained  as  a  "fatty  infiltration,"  i.e.,  the  introduction  of  fat  trans- 
ported from  fat-depots  to  the  "degenerated"  tissue.  Corresponding 
with  this  view,  Rosenfeld  and  others  have  removed  from  "fatty"  livers  of 
dogs  previously  fed  abundantly  on  some  recognizable  foreign  fat  and  then 
poisoned  with  phosphorus,  the  characteristic  foreign  fat  fed.  The  "de- 
generation" fat  is  in  these  cases  not  manufactured  from  the  cell  proto- 
plasm, but  transported  and  infiltrated.  Accordingly,  further,  the  total 
fat-content  of  animals  poisoned  with  phosphorus,  which  induces  the  typi- 
cal symptoms  of  so-called  fatty  degeneration  of  the  liver,  is  not  increased, 
although  its  distribution  between  the  various  tissues  is  changed.  Recent 
studies  on  the  distribution  of  fat  in  pathological  conditions,  have  shown 
that  the  impressions  gained  by  mere  microscopic  examinations  may  be 
utterly  misleading,  as  the  fats  are  frequently  incorpoi'ated  very  intimately 
in  the  tissues. 

In  attempting  to  offer  an  explanation  of  the  fatty  metamorphosis  in  cells 
subject  to  toxic  influences,  we  quote  from  Rosenfeld,  the  champion  of  the 
infiltration  theory :  When  the  proteid  content  of  the  cell  is  attacked  by  any 
noxious  agency,  certain  molecules  of  the  protoplasm  are  thrown  out  of 
function.  In  order  to  maintain  its  vitality,  the  cell  now  obtains  its  energy 
in  the  oxidation  of  all  the  carbohydrates  which  it  controls  (hence  the  liver 
soon  becomes  glycogen -free)  or  when  this  is  impossible  the  proteid  content 
is  enriched  by  importation  of  proteid.  Accordingly  it  is  observed  that  in 
many  intoxications,  as  with  phosphorus  and  alcohol,  the  proteid  content 


GENERAL  CONSIDERATIONS  OF  METABOLISM  699 

of  the  liver  is  increased.  But  when  these  various  sparing  agents  are  no 
longer  available  in  sufficient  quantity,  the  cell  seeks  tlie  last  help  by  at- 
tempting to  recoup  its  losses  with  fat  abstracted  from  the  circulating  l^lood 
which  is  in  turn  replenished  from  the  fat -storage  depots.  With  this  infil- 
tration of  fat  into  the  cell,  the  latter  may  succeed  in  maintaining  itself  and 
its  energy  transformation  until  the  toxic  efiects  have  disap|)earcd;  if  not, 
the  infiltration  is  succeeded  by  a  true  degeneration  and  the  cell  dies. 

Referring  to  the  peculiar  aspect  of  fat-metabolism  afforded  in  the  for- 
mation of  milk-fat,  we  have  already  noted  that  the  latter  may,  in  the 
absence  of  an  abundant  fat-supply,  be  formed  from  carbohydrates.  Under 
usual  conditions,  the  fat  of  the  milk  is  partly  derived  from  the  body-fat, 
but  chiefly  from  the  fat  of  the  food.  The  fat  is  probably  not  transmitted 
directly  from  the  blood,  but  is  modified  in  the  secreting  cells  of  the  mam- 
mary gland.  If  for  any  reason  the  quality  of  the  milk  is  changed,  there  is 
always  a  tendency  to  return  to  the  normal.  The  composition  of  the  Vjutter- 
fat  is  modified  within  narrow  limits  by  the  fat  of  the  food ;  but  the  per- 
centage of  butter-fat  in  milk  is  very  little  influenced  by  foods  containing  a 
large  percentage  of  oil,  or  even  by  albuminous  foods.  Breeding  rather 
than  feeding  seems  to  play  the  important  part  in  determining  the  quantity 
and  quality  of  the  milk;  the  fact  that  foreign  fats  do  pass  into  the 
milk  is,  however,  not  to  be  overlooked  and  corresponds  with  the  newer 
findings  regarding  the  ready  transportation  of  fat  in  the  body  from  one 
depot  to  another.  There  is  also  some  evidence  in  the  case  of  the  sebace- 
ous glands  tending  to  show  an  alteration  in  the  make-up  of  their  fatty 
secretion,  depending  upon  the  character  of  the  fat  fed. 

During  embryonic  growth,  a  consumption,  rather  than  synthesis  or 
deposition  of  fat,  occurs  in  so  far  as  can  be  judged  from  experiments  on 
species  which  have  an  extra-uterine  development.  Thus  a  marked  loss 
of  fat  is  noted  in  the  chick  embryo  during  the  process  of  development. 
The  fresh  egg  containing  5.4  grams  of  fat  may  show  a  diminution  to  2.7 
grams  or  less. 

In  connection  with  fats,  reference  may  be  made  to  a  group  of  compounds 
widely  distributed  in  the  body  in  all  types  of  tissues  and  resembling  fats  in 
various  ways.  The  lecithins,  cholesterin  and  its  esters,  kephalins,  and 
cerebrins,  may  be  considered  briefly  under  the  general  term  of  "lipoids" 
or  fat -like  compounds,  which  differ  widely  among  themselves,  but  possess 
the  general  physical  properties  and  solubilities  of  fats.  They  are  especially 
prominent  in  the  nervous  tissues,  and  their  behavior  toward  the  vola- 
tile anaesthetics  is  made  the  basis  of  the  Meyer-Overton  theory  of  narcosis. 
Of  the  metabolism  of  these  substances,  little  can  be  said.  Lecithins  dis- 
appear from  the  cells  far  less  readily  than  do  the  ordinary  fats ;  their  con- 
tent is  far  more  constant  so  that  they  appear  to  be  an  integral  part  of  the 
protoplasm.  In  the  disintegration  of  nervous  structures,  decomposition 
products  of  lecithin  (cholin,  glycerylphosphoric  acid)  appear  to  be  liber- 
ated, as  well  as  in  certain  autolytic  changes  For  the  present,  it  is  scarcely 
profitable  to  do  more  than  point  out  the  possible  physiological  significance 
of  the  lipoids  in  the  work  of  the  cells.  Regarding  their  origin  little  is 
known. 

Of  the  stages  through  which  fats  pass  in  their  katabolism  to  the  end- 
products,  water  and  carbon  dioxide,  very  little  has  been  ascertained.  As 
in  the  metabolism  of  carbohydrates,  pathology  has  shed  some  Hght.    In 


700  NUTRITION 

severe  diabetes,  where  carbohydrates  are  not  burned  up,  fats  are  drawn 
upon.  In  this  condition,  as  also  in  inanition,  the  "acetone  bodies"  may 
be  eUminated  in  considerable  quantity.  This  is  not  true  under  ordinary 
conditions  on  a  mixed  diet.  Tlie  compounds  formed  in  the  intermediary 
metabolism  of  fats  under  these  conditions  of  imperfect  combustion  are 
acetone,  aceto-acctic  acid  and  ;5-oxybutyric  acid. 

Formerly,  these  compounds  were  attributed  to  the  proteids;  but  at 
present,  they  are  generally  associated  with  metabolism  of  the  fats,  and 
presumably  represent  products  of  the  incomplete  oxidation  of  higher 
fatty  acids.  In  health,  and  on  the  customary  mixed  diets,  only  a  few 
milligrams  of  acetone  are  excreted  daily.  In  hunger,  the  quantity  may 
increase  to  over  a  gram  per  day.  Carbohydrates  (and  perhaps  alcohol) 
check  this  production  at  once,  but  not  proteids  or  fats.  In  diabetes,  we 
have  the  extreme  case  in  which  figures  somewhat  as  follows  have  been 
observed:  Acetone,  15  grams;  aceto-acetic  acid,  26  grams;  /3-oxybutyric 
acid,  102  grams  per  day.  It  may  be,  as  Fr.  Mtiller  has  suggested,  that 
the  normal  metabolism  of  fats,  i.  e.,  oxidation  of  the  higher  fatty  acids 
to  carbon  dioxide  and  water,  goes  on  perfectly  only  when  a  certain  pro- 
portion of  sugar  is  simultaneously  burned  up,  in  the  failure  of  which 
oxybutyric  and  aceto-acetic  acids  arise  as  intermediary  products  which 
cannot'  be  completely  burned  up.  Whether  the  chemical  abnormality 
hinges  on  the  formation  of  these  compounds  or  on  the  inability  to  oxi- 
dize them  is  uncertain.  Accordingly,  it  is  at  present  impossible  to  say 
whether  they  represent  intermediary  stages  in  the  normal  combustion 
of  fats  or  not. 

Corpulence  is  scarcely  to  be  regarded  as  a  pathological  manifestation 
of  fat  metabolism.  Direct  observations  have  failed  to  indicate  any  dimin- 
ished capacity  of  the  organism  to  burn  the  deposited  fats.  AVe  have 
rather  to  deal  with  a  disproportionate  relation  between  intake  of  food 
and  food  utilization.  Whatever  apparent  diminution  in  energy  trans- 
formation may  occur  is  attributable  primarily  to  the  relative  muscular 
inactivity  of  corpulent  individuals.  A  small  daily  excess  may  lead  to  a 
considerable  accumulation  of  body-fat.  Finally,  all  influences  which 
diminish  the  combustion  processes  in  the  body  favor  corpulence;  these 
include  lack  of  muscular  exertion,  sleep,  and  conservation  of  body-heat. 
Some  idea  of  the  quantities  of  fat  which  may  be  retained  in  corpulency 
is  afforded  by  observations  of  Meyer  and  Falta.  In  a  person  of  111  kilo- 
grams body  weight,  the  thoracic  and  abdominal  cavities  furnished  9 
kilograms  of  fat-tissue,  the  subcutaneous  tissue  27  kilograms.  These  36 
kilograms  corresponded  to  30.2  kilograms  of  pure  fat.  The  muscles 
were  estimated  to  contain  an  additional  13  kilograms,  so  that  the  entire 
body  yielded  51  kilograms  of  fat  or  38  per  cent,  of  the  total  weight. 

Metabolism  of  Proteids. — The  characteristic  products  of  proteid 
katabolism  are  found  in  predominant  quantity  in  the  urine,  although 
the  fseces  and  sweat  also  contain  part  of  the  nitrogenous  waste.  In  addi- 
tion to  urea,  creatin,  creatinin,  uric  acid  and  other  purin  derivatives, 
hippuric  acid,  and  ammonium  salts,  a  few  others  occur  in  quantities 
which  are  normally  very  small  but  may  be  largely  increased  when  metab- 
oUsm  is  disordered.  The  sulphuric  and  phosphoric  acids  ehminated 
in  combination  with  various  bases  are  also  for  the  most  part  referable 
in  origin  to  the  proteids  which  contain  sulphur  and  phosphorus.     The 


GENERAL  CONSIDERATIONS  OF  METABOLISM  701 

chemical  nature  of  the  nitrogenous  metaboHc  products  which  escape 
with  the  stools  is  scarcely  known;  the  small  portions  lost  with  the  sweat 
are  allied  closely  to  those  found  in  the  urine. 

In  following  the  transformations  of  proteids  in  the  organism,  it  is 
necessary  to  bear  in  mind  that  they  represent  a  great  group  of  foodstuffs 
varied  in  physical  characters  and  chemical  behavior,  yet  essentially  allied 
in  structure  in  so  far  as  they  yield  similar  decomposition  products.  The 
latter  are  generally  comparable,  whether  produced  by  hydrolysis  with 
acids  or  by  cleavage  with  proteolytic  enzymes.  The  simpler  types  of 
proteid  subjected  to  such  decomposition  yield  leucin,  glycocoll,  a-amino- 
valerianic  acid,  alanin,  aspartic  acid,  glutamic  acid,  serin,  cystin,  tyrosin, 
phenylalanin,  pyrroHdin  carbonic  acid  (prolin),  oxypyrrolidin  carbonic 
acid,  lysin,  arginin,  histidin,  tryptophan,  and  ammonia. 

The  individual  groups  of  proteids  differ  in  the  proportions  of  these 
different  derivatives  and  future  investigation  will  doubtless  afford  addi- 
tions. From  the  chemical  standpoint,  it  will  be  noted  that  the  products 
thus  far  obtained  are  for  the  most  part  amino-acids  or  similar  com- 
pounds, a  preponderance  of  NHg  groups  in  some  of  them  giving  a  de- 
cidedly basic  character  to  the  molecule.    The  conspicuous  feature  of  the 

H 

I 
structure  of  all  these  derivatives  is  the  presence  of  the  group — C-NH2, 

I 
COOH 

and  Fischer  has  shown  that  such  groups  are  prone  to  form  continuous 
syntheses  in  which  the  carboxyl  group  of  one  becomes  united  with  the 
amino  group  of  another.  This  explains  the  characteristic  cleavage  of 
the  proteids  into  a-amino  acids  and  their  corresponding  behavior  toward 
enzymes  as  well  as  their  characteristic  deportment  like  acids  and  bases 
simultaneously.  The  sulphur  is  largely,  if  not  entirely,  grouped  in  the 
form  represented  in  the  cleavage  product,  cystin;  and  this  throws  light 
upon  the  origin  of  the  cystin  which  is  excreted  in  the  rare  metabolic  dis- 
turbance connected  with  cystinuria.  Many  proteids  apparently  contain 
a  carbohydrate  group;  but  the  typical  carbohydrate  derivatives  obtained 
from  the  compound  proteids  like  the  mucoids  are  now  recognized  as 
amino-sugars,  of  which  glycosamine  is  the  most  common.  Other  pro- 
teids, like  the  vitellin  of  egg-yolk  and  casein  of  milk,  contain  phosphorus 
in  radicals  not  yet  recognized  by  the  chemist.  This  element  plays  an 
important  part  in  nutrition,  and  the  phosphorized  proteids  may  thus 
become  responsible  in  no  small  degree  for  the  phosphates  eliminated. 
In  nucleoproteids,  the  presence  of  the  nucleic-acid  group  introduces  a 
new  series  of  complexes  which  have  a  significant  role.  The  cleavage 
products  of  the  nucleic  acids  include — 

1.  Phosphoric  acid: 

2.  Pyrimidin  derivatives: 

NH— CO  NH— CO  NH=C.NHo 

II  II  II' 

CO     CH  CO      C.CH,  CO      CH 

I         II  I  II  I         11 

NH— CH  NH— dn  NH— CH 

Uracil  Thymin  Cytosin 


702  NUTRITION 

3.  Purin  derivatives: 
N=C.NH,  HN-CO  HN— CO  HN— CO 

C     C— NH,        OC      C— NH         liC     C— NH  R,N— C     C— NH 


I  CH       I        I  CH       II       II  CH  II      II  CH 

C— N/-       -HN— C— N/-  N— C— N/-  N— C— N/- 

Adenin  Xanthin  Hypoxanthin  Guanin 

4.  Pentoses  CJIjoO,;. 

5.  Levulinic  Acid. 

The  ferruginous  protcids  like  the  haemoglobins,  as  well  as  the  albumin- 
oids (scleroproteins)  gelatine,  elastin,  etc., — all  otter  specific  ditt'erences. 
The  reader  is  referred  to  the  text-books  of  physiological  chemistry  for  a 
detailed  stuily  of  their  chemical  i)eculiarities.  Enough  has  been  indi- 
cated to  make  clear  the  possibility  of  very  different  nitrogenous  trans- 
formations, in  accord  with  the  varying  complexity  and  chemical  make-up 
of  the  specific  proteids  attacked. 

In  following  the  ingested  proteids  we  are  at  once  confronted  with 
the  question  as  to  how  far  they  are  altered  by  the  digestive  changes  in 
the  alimentary  canal  before  absorption.  In  respect  to  this,  the  views 
of  physiologists  have  been  altered  most  distinctly  in  recent  years.  So 
long  as  proteoses  and  peptones  were  recognized  as  the  essential  end-prod- 
ucts of  digestive  proteolysis,  attention  was  particularly  directed  to  the 
fate  of  these  products  in  absorption.  Inasmuch  as  they  were  found  to 
disappear  quickly  in  contact  with  the  intestinal  mucosa,  while  the  blood 
stream  beyond  was  apparently  free  from  them,  it  was  naturally  concluded 
that  they  "are  regenerated  to  native  proteid  in  their  passage  through  the 
living  intestinal  wall.  Such  a  view  has,  however,  been  rendered  unten- 
able by  the  discovery  that  proteids  can  be  and  presumably  are  broken 
down  far  more  completely  in  the  process  of  digestion  than  was  formerly 
assumed;  and  furthermore,  it  has  been  found  that  the  disappearance  of 
peptones  in  contact  with  the  intestinal  mucosa  is  in  reality  due  to  a  diges- 
tive cleavage  to  non-proteid  nitrogenous  derivatives  through  the  agency 
of  the  enzyme  erepsin.  Whether  proteids  are  ordinarily  completely  dis- 
integrated' in  the  process  of  digestion  into  compounds  which  no  longer 
give  the  typical  proteid  (biuret)  reactions  before  absorption  occurs,  or 
whether  even  the  more  complex  derivatives  such  as  peptones  normally 
traverse  the  intestinal  wall,  cannot  be  decided  conclusively  from  the  evi- 
dence at  hand.  It  seems  unlikely  that  the  proteid  derivatives  circulate 
in  the  blood  stream  in  anything  more  than  traces;  otherwise,  they  would 
not  have  escaped  detection  so  often.  Tentatively,  we  may  picture  the 
digestive  change  as  occurring  in  accord  with  the  following  scheme,  which 
represents  the  results  of  recent  experimental  observations  (Abderhalden) : 

Native  Proteid, 

Peptone. 


Polypeptid.  Tyrosin,   Leucin,  Glutaminic  Acid,  Aspartic 

Acid,  Trj'ptophan,  etc.    Histidin,  Arginin, 
ProHn,  Lysin. 


GENERAL  CONSIDERATIONS  OF  METABOLISM  703 

The  polypcptids  represent  intermediate  products,  and  the  controversial 
features  of  the  question  centre  in  the  extent  to  which  digestive  cleavage 
actually  occurs  in  the  gut.  The  determination  of  the  fate  of  the  proteid 
products — ^whatever  they  may  be — after  they  leave  the  lumen  of  the 
digestive  tube  is  attended  with  even  greater  difficulties.  In  the  absence 
of  convincing  proof  of  the  proteid  "fragments"  in  the  portal  blood,  it 
has  been  natural  to  assume  a  "regeneration"  of  the  proteid  in  the 
intestinal  structures.  At  the  present  time,  however,  the  occurrence  of 
proteoses  and  further  disintegration  products  of  proteids  in  the  blood, 
especially  after  meals,  is  not  at  all  unlikely.  It  is  less  difli(,-ult  to  a])pre- 
ciate  how  a  few  types  of  circulating  proteids  can  be  constructed  from  the 
ultimate  cleavage  products  of  the  proteids  than  from  such  different 
complexes  as  must  exist  in  the  diverse  proteids  of  the  food.  In  other 
words,  it  is  easier  to  understand  how  flesh-,  or  milk-,  or  wheat-proteids  can 
give  rise  to  the  same  serum  albumin  or  muscle  globulin  if  they  are  first 
broken  down  to  simple  fragments  which  enter  into  the  composition  of  all 
the  proteids,  though  in  varying  proportions.  From  the  teleological  stand- 
point, however,  it  is  not  apparent  why  a  complete  break-down  of  pro- 
teids should  occur,  only  to  be  followed  by  immediate  resynthesis.  It  is 
more  reasonable  to  assume  a  cleavage  into  larger  nuclei  only,  which 
might  serve  equally  well  in  the  anabolic  disposition  of  the  nitrogenous 
materials. 

The  unsolved  problems  which  have  arisen  in  the  study  of  this  first 
step  in  proteid  assimilation  have  been  thus  broadly  presented  because 
it  is  impossible  at  present  to  form  anything  like  a  satisfactory  hypothesis 
of  changes  which  actually  take  place.  It  is  by  no  means  certain  that  only 
"regenerated"  proteid  reaches  the  blood  current  from  the  intestinal 
sources;  and  it  may  be  found  that  the  quantities  of  cleavage  products 
absorbed  at  ordinary  intervals  escape  detection  by  the  methods  now 
available.  The  increase  of  ammonia  nitrogen  in  the  portal  blood  during 
digestion  implies  an  increase  in  the  non-proteid  nitrogen  of  the  blood, 
but  the  failure  to  demonstrate  it  may  be  ascribed  to  unfavorable  condi- 
tions or  inaccurate  technique.  The  constancy  of  composition  of  the 
systemic  blood  in  respect  to  its  proteids  is  as  striking  as  is  its  fixed  sugar- 
content;  and  the  intervention  of  the  liver  in  some  regulatory  or  regenera- 
tive function  is  at  once  brought  to  mind. 

Nor  are  we  better  instructed  with  regard  to  the  further  intermediary 
metabolism  of  the  nitrogenous  compounds.  We  have  pointed  out  the 
conspicuous  behavior  of  the  proteids  in  their  failure,  under  ordinary 
conditions  of  diet  and  health,  to  be  retained.  The  elimination  of  nitrogen 
begins  to  increase  almost  immediately  after  a  meal  rich  in  proteids. 
Experiments  by  Sherman  and  Hawk  illustrate  the  character  of  this 
response.  When  lean  beef  sufficient  to  furnish  about  64  grams  of  extra 
proteid  was  taken  with  breakfast,  the  nitrogen  in  the  urine  began  to 
rise  in  the  first  three  hours  and  reached  a  maximum  between  the  sixth 
and  ninth  hours,  after  which  it  declined  at  first  rapidly  and  then  more 
slowly.  The  increased  excretion  of  sulphates  was  proportional  to  that 
of  the  nitrogen  and  followed  the  same  general  course.  It  is  interesting 
to  note  further  that  the  increased  heat  of  combustion  of  the  urine  was 
but  little  greater  than  would  correspond  to  an  amount  of  urea  equivalent 
to  the  extra  nitrogen  eliminated.     The  other  constituents  of  the  urine 


704  NUTRITION 

were  therefore  but  little  affected,  and  a  moderate  gain  or  loss  of  body 
nitrogen  did  not  seem  to  affect  the  changes  noted. 

Faita  has  observed  that  after  the  ingestion  of  equal  quantities  of  nitro- 
gen in  the  form  of  different  proteid  substances  such  as  egg  albumin, 
casein,  gelatin,  etc.,  the  rate  at  which  nitrogenous  equilibrium  is  again 
established  varies  with  the  materials  used.  It  is  not  improbable  that 
these  differences  in  rapidity  of  katabolism  are  ascribable  to  an  unlike 
resistance  of  the  proteids  to  the  alimentary  digestive  processes,  which 
accordingly  alters  tlicir  rate  of  absorption. 

Theories  of  Proteid  Metabolism. — In  any  attempt  at  a  theory  of  pro- 
teid katabolism,  certain  fundamental  observations  must  be  borne  in 
mind;  namely,  that  this  process  never  stops  in  the  animal  body,  and 
that  the  adult  organism  has  the  capacity  of  rapidly  adapting  its  proteid 
katabolism  to  the  extent  of  proteid  supply.  According  to  Voit,  a  dis- 
tinction must  be  drawn  between  the  organized,  or  tissue  proteid,  which 
constitutes  an  essential  part  of  the  living  bioplasm,  and  the  circulat- 
ing proteid  representing  the  variable  store  of  rapidly  metabolized  pro- 
teid transported  in  the  blood  and  lymph  stream  and  temporarily  located 
in  the  interstices  of  the  tissues  and  independent  of  the  living  substance. 
The  organized  proteid  is  replenished  only  to  a  slight  degree  by  the 
proteid  intake,  since  only  a  small  part  of  this  living  bioplasm  undergoes 
destruction  under  ordinary  circumstances.  The  circulating  proteid,  on 
the  other  hand,  is  readily  disintegrated  to  the  extent  that  it  is  not 
drawn  upon  for  tissue  construction  and  its  nitrogenous  groups  are 
speedily  eliminated.  Such  a  distinction  becomes  plausible  in  consider- 
ation of  the  rapid  metamorphosis  of  proteid  when  a  large  supply  is 
taken  in,  the  assumption  of  a  previous  incorporation  mto  some  organic 
structure  and  immediate  degradation  being  rendered  unnecessary  thereby. 
As  Hammarsten  has  expressed  it:  The  tissue  elements  constitute 
an  apparatus  of  relatively  stable  nature  which  has  the  power  of  taking 
proteids  from  the  fluid  bathing  the  tissues  and  appropriating  them, 
while  their  own  proteids,  the  tissue  proteids,  are  ordinarily  katabolized 
to  only  a  small  extent.  By  an  increased  supply  of  proteids,  the  activity 
of  the  cells  and  their  ability  to  decompose  nutritive  proteids  is  also 
increased  to  a  certain  degree.  When  nitrogenous  equilibrium  is  obtained 
after  an  increased  supply  of  proteids,  it  denotes  that  the  decomposing 
power  of  the  cells  for  proteids  has  increased,  so  that  the  same  quan- 
tity of  proteids  is  metabolized  as  is  supplied  to  the  body.  If  proteid 
metabolism  is  decreased  by  the  simultaneous  administration  of  other 
non-nitrogenous  foods,  a  part  of  the  circulating  proteids  may  have  time 
to  become  fixed  and  organized  by  the  tissues,  and  in  this  way  the  mass 
of  flesh  of  the  body  increases.  During  starvation,  or  w'ith  a  lack  of  pro- 
teids in  the  food,  the  reverse  takes  place;  for  a  part  of  the  tissue  proteids 
is  converted  into  circulating  proteids  which  are  metabolized,  and  in  this 
case  the  flesh  of  the  body  decreases.  The  most  essential  part  of  Voit's 
theory  is  the  supposition  that  the  food  proteid  of  the  cells  is  more  easily 
destroyed  than  the  organized  or  true  protoplasmic  proteid. 

Pfluger  contends  that  it  is  only  organized  proteid  which  can  undergo 
metabolic  transformation — that  the  circulating  proteid  must  be  con- 
structed into  tissue  proteid  or  bioplasm  before  it  can  take  part  in  the 
oxidation  or  katabolism  characteristic  for  proteids.     It  is  the  state  of 


GENERAL  CONSIDERATIONS  OF  METABOLISM  705 

nutrition  of  the  body  cells,  rather  than  the  circulating  proteid  which 
determines  the  extent  of  proteid  katabolism,  a  view  which  is  in  a  way 
merely  a  modification  of  the  older  theory  of  Liebig. 

The  theory  of  Voit  owed  its  formulation  to  the  inadequacy  of  the 
older  views  of  Liebig,  which  assumed  that  proteid  katabolism  must  be 
proportional  to  muscular  activity.  Voit  beUeves  that  the  living  substance 
is  scarcely,  if  at  all,  disintegrated  in  such  cases  when  the  nutritive  condi- 
tions are  satisfactory.  The  greater  part  of  the  excreted  nitrogen  is  ac- 
cordingly derived  from  destroyed  food  proteid.  The  ra])idity  with  which 
metabolic  changes  in  proteids  occur  in  the  body,  and  the  large  amount 
of  such  metabolism  which  may  take  place  when  excess  of  proteid  is 
taken  with  the  food,  renders  unlikely  the  previous  construction  of  the 
latter  into  living  matter.  Pfliiger's  contention  regarding  the  importance 
of  the  muscle  cell  is  based  upon  the  experiments  of  Schondorff,  who 
observed  that  the  extent  of  urea  formation  in  the  muscles  and  livers  of 
dogs  depends  upon  the  nutritive  condition  of  these  cells  rather  than 
upon  the  character  of  the  blood  circulating  through  them.  The  experi- 
mental data  are,  however,  by  no  means  convincing  and  have  lately  re- 
ceived adverse  criticism. 

Kassowitz  has  advanced  a  modified  conception  of  proteid  metabolism 
based  upon  his  view  that  all  true  foodstuffs  are  constructed  into  proto- 
plasm prior  to  utilization.  Carbohydrates  and  proteids  together  enter 
into  the  composition  of  the  living  material,  which  in  turn  can  split  off 
glycogen  or  nitrogenous  residues  no  longer  assimilable  and  accordingly 
excreted.  This  view  differs  essentially  from  Pfliiger's,  in  demanding 
non-nitrogenous  as  well  as  nitrogenous  components  for  the  constructive 
feature.  Kassowitz  remarks  that  if  food  proteid  can  be  "organized" 
directly  and  alone,  it  is  not  easy  to  understand  the  difficulty  in  putting 
on  flesh  when  large  quantities  of  proteid  are  fed  without  any  non-nitrog- 
enous foodstuffs,  whereas  this  synthesis  is  accomplished  far  more  effectu- 
ally with  less  proteid,  when  sugar  is  simultaneously  available.  According 
to  him  the  excretion  of  nitrogen  has  a  twofold  source,  namely,  an 
"active"  protoplasmic  katabolism,  inaugurated  by  nervous  stimulation 
and  affording  little  of  the  nitrogenous  excretives;  and  an  "inactive" 
destruction  yielding  certain  reserve  products,  together  with  a  large  part 
of  the  nitrogenous  fragments  now  in  a  form  no  longer  capable  of  assimi- 
lation. There  is,  from  this  standpoint,  no  luxus  consumption  of  proteid 
and  no  direct  decomposition  of  surplus  food  proteid,  but  rather  a  luxus 
production  of  protoplasm  which  in  turn  suffers  an  "inactive"  degrada- 
tion and  eliminates  its  nitrogen.  Thus  it  is  that,  in  a  full  grown  and 
well  nourished  organism,  every  increase  in  proteid  supply  is  followed  by 
a  corresponding  increase  in  nitrogen  excretion. 

Such  a  view,  following  closely  the  standpoint  of  Pfliiger,  involves  much 
that  is  purely  hypothetical,  and  touches  closely  upon  the  question  as  to 
what  constitutes  a  true  food.  If  we  carry  the  contention  of  Kassowitz 
to  its  extreme,  then  no  toxic  substance  can  ever  act  as  a  true  food;  for 
toxic  action  implies  protoplasmic  destruction,  whereas  nutritive  proper- 
ties involve  some  participation  m  the  construction  of  the  protoplasm. 
If  the  calories  furnished  by  a  substance  like  alcohol  are  merely  converted 
into  heat,  which  only  serves  to  increase  the  useless  excess  already  present 
• — if  they  can  in  no  wise  participate  in  the  liberation  of  energy  as  mechan- 

45 


706  NUTRITION 

ical  work  because  the  alcohol  is  incapable  of  incorporation  in  the  con- 
tractile protojilasma,  the  real  food  value  of  such  a  compound  may  be 
questioned.  There  are  many  substances,  such  as  lactic  acid,  butyric 
acid,  uric  acid,  etc.,  which  are  certainly  oxidized  in  the  body.  We  are 
not  prepared  to  accept  the  view,  however,  that  the  result  of  their  metab- 
olism is  solely  a  liberation  of  waste  heat;  at  any  rate  the  question  as 
to  the  nutritive  value  of  compounds  which  unquestionably  liberate  energy 
in  their  transformations  in  the  body  seems  debatable  .still. 

Folin  has  recently  made  extensive  and  careful  analyses  of  the  urines 
of  healthy  persons  living  on  diets  in  which  the  protcid  intake  was  varied 
within  wide  limits.  This  range  in  the  daily  output  in  the  same  person 
is  shown  in  the  following  table: 

July  13.  July  20. 

Volume  of  urine 1170.  cc.  385.   cc. 

Total  nitrogen 16.8  grams.  3.60  grams. 

Urea  nitrogen 14 . 70  =87 . 5  per  cent.  2 . 20  =  61 . 7  per  cent 

Ammonia  nitrogen 0.49=3.0     "  "       0.42  =  11.3  "  " 

Uric  acid  nitrogen 0.18=1.1  "  "       0.09=2.5  "  " 

Creatinin  nitrogen 0.58=3.6  "  "       0.60  =  17.2  "  " 

Undetermined  nitrogen 0.85=   4.9  "  "       0.27=   7.3  "  " 

Total  SO3 3.64  "  "       0.76  "  " 

Inorganic  SO., 3.27=90.0  "  "       0.46=60.5  "  " 

EtherealSOa 0.19=5.2  "  "       0.10  =  13.2  "  " 

NeutralSOg 0.18=4.8  "  "       0.20=26.3  "  " 

The  diet  during  the  period  in  which  the  urine  of  July  20  was  collected 
consisted  of  pure  starch  and  cream,  so  that  the  intake  of  proteid  was 
minimal  though  the  quantity  of  food  was  considerable.  The  striking 
feature  is  the  pronounced  change  in  the  distribution  of  the  urinary  nitro- 
gen and  sulphur,  the  characteristic  end-products  of  proteid  katabolism. 
For  example,  the  relative  proportion  of  nitrogen  eliminated  in  the  form 
of  urea  is  greatly  diminished  in  the  absence  of  proteid  feeding,  w^hile  the 
output  of  creatinin  is  absolutely  unchanged,  the  relative  quantity  being 
greatly  increased.  In  discussing  the  bearing  of  these  facts,  we  shall  quote 
freely  from  the  papers  of  Folin.  To  explain  such  changes,  it  seems  neces- 
sary to  assume  that  proteid  katabolism  is  of  tAvo  kinds,  which  are  essen- 
tially independent  and  quite  different.  The  one  kind,  extremely  variable 
in  quantity,  yields  chiefly  urea  and  inorganic  sulphates,  no  creatinin  and 
probably  no  neutral  sulphur.  The  other,  the  constant  katabolism,  is 
largely  represented  by  creatinin  and  neutral  sulphur,  and  to  a  less  extent 
by  uric  acid  and  ethereal  sulphates.  The  more  the  total  katabolism  is 
reduced,  the  more  prominent  become  these  representatives  of  the  con- 
stant katabolism,  the  less  prominent  become  the  two  chief  representatives 
of  the  variable  katabolism. 

If  there  are  two  distinct  forms  of  proteid  metabolism  represented  by 
two  different  sets  of  waste  products,  it  becomes  important  to  determine, 
if  possible,  the  nature  and  significance  of  each.  The  fact  that  the  crea- 
tinin elimination  is  not  chminished,  when  practically  no  protein  is 
furnished  with  the  food,  and  that  the  elimination  of  some  of  the  other 
constituents  is  only  slightly  reduced,  shows  why  a  certain  amount  of 
proteid  must  be  furnished  with  the  food  if  nitrogen  equilibrium  is  to 
be  maintained.  It  is  clear  that  the  metabolic  processes  resulting  in  the 
end-products  which  tend  to  be  constant  in  quantity  appear  to  be  indis- 


GENERAL  CONSIDERATIONS  OF  METABOLISM  707 

pensable  for  the  continuation  of  life;  or  those  metabolic  processes 
probably  constitute  an  essential  part  of  the  activity  which  distinguishes 
living  cells  from  dead  ones.  Folin,  therefore,  calls  the  proteid  metab- 
olism vi^hich  tends  to  be  constant,  tissue  metabolism  or  endor/enous 
metabolism,  and  the  other  variable  proteid  metabolism,  exogenous  or 
intermediary  metabolism. 

The  endogenous  metabolism  sets  a  limit  to  the  lowest  level  of  nitrogen 
equilibrium  attainable.  Just  where  that  level  is  fixed  will  depend  on 
how  much,  if  any,  urea  is  derived  from  the  same  katabolic  processes 
that  produce  the  creatinin  With  reference  to  the  remainder  of  the  pro- 
teid involved,  an  extensive  formation  of  Voit's  "circulating  proteid" 
followed  by  a  second  decomposition  and  elimination  as  urea  seems 
almost,  if  not  quite,  as  improbable  as  the  corresponding  formation  and 
decomposition  of  Pfluger's  organized  protoplasm.  Folin  has  therefore 
arrived  at  the  following  conclusion :  The  greater  part  of  the  protein  fur- 
nished with  standard  diets  represents  exogenous  metabolism  and  is  not 
needed;  or,  to  be  more  specific,  its  nitrogen  is  not  needed.  The  organism 
has  developed  special  facilities  for  getting  rid  of  such  excess  of  nitrogen 
so  as  to  gain  the  use  of  the  carbon  moiety  of  the  protein  containing  it. 
The  first  step  in  this  process  is  the  decomposition  of  proteid  in  the  diges- 
tive tract  into  proteoses,  amino-acids,  ammonia,  etc.  The  hydrolytic 
cleavages  are  carried  further  in  the  mucous  membrane  of  the  intestines, 
and  are  completed  in  the  liver,  each  decomposition  being  such  as  to 
further  the  formation  of  urea. 

We  have  in  these  special  hydrolytic  decompositions,  the  result  of 
which  is  to  remove  the  unnecessary  nitrogen,  an  explanation  of  why  and 
how  the  animal  organism  tends  to  maintain  nitrogen  equilibrium  even 
when  excessive  amounts  of  protein  are  furnished  with  the  food.  This 
excess  is  not  stored  up  in  the  organism  as  such,  because  the  actual  need 
of  nitrogen  is  so  small  that  an  excess  is  always  furnished  with  the  food. 
The  ordinary  food  of  the  average  man  contains  more  nitrogen  than  the 
organism  can  use,  and  increasing  the  nitrogen  still  further  will  therefore 
necessarily  only  lead  to  an  immediate  increase  in  the  elimination  of  urea, 
and  does  not  increase  the  proteid  katabolism  involved  in  the  creatinin 
formation  any  more  than  does  an  increased  supply  of  fats  and  carbo- 
hydrates. 

Finally,  the  normal  human  organism  can  be  made  at  almost  any  time 
to  store  up  fats  and  carbohydrates.  The  katabolism  of  these  products 
consists  chiefly  of  oxidation,  a  decomposition  which  sets  free  large  quan- 
tities of  energy  useful  to  the  organism.  The  hydrolytic  removal  of  nitro- 
gen from  protein  involves  by  comparison  a  very  small  transformation  of 
energ}  and  yields  a  non-nitrogenous  rest  of  great  fuel  value.  The  latter 
may  be  directly  transported  in  part  to  the  different  tissues,  and  thus  at 
once  supply  oxidative  material  where  needed,  but  in  all  probability  it  is 
partly  converted  into  fats,  or  at  least  into  carbohydrates,  and  then  be- 
comes subject  to  the  laws  governing  the  katabolism  of  these  two  groups 
of  food  products.  It  may  be  added,  there  is  no  urgent  reason  for  assum- 
ing that  the  katabolism  of  the  proteid  nitrogenous  derivatives  is  brought 
about  by  oxidations  like  those  which  decompose  the  fats  and  the  carbo- 
hydrates; for  such  cleavages  are  more  easily  accomplished  by  hydro- 
lytic reactions  than  by  oxidations. 


708  NUTRITION 

The  experience  of  the  writers  lends  support  to  many  features  of  the 
theory  of  proteid  metabohsm  outUned  by  FoUn.  It  makes  intclUgible 
the  ordinary  absence  of  any  demonstrable  effect  of  physical  work  on 
nitrogen  elimination,  and  indicates  how  excess  of  nitrogen  furnished 
Mith  the  food  is  quickly  converted  under  normal  circumstances  into  urea 
and  made  harmless  by  elimination.  Even  in  starvation  it  is  presumably 
not  the  muscle  proteid  which  is  first  attacked.  Folin  suggests  the  fol- 
lowing ex])lanation  for  this  case:  "All  living  protoplasm  in  the  animal 
organism  is  suspended  in  a  fluid  very  rich  in  protein,  and  on  account 
of  the  habitual  use  of  more  nitrogenous  food  than  the  tissues  can  use  as 
protein,  the  organism  is  ordinarily  in  possession  of  approximately  the 
maximum  amount  of  reserve  protein  in  solution  that  it  can  advantage- 
ously retain.  When  the  supply  of  food  protein  is  stopped,  the  excess  of 
reserve  protein  inside  the  organism  is  still  sufficient  to  cause  a  rather 
large  destruction  of  protein  during  the  first  day  or  two  of  protein  starva- 
tion, and  after  that  the  protein  katabolism  is  very  small,  provided  suffi- 
cient non-nitrogenous  food  is  available.  But  even  then,  and  for  many 
days  thereafter,  the  protoplasm  of  the  tissues  has  still  an  abundant  supply 
of  dissolved  protein  and  the  normal  activity  of  such  tissues  as  the  muscles 
is  not  at  all  impaired  or  diminished.  When  30  or  40  grams  of  nitrogen 
have  been  lost  by  an  average-sized  man  during  a  week  or  more  of  absti- 
nence from  nitrogenous  food,  the  living  muscle  tissues  are  still  well  sup- 
plied with  all  the  protein  that  they  can  use.  That  this  is  so,  is  indicated 
on  the  one  hand  by  the  unchanged  creatinin  elimination,  and  on  the 
other  by  the  fact  that  one  experiences  no  feeling  of  unusual  fatigue  or 
of  inability  to  do  one's  customary  work.  Because  the  organism  at  the 
end  of  such  an  experiment  still  has  an  abundance  of  available  protein 
in  the  nutritive  fluids,  it  is  at  once  seemingly  wasteful  of  nitrogen  when 
return  is  made  to  nitrogenous  food.  This  is  why  it  only  gradually,  and 
only  under  the  prolonged  pressure  of  an  excessive  supply  of  food  protein, 
again  acquires  its  original  maximum  store  of  this  reserve  material."     • 

If  views  such  as  this  approach  the  truth,  it  is  obvious  that  the  prevail- 
ing ideas  regarding  the  high  proteid  requirement  of  man  are  erroneous. 
We  shall  refer  to  this  when  treating  of  the  dietetic  needs  of  the  body, 
in  connection  with  the  determination  of  the  minimum  proteid  require- 
ment. Landergren  has  observed  that  nitrogen  elimination  may  fall  to 
a  low  level  on  a  nitrogen-free  diet,  and  that  the  extent  of  the  endogenous 
output  under  these  circumstances  is  conditioned  by  the  presence  of  a 
certain  amount  of  carbohydrate  in  the  food.  So  long  as  the  carbohydrate 
requirement  can  be  satisfied,  the  output  of  nitrogen  is  minimal.  In  the 
absence  of  carbohydrate  an  additional  quantity  of  proteid  is  destroyed, 
perhaps  to  furnish  sugar  for  the  blood,  and  this  additional  loss  cannot 
be  prevented  by  the  feeding  of  fat.  According  to  Landergren,  a  third 
or  more  of  the  proteid  destruction  in  hunger  is  attributable  to  the  demand 
of  the  organism  for  carbohydrate  which  is  accordingly  furnished  from 
the  carbon  moiety  of  the  proteids.  In  this  way,  the  increased  proteid 
destruction  noted  during  complete  inanition  in  contrast  with  specific 
nitrogen  starvation  is  explained. 

The  Proteids  in  Intermediary  Metabolism. — If  we  follow  more  closely 
the  history  of  the  various  nitrogenous  urinary  constituents  we  shall  find  that 
they  represent  quite  distinct  processes  in  intermediary  metaboUsm.    The 


GENERAL  CONSIDERATIONS  OF  METABOLISM  709 

urea  output,  in  proportion  to  the  total  nitrogen  elimination,  may  be  greatly 
diminished  in  disease.  The  experiments  of  Folin  make  it  yjrobable 
that  even  in  health  the  urea  fraction  of  the  nitrogenous  excretives  may  be 
very  greatly  reduced  when  the  minimum  proteid  recjuirement  of  the 
organism  is  not  overstepped.  The  theories  bearing  on  the  immediate 
origin  of  urea  are  numerous  and  cannot  be  examined  here  in  detail. 

Urea. — It  is  well  known  that  the  liver  has  the  power  of  forming  urea  from 
ammonium  salts,  and  from  simple  amino-acids  like  glycocoll.  The  evi- 
dence is  increasing  to  indicate  a  larger  proportion  of  ammonia  in  the 
portal  blood,  especially  at  the  height  of  digestion,  than  is  found  in  the 
hepatic  vein.  Digestion  thus  furnishes  many  factors  which  may  play  a 
part  in  the  synthesis  of  urea.  Some  of  the  tissues  contain  urea-forming 
enzymes.  Thus  arginase  acts  upon  the  proteolytic  derivative  arginin 
to  form  urea  and  ornithin  and  this  mode  of  origin  may  explain  the  occur- 
rence of  urea  when  the  liver  is  completely  excluded.  That  the  liver  is  the 
chief  organ  involved  in  urea  formation  is  suggested  by  the  results  found 
when  it  is  completely  excluded  from  the  circulation.  A  greatly  increased 
elimination  of  ammonia  follows,  with  diminution  in  the  output  of  urea; 
.the  latter,  however,  never  completely  disappears,  possibly  owing  to  its 
production  from  proteolytic  products  like  arginin  in  various  parts  of  the 
body  by  the  agency  of  urea-forming  enzymes.  Kossel  has  already  found 
arginase  in  various  tissues.  There  is  no  evidence  of  the  direct  formation 
of  urea  from  proteids  in  the  body,  although  Hofmeister  has  succeeded  in 
forming  it  by  oxidation  with  permanganate  in  the  presence  of  ammonia 
at  40°  C.  from  both  nitrogenous  and  non-nitrogenous  compounds. 

In  certain  diseases,  especially  such  as  seriously  involve  the  functions 
of  the  liver,  the  proportion  of  urea  nitrogen  eliminated  may  diminish 
very  markedly,  falling  even  below  10  per  cent,  of  the  total  output.  In 
some  instances  this  may  be  due  to  the  small  intake  of  proteid  and  corre- 
sponding diminution  of  exogenous  proteid  metabolism.  But  as  the  out- 
put of  ammonia  is  almost  always  very  large  in  these  cases,  amounting 
at  times  to  40  per  cent,  of  the  entire  nitrogen  output,  it  is  more  likely  that 
the  formation  of  acid  products  in  intermediary  metabolism — the  condi- 
tion known  as  acidosis — may  draw  upon  the  ammonia  for  purposes  of 
neutralization.  For  this  reason,  the  elimination  of  ammonia  is  increased 
by  administration  of  mineral  acids;  and  under  such  conditions  and  in 
such  diseases  as  in  fevers  and  diabetes,  where  an  increased  formation 
of  acid  takes  place,  the  quantity  of  ammonia  in  the  urine  is  increased. 
The  ammonia  may  be  afforded  by  additional  proteid  katabolism  and  the 
destructive  removal  of  fixed  alkali  thus  prevented.  The  absolute  quan- 
tity of  ammonia  eliminated  ordinarily  is  small, — approximately  one-half 
gram  per  day. 

Creatinin. — The  current  views  regarding  the  significance  of  creatinin  in 
the  urine  have  experienced  a  marked  change  in  recent  times.  The  tra- 
ditional opinion  is  that  creatinin  in  the  urine  is  largely  derived  from  the 
creatin  of  meat  ingested.  We  have  observed,  however,  that  creatinin  and 
creatin  are  not  lacking  in  the  urine  of  suckling  animals,  contrary  to  the 
statements  of  most  writers.  That  the  creatinin  output  is  at  once  increased 
by  ingestion  of  meat  has  received  abundant  confirmation.  On  the  other 
hand,  both  Long  and  the  authors  have,  in  distinction  from  several  other 
investigators,  found  creatinin  abundant  in  the  urine  of  vegetarians  who 


710 


NUTRITION 


abstained  for  months  from  meat  or  other  ereatin-eontainino;  foods.  Folin 
maintains  that  the  absohite  (|uantit_v  of  ereatinin  eHminated  in  the  urine 
on  a  meat-free  diet  is  a  constant  quantity  different  for  different  individ- 
uals, but  wholly  independent  of  quantitative  changes  in  the  total  amount 
of  nitrogen  eliminated.  Creatinin  in  the  urine  would,  on  this  assump- 
tion, become  a  measure  of  the  extent  of  endogenous  proteid  metabolism 
under  ai)propriate"  conditions  of  diet.  AYhether  creatinin  production  is 
increased  with  excessive  muscular  work  is  as  yet  rather  uncertain,  as  is 
the  immediate  antecedent  of  the  creatinin.  Lecithin  has  been  suggested 
by  Koch  as  a  possible  i)recursor,  though  the  evidence  is  far  from  convinc- 
ing. The  experience  of  the  writers  agrees  in  many  ways  with  the  essen- 
tial requirements  of  Folin's  views.  We  have  noted  a  production  of 
creatinin  in  starvation  in  man,  and  have  observed  an  elimination  of  this 
compound  proportional,  broadly  speaking,  to  the  body  weight  or  bulk 
of  the  active  tissues  on  diets  practically  creatin-free.  The  following  sum- 
mary represents  average  figures  drawn  from  protocols  regarding  endoge- 
nous creatinin  obtained  in  our  laboratory: 


Subject. 

Body  weight. 

Creatinin. 

Creatinin  per  kilo. 

Kilos. 

Grams. 

Milligrams. 

A.C. 

22 

0.37 

17 

P. 

27§ 

0.44 

16 

E.H.R. 

57 

1.10 

19 

R.H.C. 

57i 

0.87 

15 

G.M.B. 

6U 

1.17 

19 

O.E.C. 

62^ 

1.46* 

23* 

F.P.U. 

65 

1.21 

19 

L.B.M. 

70 

1.18 

17 

J.I. 

90 

1.87* 

21* 

*These  figures  represent  creatinin  plus  creatin. 


It  is  therefore  not  at  all  improbable  that  we  may  have  in  creatinin  a 
most  reliable  index  as  to  the  extent  of  certain  aspects  of  proteid  metab- 
olism— the  tissue  metabolism. 

Purins. — In  the  case  of  uric  acid  and  other  purin  derivatives,  it  is  appar- 
ent from  recent  studies  that  there  exists  likewi-se  a  twofold  source,  viz.,  an 
exogenous  source  related  to  the  foodstuffs  and  an  endogenous  one.  No 
convincing  e\ndence  has  yet  been  furnished  of  a  synthetic  formation  of  uric 
acid  in  man,  although  this  is  a  familiar  process  in  birds  and  reptiles  where 
uric  acid  represents  the  chief  end-product  of  nitrogenous  metabolism. 
The  exogenous  sources  of  uric  acid  production  are  found  in  all  those 
compounds  which  contain  the  purin  nucleus  in  a  form  in  which  it  can  be 
attacked  in  the  body.  They  include  especially  the  nucleoproteids  (nu- 
cleins)  occurring  abundantly  in  glandular  tissues  like  liver,  thymus,  kid- 
ney, etc.  To  this  may  be  added  the  free  purin  bases  like  hypoxanthin 
and  xanthin  which  are  present  in  tissue  extracts,  especially  in  the  muscle. 
In  smaller  quantity,  nucleic  acid  derivatives  and  purin  compounds  are 
found  in  vegetable  foods.  In  all  these  cases,  the  purin  group  is  either 
present  preformed  or  is  liberated  by  metabolic  (enzymatic)  changes  and 


GENERAL  CONSIDERATIONS  OF  METABOLISM  711 

then  oxidized  further  to  uric  acid,  and  in  much  smaller  proportion  appears 
in  the  form  of  other  purin  derivatives:  xanthin,  guanin,  hypoxanthin, 
adenin,  paraxanthin,  heteroxanthin,  etc.  But  even  on  a  purin-free  diet, 
or  during  starvation,  uric  acid  continues  to  be  eliminated  in  small, 
though  noteworthy,  amounts,  and  there  is  considerable  evidence  to  show 
that  this  endogenous  purin  output  is  a  fairly  constant  quantity  for  any 
individual,  whatever  the  character  of  the  (purin-free)  diet.  That  the 
body  is  not  entirely  destitute  of  the  power  to  form  nucleoproteids,  is  seen 
in  the  construction  of  these  compounds  in  the  developing  egg  and  in 
the  growing  infant  nourished  with  milk,  which  is  practically  purin-free. 
In  the  purin  metabolism  of  the  adult,  however,  food  purins  are  of  fore- 
most importance  and  the  synthetic  processes,  if  they  occur  at  all,  are 
inconspicuous. 

In  attempting  to  render  account  of  the  intermediary  metabolism  of 
the  purins,  it  is  apparent  at  once  that  we  have  to  deal  with  a  chemical 
transformation  which,  as  in  the  case  of  creatinin,  is  quite  independent 
of  urea  production  and  calls  for  a  special  interpretation.  For  many 
years  it  was  believed  that  uric  acid  represented  an  intermediate  stage  in 
the  katabolism  of  proteids  to  urea.  It  is  indeed  true  that  uric  acid  can 
readily  be  decomposed  so  as  to  yield  urea  and  such  a  process  doubtless 
occurs  when  uric  acid  is  broken  down  in  the  body.  Further  than  this 
the  relation  does  not  hold,  since  we  have  learned  to  recognize  chemical 
differences  in  the  nitrogenous  foodstuffs,  involving  the  presence  of  the 
purin  group  in  some,  and  an  entire  absence  of  it  in  others.  As  an  illus- 
tration of  this,  we  may  cite  experiments  of  our  own,  in  which  20  grams 
of  nitrogen  ingested  largely  in  the  form  of  sweetbread  (thymus  glands 
rich  in  nucleoproteid)  afforded  an  output  of  nearly  2.0  grams  of  uric 
acid,  whereas  the  same  quantity  of  nitrogen  taken  in  the  form  of  the 
purin-free  substances  yielded  only  0.3  gram  of  uric  acid  per  day.  The 
quantity  of  uric  acid  (and  other  purins)  eliminated  is  not  equivalent  to 
the  amount  ingested,  but  represents  only  a  fraction  of  it.  Simultaneously 
with  the  tissue  processes  which  result  in  the  oxidative  formation  of  uric 
acid,  a  destruction  of  the  latter  occurs;  so  that  the  quantity  of  uric  acid 
actually  excreted  represents  the  equilibrium  reached  between  the  forma- 
tion and  further  oxidation  of  that  compound.  Recent  studies  make  it 
probable  that  tissue  enzymes  cooperate  in  these  changes  in  various  ways. 
Nucleases  may  liberate  the  amino-purins,  adenin,  and  guanin,  from 
nucleoproteids  or  nucleic  acids;  amidases  (adenase  and  guanase)  trans- 
form these  amino-purins  to  hypoxanthin  and  xanthin  respectively;  and 
axidases  effect  an  oxidation  of  the  latter  to  uric  acid  and  even  further. 
All  of  these  reactions  have  been  demonstrated  with  various  tissue  ex- 
tracts; and  it  is  interesting  to  observe  that  whereas  many  tissues,  like 
the  liver,  testes,  etc.,  which  are  rich  in  nucleoproteids,  yield  adenin  and 
guanin  on  direct  hydrolysis  with  acids,  after  autolysis  they  afford  hypo- 
xanthin and  xanthin  in  place  of  the  amino-purins.  In  addition  to  this, 
liver  extracts  are  capable  of  oxidizing  added  xanthin  and  hypoxanthin 
to  uric  acid  through  intermediation  of  a  special  enzyme  (xanthinoxy- 
dase),  and  to  decompose  the  uric  acid  still  further.  A  special  influence 
on  purin  metabolism  was  at  one  time  attributed  to  the  spleen.  Experi- 
ments by  the  writers  have  failed  to  substantiate  such  a  view.  In  fact, 
there  is  no  evidence  that  the  spleen  exerts  any  special  influence  on  either 


712 


NUTRITION 


carbohydrate  or  proteid  metabolism  in  general.  The  liver  doubtless 
plays  an  important  role  in  these  reactions,  especially  in  the  destruction 
of  the  intermediary  uric  acid.  Herein  probably  lies  the  explanation  of 
the  increased  (or  at  least  undiminished)  output  of  vu'ic  acid  in  organic 
disturbances  of  the  liver,  involving  a  complete  or  partial  exclusion  of  its 
functions.  Thus,  too,  we  may  believe  that  substances  which  disturb 
these  functions,  as  alcohol,  facilitate  increased  uric  acid  output  by  dimin- 
ishing the  normal  katabolic  action.  At  any  rate,  the  organism  has  the 
capacity,  invested  no  doubt  in  difi'erent  tissues,  of  converting  food  purins 
into  uric  acid  which  nuiy  escape  destruction  and  be  excreted  as  such, 
or  may  be  further  oxidized.  When  the  latter  occurs,  allantoin  has  been 
demonstrated  as  a  characteristic  product,  rarely  arising  in  man,  however. 
It  is  not  unlikely  that  oxalic  acid  represents  a  further  intermediary  stage. 
The  relation  between  these  compounds  is  shown  below: 


HN— CO 

I      I 
OC      C— NH 


HN— CO 


OC 


CO 


HN— C— NH 
Uric  Acid. 


/ 


H.N 


CO 


HN— CH— NH 

Allantoin. 


NH, 


NH. 

Urea. 


COOH 


COOH 
Oxalic  Acid. 


The  purin  bases  which  serve  as  antecedents  of  endogenous  uric  acid 
have  been  supposed  to  arise  from  the  nucleoproteids  of  disintegrated 
cells,  in  particular  the  leukocytes.  As  a  matter  of  fact,  increased  elimi- 
nation of  uric  acid  has  been  observed  in  conditions  attended  with  pro- 
nounced leukocyte  destruction,  enormous  quantities  (5  grams  and  over) 
ha\dng  been  reported  in  cases  of  leukgemia.  If  we  may  trust  the  obser- 
vations of  Burian,  however,  the  greater  bulk  of  the  endogenous  purins  is 
formed  in  the  muscles,  thus  explaining  in  a  way  the  relative  constancy  of 
the  endogenous  uric  acid  production  in  the  same  individual  as  well  as  the 
variations  attributable  to  different  personality,  i.e.,  mass  of  active  tissue. 

Amino-acids. — The  hippuric  acid  CeHgCO.NH.CHaCOOH  in  human 
urine  originates  in  part  at  least  from  aromatic  substances  derived  from 
the  diet,  especially  fruits  and  vegetables.  Benzoic  acid  is  speedily  effective 
in  bringing  about  the  synthesis;  and  a  small  part  may  be  formed  indi- 
rectly tlirough  putrefactive  processes  in  the  intestine.  The  place  of  syn- 
thesis ai)pears  to  be  in  the  kidneys  as  well  as  other  tissues.  Theglycocoll 
required  to  conjugate  with  the  aromatic  radical  is  derived  from  proteids. 
In  fasting  animals  repeatedly  fed  with  benzoates,  the  amount  of  glycocoU 
eliminated  through  the  urine  as  hippuric  acid  (benzoyl-glycocoll),  com- 
pared with  the  total  nitrogen  metabolism,  indicates  that  4  grams  of  gly- 
cocoU may  be  derived  from  the  metabolism  of  every  100  grams  of  body 
proteid.  The  glycocoll  excretion  runs  parallel  with  the  proteid  destroyed. 
Feeding  carbohydrates  does  not  increase  the  formation  of  glycocoll;  but 
the  proportions  formed  after  feeding  gelatin  and  casein  are  between  3 
and  4  per  cent,  of  the  proteid  metabolized.  The  formation  of  glycocoll 
in  the  body  is  unquestioned;  and  the  significance  of  the  hippuric  acid 
eliminated  is  therefore  connected  with  the  origin  of  the  benzoic  acid. 

Of  the  sulphur  compounds  in  the  urine,  the  ethereal  sulphates  represent 
veliicles  of  elimination  for  different  conjugated  groups.    In  indican,  the 


GENERAL  CONSIDERATIONS  OF  METABOLISM  713 

organic  radical  is  derived  from  indol  formed  by  intestinal  putrefaction 
from  the  tryptophan  group  in  the  proteids.  In  accordance  with  this 
view,  Underhill  has  found  that  after  feeding  gelatin  (which  contains  no 
tryptophan  group)  in  place  of  ordinary  proteids,  the  excretion  of  indican 
is  greatly  diminished.  The  ethereal  sulphates  also  represent  other  organic 
radicals  Kke  phenyl  and  cresyl.  The  immediate  source  of  all  these  com- 
ponents is  not  yet  established.  The  inorganic  sulphates  appear  to  follow 
the  fluctuations  of  urea,  the  neutral  sulphur  on  the  other  hand  showing 
a  possible  connection  with  some  endogenous  proteid  katabolic  process. 

Pathology  has  furnished  several  illustrations  of  perverted  metabolism 
of  proteids,  which  throw  some  light  on  the  character  of  the  normal  inter- 
mediary changes.  In  alkaptonuria,  the  usual  destruction  of  the  aro- 
matic proteid  cleavage  products,  tyrosin  and  phenylalanin,  appears  to 
be  interfered  with.  IJnder  conditions  of  health  these  compounds  are 
completely  burned  in  the  body;  but  in  the  anomalous  condition  under 
consideration  they  leave  the  body  as  homogentisic  or  uroleucic  acid. 

That  the  "alkapton"  substances  owe  their  origin  to  the  aromatic  group 
of  the  proteid  molecule  is  evident  from  the  proportionate  relation  between 
homogentisic  acid  and  proteid  destruction,  and  the  fact  that  the  quan- 
tity of  the  acid  eliminated  after  a  diet  of  some  specific  proteid  substance 
is  generally  equivalent  to  the  amount  of  tyrosin  and  phenylalanin  yielded 
by  it.  Furthermore,  feeding  of  tyrosin  and  phenylalanin  to  patients 
with  alkaptonuria  is  followed  by  increased  output  of  homogentisic  acid, 
whereas  in  normal  individuals  these  aromatic  amino-acids  are  completely 
burned  up.  The  experimental  evidence  gives  no  support  to  the  idea  of 
an  abnormal  production  of  homogentisic  acid  from  proteids  in  this  dis- 
ease; but  rather  that  the  katabolism  of  the  aromatic  complexes  ordinarily 
proceeds  through  the  stages  above  described,  and  in  alkaptonuria  meets 
with  a  condition  where  the  final  cleavage  of  the  benzine  ring  represented 
in  homogentisic  acid  is  no  longer  possible  Accordingly,  the  healthy  in- 
dividual readily  burns  up  ingested  homogentisic  acid,  while  in  alkapto- 
nuria it  is  excreted  unchanged. 

Cystinuria  furnishes  another  pathological  condition  which  consists 
in  an  inability  to  burn  some  of  the  amino-acids  formed  in  intermediary 
metabolism,  notably  the  sulphur-containing  complex  of  the  proteids 
represented  by  cystin.  When  this  compound  is  fed  to  healthy  individuals 
in  quantities  as  large  as  8  grams,  it  is  completely  oxidized  and  the  sul- 
phur is  eliminated  in  the  form  of  sulphates  and  thiosulphates.  It  may 
in  part  be  converted  into  taurin  and  enter  into  the  composition  of  the 
bile  as  taurocholic  acid.  The  relation  of  proteids  to  the  production  of 
bile  salts  thus  becomes  clear  in  the  case  of  glycocholic  and  taurocholic 
acids,  since  the  origin  of  glycocoll  and  taurin  in  the  intermediary  metab- 
olism of  proteids  is  understood. 

Normally,  urine  is  free  from  cystin  even  when  the  latter  is  fed;  but 
when  cystin  is  given  to  cystinuric  patients  it  may  be  in  part  excreted 
again.  There  is  at  present  some  divergence  of  opinion  on  this  point. 
It  is  further  claimed  that  cystin  is  not  the  only  amino-acid  which  is  not 
burned  in  cystinuria;  in  some  cases  it  has  been  reported  that  ingested 
tyrosin  and  aspartic  acid  are  excreted  unchanged.  The  diamino-acids 
take  a  peculiar  position  in  the  metabolism  of  some  of  the  cystinuric  in- 
dividuals.    They  are  partly  split  up  with  liberation  of  carbon  dioxide 


714  NUTRITION 

and  reappear  as  diamines.  It  is  likely  that  this  change  is  attributable  to 
the  action  of  intestinal  bacteria,  so  that  the  diamines  are  absorbed  as 
such  from  the  intestine  and  eliminated  unchanged.  This  seems  the  more 
probable  because  the  diamines  here  concerned,  putrescin  and  cadaverin, 
have  been  produced  experimentally  by  the  action  of  bacteria  upon  the 
diamino-acids,  arginin  and  lysin,  and  the  diamines  are  found  in  the  fjeces 
as  well  as  the  urine  in  cystinuria.  Arginin  is  doubtless  first  converted 
into  urea  and  ornithin,  which  in  turn  is  transformed  into  putrescin  and 
carbon  dioxide.  The  interesting  cases  of  cystinuria  and  diaminuria  fre- 
quently found  combined  in  the  same  individual,  give  further  evidence  of 
stages  through  which  proteids  presumably  may  pass  in  their  normal 
katabolism,  and  at  which  tlie  decompositions  may  be  arrested  in  patho- 
logical conditions.  Further  evidence  of  the  formation  of  cystin  as  a 
normal  intermediary  stage  in  proteid  katabolism  has  been  afforded  by 
a  type  of  experimental  cystinuria  made  known  by  Baumann.  Dogs  fed 
with  brombenzol  excrete  the  so-called  mercapturic  acid,  which  readily 
yields  bromphenyl  cystein,  the  halogen  benzol  compound  apparently 
protecting  the  cystin  radical  from  oxidation.  Doubtless  there  are  vary- 
ing degrees  of  incapacity  for  the  katabolism  of  proteids  in  different 
patients,  just  as  we  have  different  degrees  of  inability  to  burn  sugar  in 
diabetics. 

Additional  evidence  regarding  the  occurrence  of  the  characteristic 
proteolytic  derivatives  as  stages  in  intermediary  metabolism  is  gradually 
accumulating.  Aside  from  the  typical  conditions  described  above,  there 
are  other  pathological  states  in  which  unoxidized  amino-acids  are  excreted 
in  complete  analogy  with  the  ideas  we  have  put  forward  regarding 
elimination  of  the  intermediary  products  of  carbohydrate  katabolism, 
exemplified  in  glycuronic  acid  and  oxalic  acid.  Thus,  in  acute  yellow 
atrophy  of  the  liver,  in  phosphorus  poisoning,  in  gout,  pneumonia,  and 
leukffimia,  tyrosin,  leucin,  glycocoll,  etc.,  have  been  isolated  from  the 
urine,  from  which  they  are  absent  in  health  even  when  introduced  as 
such  into  the  organism.  The  conditions  met  with  in  these  cases  may  be 
classed  as  jjerversions  or  disturhances  in  the  metabolism  of  the  amino-acids. 

We  have  seen  that  nucleoproteids  follow  transformations  in  metabo- 
lism somewhat  distinct  from  those  of  the  simpler  proteids,  the  character- 
istic differences  being  associated  with  the  purin  complexes  in  particular. 
It  is  not  unnatural,  therefore,  that  perversions  of  'puriji  metabolism 
should  occur.  The  phenomena  of  gout  have  long  been  associated  with 
such  disturbances,  and  the  discussion  of  the  pathology  of  this  condi- 
tion has  been  prominently  connected  with  the  behavior  of  uric  acid  in 
the  body,  though  with  somewhat  questionable  justification  at  times. 
It  would  be  unprofitable  to  review  the  enormous  literature  on  this  sub- 
ject here;  yet  it  is  impossible  to  make  any  concise  statements  which 
are  at  all  adequate  or  undebatable.  Certain  features  connected  with 
purin  metabolism  in  gout  deserve  mention.  The  particular  attention 
which  has  been  directed  to  uric  acid  in  this  connection  has  arisen  pri- 
marily from  the  fact  that  urate  depositions  unquestionably  are  found  in 
the  tissues  and  joints.  The  cause  for  this  is  quite  uncertain.  It  is  true 
that  the  blood  in  gout  has  been  found  to  be  richer  than  usual  in  dissolved 
uric  acid;  but  it  is  by  no  means  saturated  with  purin  compounds,  and 
from  this  point  of  view  no  apparent]  occasion  for  a  deposition  exists. 


GENERAL  CONSIDERATIONS  OF  METABOLISM  715 

Certain  it  is  that  both  in  experimental  gout  (produced  by  meat  feeding 
to  animals)  and  in  human  gout  the  liver  is  frequently  involved.  The 
important  influence  of  this  organ  has  been  noted  especially  by  the  writers 
in  studying  the  fate  of  uric  acid  injected  intravenously.  In  animals, 
allantoin  is  produced  in  this  way;  the  quantity  is  far  greater,  however, 
after  injection  directly  into  the  portal  circulation  than  into  a  systemic 
vein. 

Acute  attacks  of  gout  are  accompanied  by  marked  variations  in  the 
elimination  of  uric  acid,  a  retention  or  deposition  of  the  latter  being  fol- 
lowed by  a  sweeping  out,  as  it  were,  of  accumulated  urates.  In  many 
cases,  the  rate  of  uric  acid  elimination  after  a  meal  containing  meat  is 
greatly  altered  in  comparison  with  the  healthy  individual.  Questions  of 
solubility  may  be  concerned  herein.  Enough  has  been  said,  we  think, 
to  indicate  that  in  gout  it  is  not  so  much  a  disturbance  in  purin  metab- 
olism as  a  perverted  function  of  one  or  more  organs  and  tissues  which 
is  of  pathogenetic  moment. 

Before  leaving  the  subject  of  proteid  metabolism,  we  must  consider 
one  aspect  of  the  anabolism  of  proteid  which  frequently  attains  clinical 
importance.  Can  the  organism  build  or  store  up  proteid  elements  in  the 
form  of  flesh  (Fleischmast) ,  in  distinction  from  fattening.  As  a  contin- 
uous process  this  is  impossible  in  view  of  the  tendency  toward  nitrogen 
equilibrium  which  has  already  been  explained.  Otherwise  the  growth 
of  muscle,  for  example,  might  be  facilitated  enormously.  As  a  matter 
of  fact,  flesh  formation,  whether  directly  from  circulating  proteid,  or 
indirectly  from  proteid  cleavage  fragments,  can  at  times  be  accomplished. 
It  seems  to  depend  primarily  upon  the  nutritive  condition  of  the  cells 
rather  than  upon  any  surplus  of  food.  Proteid  tissue  anabolism  may 
take  place  in  the  muscles  as  it  is  seen  in  hypertrophy  induced  by  vigor- 
ous muscular  work;  it  is  characteristic  of  growth  in  the  developing 
organism;  and  can  also  be  induced  in  the  adult  organism  after  malnutri- 
tion or  undernourishment.  In  all  of  these  instances,  nitrogen  retention 
may  accompany  the  regeneration  of  the  protoplasm. 

Pathology  of  Nutrition. — In  outlining  the  more  important  features  in 
the  metabolism  of  proteids,  fats,  and  carbohydrates,  numerous  refer- 
ences have  been  made  to  pathological  variations  in  the  transformations 
which  these  compounds  undergo.  Thus,  the  bearing  of  gout  and  diabetes 
upon  the  metabolism  of  purins  and  carbohydrates  has  been  pointed  out; 
and  some  of  the  features  of  the  abnormal  katabolism  of  the  proteids 
illustrated  in  the  case  of  alkaptonuria,  cystinuria,  and  diaminuria.  In 
this  section  we  propose  to  consider  certain  more  general  and  unrelated 
phenomena  which  are  of  interest  in  the  study  of  the  pathology  of  nutrition. 

Autolysis  and  Intracellular  Enzymes. — The  recognition  of  the  im- 
portance of  enzymatic  processes,  and  the  increasing  acquaintance  with 
types  of  enzymes  capable  of  transacting  the  work  of  the  cells  under  physio- 
logical conditions,  has  directed  attention  to  the  possible  significance 
of  these  enzymes  in  pathological  processes.  As  certain  functional  acti%i- 
ties  have  long  been  associated  with  definite  morphological  structures, 
the  integrity  of  which  was  conceived  to  be  essential  for  their  work, 
pathology  has  depended  upon  structural  or  vague  "functional"  altera- 
tions to  account  for  the  unusual  or  abnormal.  But  since  proteolysis, 
lipolysis,  glycolysis,  oxidation,  deamidization,  are  all  referable  to  appro- 


716  NUTRITION 

priate  enz}Tnes,  some  of  which  seem  to  be  regulated  by  corresponding 
anti-enzymes  or  activated  by  kinases,  new  features  are  introduced  into 
the  study  of  pathological  manifestations.  In  a  system  of  coo])erating 
and  interdependent  chemical  reactions,  it  is  quite  conceivable  that  the 
impairment  or  omission  of  one  link  in  the  chain  may  throw  the  entire 
complex  out  of  gear.  The  autolysis  of  certain  tissues  in  disease  is  doubt- 
less associated  with  some  such  disturbance.  Autolytic  enzymes  are 
widely  distributed;  and  in  phosphorus  poisoning  and  acute  yellow 
atrophy  an  intravital  autolysis  of  the  liver  frequently  leads  to  a  softening 
of  that  organ,  with  fonnation  of  ty})ical  products  of  proteolysis.  In  car- 
cinoma, in  the  lungs  during  pneumonia,  in  abscess  formation,  and  espe- 
cially where  a  destruction  of  polynuclear  leukocytes  is  accompanied  by 
a  liberation  of  autolytic  enzymes,  autolytic  changes  may  take  place.  The 
proteolytic  products  are  then  further  destroyed  in  the  usual  ways,  or 
they  may  accumulate  in  the  blood  and  be  excreted  as  such.  Autolysis 
seems  to  be  the  effective  agent  in  the  destruction  or  metabolism  of  all 
necrotic  tissues.  The  occurrence  of  amino-acids,  like  leucin,  tyrosin, 
and  glycocoU  in  the  urine,  is  perhaps  attributable  in  some  cases  to  undue 
autolysis  which  is  checked  in  conditions  of  health.  It  is  not  unlikely 
that  analogous  changes  take  place  in  the  degeneration  of  nervous  tissue, 
by  which  cholin  is  liberated  from  lecithins.  As  further  peculiar  products 
of  tissue  self-digestion,  bactericidal  and  antitoxic  products  may  be  men- 
tioned; and  lately  the  lack  of  suitable  glycolytic  enzymes  has  been 
proclaimed  as  a  possible  cause  of  the  imperfect  utilization  of  sugars  in 
diabetes. 

Acidosis. — This  term  is  used  to  designate  a  pathological  condition 
clearly  pictured  by  Naunyn,  in  which  acids  arise  in  metabolism.  It  is 
not  easy  to  determine  in  every  case  whether  the  acid  owes  its  origin  to 
abnormal  formation,  or  to  imperfect  destruction  of  some  compound 
ordinarily  generated  in  intermediary  metabolism  and  at  once  subjected 
to  further  decomposition.  There  are  several  w^ays  in  which  these  acid 
products  may  become  a  source  of  harm.  They  are  likely  to  withdraw 
from  the  body  bases  in  combination  wuth  which  they  are  then  eliminated 
as  relatively  harmless  salts;  and  when  the  organism  is  overwhelmed 
with  large  quantities  of  these  unneutralized  organic  acids,  toxic  symp- 
toms may  be  occasioned.  The  most  interesting  feature  of  the  general 
condition  of  acidosis,  w'hatever  the  mode  of  its  generation,  is  the  accom- 
panying increased  elimination  of  ammonia.  This,  however,  does  not 
necessarily  signify  any  increased  production  of  ammonia  in  metabolism. 
Ammonia  is  the  acid  indicator  of  intermediary  metabolism.  When 
mineral  acids  are  introduced  into  the  body,  or  organic  acids  are  formed 
by  some  unusual  circumstance  within  it,  they  are  at  once  neutralized  by 
ammonia,  the  nitrogen  elimination  in  other  types  of  compounds  being 
correspondingly  diminished.  The  dangers  of  acid  intoxication  are 
thereby  avoided,  and  the  alkali  content  of  the  blood  and  tissues  pro- 
tected from  loss.  This  typical  behavior  of  ammonia  in  intermediary 
nitrogen  exchange  is  a  valuable  protective  reaction  for  the  organism; 
and,  conversely,  the  elimination  of  proportionately  large  quantities  of 
nitrogen,  in  the  form  of  ammonium  salts,  is  to  be  referred  not  to  any 
increased  katabolism  resulting  in  ammonia  production,  but  rather  to 
acids  which  have  neutraUzed  it  prior  to  its  conversion  into  urea.     Of 


GENERAL  CONSIDERATIONS  OF  METABOLISM  717 

possible  conditions  which  might  initiate  such  an  excretion  there  are 
many.  The  intermediary  production  of  lactic  acid,  /^-oxybutyric  acid, 
aceto-acetic  acid,  glycuronic  acid,  oxalic  acid,  etc.,  .suggests  the  types 
of  acid  compounds  which  may  be  formed.  It  has  already  been  sug- 
gested that  a  probable — perhaps  the  most  plausible — theory  of  the  origin  of 
these  compounds  is  one  which  refers  them  to  arrested  stages  in  normal 
katabolism.  Hence  they  are  wanting  in  the  healthy  organism.  Mineral 
acids  (phosphoric  and  sulphuric)  may  likewise  arise  in  metabolism.  As 
a  rule,  however,  the  quantity  of  these  is  far  too  small  to  account  for  the 
high  ammonia  output  in  many  pathological  conditions,  and  it  is  neces- 
sary to  assume  the  production  of  a  considerable  portion  of  organic  acids. 
There  are  even  cases  in  which  the  production  of  acids  is  sufficiently  large 
apparently  to  call  forth  a  destruction  of  proteid  in  order  to  furnish  suffi- 
cient ammonia  for  the  acidosis  presented. 

When  the  quantities  of  the  chief  bases,  sodium,  potassium,  calcium, 
magnesium,  and  ammonium,  and  the  chief  acids,  sulphuric,  phosphoric, 
hydrochloric,  and  uric,  eliminated  in  the  urine,  are  compared  or  "bal- 
anced," any  excess  of  the  sum  of  the  bases  over  the  equivalent  sum  of 
the  acids  may  at  once  be  referred  to  the  presence  of  unknown  organic 
acids.  In  diabetes,  where  the  carbohydrates  are  no  longer  burned  up, 
the  nutritive  demands  of  the  body  draw  upon  the  fat  supply  in  corre- 
spondence with  which  the  fat-content  of  the  blood  has  actually  been 
observed  to  be  higher  than  usual.  We  have  seen  that  /3-oxybutyric  acid 
and  its  derivatives,  aceto-acetic  acid  and  acetone,  may  arise  in  the  katab- 
olism of  the  fats.  The  diabetic  patient  in  the  advanced  stages  of  the 
disease  also  loses  his  capacity  to  burn  up^-oxybutyric  acid  in  contrast  with 
the  normal  individual  in  whom  it  is  readily  and  completely  oxidized. 
In  the  more  extreme  cases,  other  bases,  calcium,  magnesium,  even  potas- 
sium and  sodium,  may  contribute  to  the  "disintoxicating"  or  neutraliz- 
ing process,  and  the  body  may  be  robbed  of  its  bases  in  addition  to  losses 
of  proteid  katabolized  to  yield  ammonia.  The  lethal  symptoms  in  dia- 
betic coma  are  those  of  an  acid  intoxication,  while  loss  of  alkali  doubt- 
less plays  a  contributory  role  in  the  effects  produced.  A  severe  acid 
intoxication  tends  to  diminish  the  alkalinity  of  the  blood  markedly,  and 
the  carbon-dioxide  content  has  been  found  to  be  diminished  to  one-sixth 
or  less.  Furthermore,  the  physiological  capacity  for  excretion  by  the 
kidneys  is  not  infrequently  seriously  impaired,  so  that  imperfect  elimi- 
nation adds  to  the  gravity  of  the  situation. 

The  complications  of  perverted  intermediary  metabolism  are  far- 
reaching.  The  situation  in  diabetes  is,  perhaps,  somewhat  extreme, 
yet  sufficiently  characteristic  to  portray  the  salient  features  of  acidosis. 
It  is  well,  perhaps,  to  emphasize  the  fact  that  the  fundamental  disturb- 
ance is  a  nutritive  one.  Organic  acids  left  unburned  deplete  the  store 
of  available  bases.  They  may  unite  with  ammonia,  which  the  organism 
can  almost  always  furnish  with  liberality  when  the  proteid  of  the  diet 
is  present  in  customary  abundance,  or  which  it  can  requisition  by  in- 
creased katabolism  if  need  be.  Or  the  acids  may  unite  with  other  bases 
and  induce  a  new  series  of  nutritive  difficulties;  so  that  there  are  cases 
in  which  the  extent  of  ammonia  output  is  not  a  reliable  measure  of  the 
degree  of  acidosis.  In  such  instances  the  "balance"  of  acids  and  bases 
must  be  depended  on  for  more  reliable  indications. 


718  NUTRITION 

All  grades  of  acid  intoxication  may  be  observed.  Thus  Herter  be- 
lieves that  small  quantities  of  organic  acids  pass  from  the  blood  into 
the  urine  in  cases  of  dilatation  of  the  stomach  and  in  some  other  dis- 
orders of  digestion.  The  character  of  the  pathological  acid  or  acids 
has  not  been  made  out  here  with  certainty.  The  evidence  rests  upon  the 
observed  excess  of  known  bases  over  known  acids  in  the  urine.  It  is 
more  likely  that  any  organic  acid  formed  in  such  gastric  disturbance 
owes  its  origin  to  fermentative  processes,  than  to  some  obscure  meta- 
bolic disturl)ance  caused  by  toxic  protlucts  absorbed  from  the  gastro- 
intestinal tract. 

There  are  various  forms  of  hepatic  disease  accompanied  and  even 
characterized  by  the  chemical  symptoms  of  acidosis.  Cirrhosis,  degen- 
eration following  phosphorus  poisoning,  acute  yellow  atrophy,  and 
chronic  abnormality  of  the  liver,  differing  in  their  pathogenesis,  are  all 
characterized  by  relatively  high  proportions  of  ammonia-nitrogen  in  the 
urine.  The  characteristic  high  ammonia  elimination  in  liver  affections 
may  be  associated  with  an  inhibition  of  the  urea-forming  powers  of  the 
hepatic  cells.  Seldom  is  urea  absent  from  the  urine,  however;  and  the 
low  urea  output  may  equally  well  be  attributed,  in  the  experience  of  the 
writers,  to  the  small  proteid  intake  of  patients  suffering  from  serious 
hepatic  impairment.  Furthermore,  it  has  been  found  that  even  in  ad- 
vanced stages  of  hepatic  degeneration  ammonia  salts  administered  by 
mouth  can  still  be  converted  to  urea.  The  differences  which  the  meta- 
bolic disturbances  may  exhibit  under  changed  conditions  are  well  illus- 
trated by  the  distinction  between  the  phenomena  of  complete  liver 
elimination  in  animals  and  those  observed  after  production  of  the  Eck 
fistula.  When  the  liver  is  completeUj  excluded  from  the  circulation,  am- 
monia is  eliminated  in  abundance  and  urea  decreases,  as  is  true  in  Eck 
fistula  cases;  but  the  reaction  of  the  urine  becomes  markedly  acid,  and 
it  cannot  be  made  alkaline  even  by  administration  of  large  doses  of  soda, 
although  the  ammonia  output  is  thereby  diminished.  The  marked 
acidosis  is  presumably  attributable  to  other  acids  than  those  character- 
istic of  diabetic  derangement. 

In  many  cases  of  acidosis  the  factor  appears  to  be  lactic  acid,  to  which 
we  are  inclined  to  add  various  amino-acids — leucin,  tyrosin,  alanin, 
glycocoU — lately  isolated  from  the  urine  of  patients  with  severe  hepatic 
insufficiency.  Much  of  the  lactic  acid  doubtless  is  referable  to  carbo- 
hydrates; some  of  it  may  be  derived  indirectly  from  proteids.  Perfusion 
of  the  glycogen-yielding  livers  of  well-nourished  animals  with  blood 
results  in  a  production  of  lactic  acid — a  result  not  noted  when  glycogen- 
free  livers  from  starving  animals  are  used.  But  alanin,  a  proteid  deriva- 
tive, likewise  appears  to  form  lactic  acid  under  similar  conditions.  The 
relation  between  these  compounds  is  very  close.  Contrasting  these  facts 
with  the  presvmiable  origin  of  the  pathological  organic  acids  of  diabetic 
urine  from  fats,  it  appears  likely  that  acidosis  as  a  condition  can  be 
brought  about  through  imperfect  intermediary  metabolism  of  all  the 
types  of  foodstuffs — fats,  carbohydrates,  and  proteids. 

An  interesting  disturbance  of  metabolism  closely  related  to  the  phe- 
nomena of  typical  acidosis  has  been  disclosed  in  connection  with  imper- 
fect fat  absorption  from  the  intestine.  When  this  is  brought  about  by 
lack  of  bile  secretion  or  pancreatic  disease,  the  fatty  acids  liberated  in 


GENERAL  CONSIDERATIONS  OF  METABOLISM  719 

the  alimentary  tract  from  ingested  fats  appear  to  be  excreted  in  the  faeces 
in  increased  quantity  as  soaps  of  calcium  and  magnesium.  The  diver- 
sion of  these  alkali  earths  into  this  channel  of  elimination  occasions  dimin- 
ished excretion  of  them  in  the  urine.  Indirectly,  the  formation  of 
lime  soaps  leads  to  a  deficiency  of  alkali  and  a  compensatory  elimination 
of  ammonia — phenomena  characteristic  of  acidosis  in  metabolism.  It 
has  been  suggested  that  the  high  ammonia  output  of  infants  suffer- 
ing from  gastro-intestinal  disturbances  may  be  directly  attributable 
to  disturbed  absorption  of  fat  with  the  chain  of  consequences  just 
outlined. 

Obesity. — ^The  physiology  of  fat  formation  and  deposition  in  the  body 
has  already  been  considered.  It  is  indeed  difficult  to  say  to  what  extent, 
if  at  all,  corpulence  represents  a  pathological  condition;  at  any  rate  from 
a  metabolic  point  of  view  the  body  is  concerned  here  simply  with  an  ex- 
aggeration of  normal  processes.  When  once  a  beginning  has  been  made, 
the  conditions  thereby  developed  tend  to  perpetuate  and  aggravate  the 
difficulties  encountered.  Thus  with  increase  in  weight  and  growing 
corpulence  the  body  becomes  less  and  less  capable  of  active  exertion, 
which  in  itself  is  conducive  to  further  storage  of  fat.  As  the  corpulence 
increases  the  muscles  tend  to  be  brought  less  into  use,  and  the  lack  of 
exercise  in  turn  tends  to  weaken  them  and  render  them  still  more  unfit 
for  work.  The  conservation  of  body  warmth  by  the  highly  developed 
panniculus,  the  low  metabolism  of  energy  called  forth  by  the  attendant 
slothfulness,  in  addition  to  the  abundant  food  intake  in  the  corpulent, 
all  contribute  to  protect  the  body  fat.  A  cumulative  effect  thus  induced 
can  only  be  counteracted  by  a  restricted  intake  and  increased  exercise, 
the  latter  being  difficult  because  of  the  discomfort  which  it  occasions. 
Alcohol  plays  a  contributory  part  by  affording  a  readily  combustible 
compound  which  may  speedily  experience  oxidation  and  protect  the 
body-fat;  and  further,  its  pharmacological  action  is  such  as  to  contribute 
to  the  general  indifference  and  inactivity  characteristic  of  obesity. 

These  factors  will  be  seen  to  be  strictly  within  the  province  of  normal 
physiological  behavior.  It  has  often  been  asked  whether  other  elements 
do  not  contribute  to  the  development  of  obesity.  A  hereditary  tendency 
cannot  be  denied.  The  common  observation  of  absence  of  any  tendency 
toward  corpulence  in^  many  individuals  who  eat  very  heartily  and  culti- 
vate no  unusual  degree  of  muscular  exertion  leads  one  to  ask  whether 
the  obese  transform  the  potential  energy  of  their  foods  more  advanta- 
geously, or  are  subject  to  functionally  diminished  oxidative  powers. 
Experiments  have  demonstrated  conclusively  that  this  is  not  the  case. 
The  oxygen  consumption  and  carbon  dioxide  production  of  corpulent 
subjects  is  precisely  comparable  with  that  of  non-corpulent  individuals 
of  the  same  weight.  Even  the  supposedly  "constitutional"  obesity 
which  is  seen  in  castrated  animals  is  referable  to  the  lesser  bodily 
activity.  Finally,  an  influence  on  the  part  of  the  nervous  system  cannot 
be  denied.  As  Miiller  expresses  it,  a  vigorous  individual  whose  spirit 
enters  into  continuous  excitement  and  activity  is  certain  to  set  his 
muscles  into  action  to  a  far  greater  extent  than  the  phlegmatic  person 
who  moves  only  when  compelled. 

Malnutrition  and  Related  Conditions. — Ordinarily  the  disturbances 
noted  are  referable  to  variations  in  the  quantitative  relations  of  nutri- 


720  NUTRITION 

tion.  As  soon  as  qualitative  changes  arise  the  term  malnutrition  is  more 
appropriately  applied  to  the  distinctly  morbid  states,  and  here  the 
phenomena  of  autolysis,  acidosis,  protoplasmic  disintegration  and  re- 
tarded katabolism  of  specific  molecular  complexes  are  met  with.  As 
regards  the  relation  of  fever  to  metabolism,  the  etiological  and  clinical 
conditions  arc  too  diverse  to  permit  any  general  theory.  Fevers  are 
usually  accompanied  by  a  noteworthy  increase  in  proteid  katabolism 
which  contributes  not  a  little  to  the  serious  physical  impairment  so  often 
brought  about.  Undoubtedly  it  is  quite  correct  to  attribute  this  to  a 
sort  of  involuntary  inanition,  but  we  believe  that  this  alone  is  insuffi- 
cient to  account  for  all  the  disturbances  of  metabolism  associated  with 
fevers.  Toxic  ])roducts  of  bacterial  or  bodily  origin  undoubtedly  may 
exert  a  direct  action  on  tissue  katabolism.  In  so-called  "aseptic"  fevers 
the  glycogen-content  of  the  body  ai)pears  to  determine  in  no  small  meas- 
ure the  possibility  of  the  rise  in  temperature.  That  the  processes  of  inter- 
mediary metabolism  may  suffer  qualitative  disturbances  is  suggested  by 
experiments  like  those  of  INIandel  on  the  purin  bases  in  aseptic  fevers. 
A  pronounced  coincidence  between  the  temperature  and  the  purin  bases 
has  been  observed;  the  quantity  of  uric  acid  eliminated  varies  with  the 
alloxuric  bases;  that  is,  the  latter  increase  in  amount  as  the  quantity  of 
uric  acid  diminishes,  and  vice  versa.  It  is  therefore  not  unlikely  that  a 
distinct  relation  between  the  fever  and  the  appearance  of  certain  pro- 
ducts of  incomplete  cell  oxidation,  as  shown  by  the  excretion  of  purin  bases, 
exists.  The  supposition  that  these  bodies  are  directly  concerned  in  the 
production  of  fevers  is  strengthened  by  the  fact  that  the  administration 
of  xanthin  and  caffeine  produces  a  decided  rise  in  body  temperature  in 
otherwise  healthy  individuals.  Without  attributing  to  the  purin  bases 
the  sole  cause  of  the  febrile  temperature  in  the  "aseptic"  cases,  it  may 
be  safe  to  assume  that  if  other  substances  are  concerned  they  are  of  sim- 
ilar origin  and  nature,  i.  e.,  intermediary  products  of  metabolism,  the 
source  of  which  is  to  be  looked  for  in  the  circulating  leukocytes  and 
tissue  cells.  "We  may  assume  that  in  a  number  of  pathological  conditions 
the  ability  of  the  cells  of  the  organism  to  oxidize -certain  substances  is 
directly  interfered  with.  Probably  this  applies  to  the  so-called  aseptic 
fevers  as,  for  instance,  rise  of  temperature  after  severe  operations,  anaes- 
thesia, convulsions,  poisons,  cachexias  of  various  forms.  In  all  these 
disturbances  we  may  suppose  that  temporary  or  more  permanent  injuries 
to  the  cells  inhibit  their  oxidation  ability  for  a  shorter  or  longer  period; 
the  consequences  will  necessarily  be  less  complete  oxidation  of  sub- 
stances to  their  proper  end-products."    (Mandel.) 

A  further  specific  factor  is  the  continued  new  formation  and  simulta- 
neous destruction  of  cells  in  inflamed  areas.  Wlaere  exudates  are  formed 
in  considerable  quantity  an  unusual  addition  may  be  made  to  the  "circu- 
lating" proteid  of  the  body;  in  such  cases  the  body  metabolizes  the  excess 
of  proteid  just  as  when  an  excess  of  the  latter  is  furnished  in  the  form  of 
food.  To  what  degree  the  disturbed  thermogenic  functions  influence 
katabolism  in  fever  is  not  determined  beyond  dispute.  A  retention  of 
chlorides  accompanying  the  increased  proteid  decomposition  has  been  re- 
ported in  many  infectious  diseases,  like  pneumonia  and  typhoid,  which  are 
attended  with  fever.  It  is  not  unlikely,  however,  that  in  most  of  these 
cases  the  deficient  salt  intake  is  the  contributing  cause.     A  marked  acido- 


GENERAL  CONSIDERATIONS  OF  METABOLISM  721 

sis,  especially  intense  in  infancy,  frequently  adds  to  the  complications 
which  metabolism  experiences  in  fever. 

Indicanuria  can  scarcely  be  spoken  of  as  a  disturbance  of  intermediary 
metaboUsm,  inasmuch  as  the  primary  cause  usually  lies  in  the  preliminary 
putrefactive  decomposition  which  the  foodstuffs  undergo  before  leaving 
the  alimentary  tract.  The  products  of  putrefaction,  indol,  skatol,  phenol, 
and  cresol,  are  synthesized  in  the  liver  to  ethereal  sulphates  orglycuron- 
ates.  The  question  as  to  whether  the  indol  derivative  indican  cannot  also 
arise  in  intermediary  metabolism — in  cases  which  are  characterized  by 
vigorous  tissue  decomposition  as  in  certain  types  of  cachexia,  in  carci- 
noma of  the  stomach,  etc. — has  been  actively  discussed.  We  agree  with 
Jaffe  in  concluding  that  the  experimental  evidence  for  a  direct  meta- 
bolic origin  of  indican  is  not  convincing.  At  present  no  positive  source  of 
urinary  indican  is  laiown  outside  of  bacterial  processes.  The  patho- 
gnomic significance  of  indicanuria  (indoxyluria)  is  therefore  restricted  to 
the  domain  of  those  diseases  which  are  attended  with  bacterial  activity, 
either  within  or  without  the  alimentary  tract. 


DIET  AND  DIETETICS. 

The  subject  of  dietetics  has  for  its  consideration  the  nutritive  demands 
of  the  body  in  health  and  disease,  and  the  conditions  and  means  whereby 
they  may  satisfactorily  be  fulfilled.  The  problems  are  manifold;  for  the 
needs  of  an  organism  vary  with  the  conditions  to  which  it  is  subjected,  and 
the  response  of  the  individual  has  been  modified  in  no  small  degree  by  uni- 
versal custom  or  personal  tastes,  as  well  as  by  his  environment.  The  ideal 
diet  for  a  healthy  man  is  one  which  will  maintain  him  in  nutritive  equilib- 
rium. The  physician,  however,  not  infrequently  has  occasion  to  depart 
from  the  limits  here  proposed,  when  he  aims  to  accomplish  beneficial 
effects  by  overfeeding  or  by  an  insufficient  diet. 

The  physiological  demands  of  the  body  can  be  determined  by  direct  ex- 
periment and  expressed  in  somewhat  general  terms;  as,  for  example,  the 
total  energy  required  to  preserve  the  chemical  integrity  of  the  body  and 
maintain  its  functions.  The  necessity  for  a  mixed  diet  and  the  inade- 
quacy of  a  diet  composed  exclusively  of  proteids  have  been  explained.  It 
need  scarcely  be  repeated  that  chemical  composition  is,  of  itself,  no  safe 
criterion  of  the  food  value  of  any  nutrient.  The  digestibility  and  conse- 
quent availability  of  the  nutrients  bear  directly  upon  their  dietetic  value, 
and  these  factors  are  influenced  in  no  small  measure  by  physical  condi- 
tions. Herein  lies  the  significance  of  the  natural  texture  of  the  food 
substances,  their  preparation  by  cooking  and  mechanical  processes,  the 
palatability  of  the  product,  and  tolerance  of  the  organism  for  it. 

Up  to  the  present  time  the  statements  regarding  the  dietetic  needs  of  the 
body  have  been  based  very  largely  on  the  observed  facts  of  consumption 
rather  than  upon  actual  trials.  The  statistical  method  has  been  applied, 
in  order  to  learn  the  kinds  and  amounts  of  food  materials  consumed  by 
persons  in  different  localities,  of  different  occupations,  ages  and  sex,  and 
under  varying  conditions.  From  such  data  dietary  standards  have  been 
suggested,  upon  the  general  supposition  that  the  body  is  best  nourished 
when  through  long  periods  the  food  approximates  the  requirements  thus 

46 


722 


NUTRITION 


■a\\\v.\  loiij 


^   Oi  o  o 


in  10  o  >o       o  o 

rtiO  — C4  IMOO 

Tji  CC'  »  05  C-l  lO 


U5"OiOOQO'0  0000'OiO 
O  C-)  '^  C  O  lO  W  C  C")  CC  OC'  'O  05 


Pi 

U 
PL, 

s 


H 

o 

W 
K 
E-i 


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•)1'J 


Cl'OOiOOSi-lCJOOt^OiO 


•uiaioj^i 


05'0MO  OCO  CO 

C005CS*-*  Oi05  o 


sajBjp 
-Xi[oqai!3 


Tt"  —  o        ■*•:(<  CO  'O        Tji  ^        CO 


oo 
•*co 


oM(^iioo-*oofocnoot~(N 

C0'*05'*!010i-li-IC0OM>C0'-l 

^  ■<}<  CO  CO o:)  w  -ji  cc  CI  lO  o  iM  00 


•?t;j 


a     .-1  ,-1  CO  rH  .-H  .-I  T 


(M  C5  -^  QC  ^  0>  CO  '^  CO  O  i.O  CI  t>. 
CCOr-HiCOi-iOt^-^t^OOCO 


•uiajojj 


C-l  C:  CO  CO  lO  O  r~  Tjl  lO  lO  •:(<  O  Cl 
COOO^'-'OCOOl'-HCO-tiCCO 


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papnpu!  saipnjs 

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OX! 
O  C3 


a  s  B  oi  c ' 

o  o  g-u  §3. 2.2 

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<a  a  <A  Z  o-S  3^ 


^^j|a 

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GENERAL  CONSIDERATIONS  OF  METABOLISM 


723 


established.  In  the  compilation  of  much  of  this  valuable  statistical 
material  the  United  States  Department  of  Agriculture  has  rendered  an 
important  service.  An  illustration  of  the  results  reached  by  this  method 
is  given  in  the  table  on  page  722  (Langworthy  and  Milner). 

Data  such  as  the  foregoing  compilations  afford,  merely  disclose  the 
dietetic  habits  of  these  individuals.  It  is  unfortunate  that  more  facts  de- 
rived from  actual  studies  of  metabolism  are  not  yet  available,  so  that  wide- 
reaching  application  cannot  be  made,  based  upon  'physiological  conditions; 
for  it  has  become  somewhat  questionable  whether  the  current  statistical 
standards  represent  the  true  needs  of  the  organism.  Custom  and  con- 
venience have  entered  so  largely  into  our  modes  of  living  and  dictated  so 
much  in  our  alimentary  habits,  that  we  may  be  in  danger  of  accepting 
their  dictum  as  a  physiological  law  without  that  critical  revision  which 
scientific  consistency  demands.  A  further  error  lies  in  the  customary 
failure  to  pay  sufficient  regard  to  the  variations  in  the  size  of  different 
individuals  and  the  consequent  variations  in  the  extent  of  metabolism 
occasioned  thereby.  Making  allowances  for  variations  in  body  weight, 
Rubner  has  calculated  the  nutritive  requirements  of  persons  of  different 
sizes  and  the  relative  participation  of  the  various  foodstuffs  as  follows : 


Body  weight. 

Energy 
metabolized. 

Proteids. 

Fats. 

Carbohydrates. 

Kilograms. 

Calories  (large). 

Grams. 

Grams. 

Grams. 

80 

2864 

134 

49 

356 

Light           ^0 
work          ^^ 

2631 

123 

46 

327 

2368 

111 

41 

294 

2102 

90 

37 

262 

.  40 

1810 

84 

32 

225 

f  80 

3372 

128 

61 

556 

70 

Moderate    J  .^r. 

work           ^0 

3094 

2792 

118 
106 

56 
60 

500 
461 

2472 

96 

44 

409 

.  40 

2129 

81 

38 

344 

The  peculiar  role  of  proteids  has  lent  a  special  interest  and  import- 
ance to  the  determination  of  the  daily  requirement  of  this  group  of  food- 
stuffs. We  have  already  seen  that  proteids  are  not  drawn  upon  under 
ordinary  conditions  as  sources  of  energy  when  muscular  work  is  done,  and 
that  they  differ  from  the  other  nutrients  in  showing  no  tendency  toward 
storage  in  the  body  beyond  certain  very  narrow  limits.  In  recent  years 
considerable  attention  has  been  devoted  to  the  determination  of  the  mini- 
mum proteid  requirement  of  the  organism.  It  seems  self-evident  regard- 
ing the  albuminous  foods  in  particular,  that  the  smallest  amount  which 
will  serve  to  keep  the  body  in  a  state  of  high  efficiency  is  physiologically 
the  most  economical,  and  hence  the  best  adapted  for  its  needs.  In  the 
dietary  standards  which  have  been  proposed  the  well-known  figures  of 
Voit  have  experienced  only  slight  revision.  For  the  proteid  elements  in 
particular  the  requirements  adopted  by  Voit  have  rarely  been  regarded 
as  excessive.  In  the  table  on  page  724  are  the  figures  representing 
dietary  standards  advocated  or  determined  by  different  investigators. 

The  figures  given  for  the  most  part  represent  opinions  formed 
from  the  data  gained  by  direct  analysis  of  the  diets  used.     Can  these 


724 


NUTRITION 


figures  be  taken  to  represent  tlie  minimal  proteid  requirement  for  the 
healthy  man?  If  not,  how  far  ean  the  proteid  intake  be  safely  and  advan- 
tageously diminished  below  the  eommonly  aeeepted  standards? 


Investigator. 


Voit 

Moleschott 

Ranke 

Forster  (Munich  workmen).  . 
Hultgren     ami     Landergren 

(Swedisli  workmen)      

Studemiind 

Sclimidt 

de  Giaxa  (Venetian  peasants) 
Erisman  (Russian  workmen) 
Atwater    (moderate   muscular 

work) 

Atwater  (very  liard  muscular 

work)  

Rubner  (Turkish  peasants) .  .  . 

Gautier  (without  work) 

Gautier  (hard  work) 


Proteids. 


Grams. 

lis 

130 
100 
132 

134 
114 

ior> 
lis 

132 

125 

175 

15(i 

7S 

1(17 


Carbohydrates. 


Grams. 

500 
550 
240 
457 

523 

551 
541 
020 
5S4 


7()1 
4SS 
092 


Fats. 


Grams. 

5(5 

40 

100 

SI 

79 
54 
03 
()4 
SO 


109 
50 

71 


Fuel  value. 


Calories  (targe). 

3000 
3100 
2324 
3174 

343G 
3229 
3235 
3623 
3G75 

3400 

5500 
477G 
2800 
4200 


*With  fat  and  carbohydrate  sufficient  to  furnish  the  total  energy  indicated. 

Obviously  any  attempt  to  determine  the  minimal  proteid  requirement 
on  the  basis  of  the  nitrogen  output  in  starvation  may  lead  to  error.  For 
the  energy  requirements  of  the  body  must  be  met  at  any  expense;  and  in 
the  absence  of  other  supply,  tissue  proteid  may  be  destroyed  far  beyond 
the  actual  katabolism  necessary  when  other  suitable  nutrients  are  fur- 
nished. The  Ijlood  sugar  for  example  must  be  maintained  under  all  cir- 
cumstances. Landergren  has  studied  the  extent  of  proteid  katabolism  in 
proteid  starvation  with  and  without  an  abundant  diet  of  fat  or  carbohy- 
drate. His  experiments  indicate  that  a  healthy  man  receiving  an  abun- 
danceof  non-nitrogenous  nutrients,  but  practically  no  proteids,  katabolizes 
proteid  represented  by  no  more  than  3  to  4  grams  of  nitrogen  per 
day.  In  combined  proteid  and  carbohydrate  starvation,  the  katabolism 
of  body  proteid  may  exceed  that  just  noted  by  100  per  cent.,  despite  a  large 
intake  of  energy  in  the  form  of  fat.  From  this  it  would  appear  that  a  cer- 
tain minimum  of  carbohydrate,  as  well  as  proteid,  is  necessary  for  the 
maintenance  of  the  sugar-content  of  the  blood.  As  soon  as  stored  carbo- 
hydrate (glycogen)  is  no  longer  available,  sufficient  proteid  is  destroyed  to 
furnish  the  desired  materials,  the  nitrogenous  moiety  being  simultaneously 
eliminated  as  useless.  If  this  is  true,  then  there  is  a  limit  to  the  extent  to 
which  fats  can  replace  carbohydrates  in  isodynamic  amounts;  and  with 
this,  experience  corresponds.  But  with  a  certain  as  yet  undefined  mini- 
mum of  carbohydrate  given,  fat  and  carbohydrates  can  replace  each  other 
in  proteid-sparing  effects;  whereas  in  the  absence  of  all  carbohydrate,  fats 
are  proteid  sparing  in  lesser  degree.  In  starvation,  according  to  Lander- 
gren, a  third  or  more  of  the  proteid  decomposition  is  occasioned  by  the 
body's  demand  for  carbohydrate — ^which  the  proteids  alone  can  satisfy  in 
this  case. 

From  what  has  just  been  stated  it  follows  that  the  minimum  proteid 
requirement  of  man  can  only  be  determined  correctly  when  due  regard  is 
had  for  the  appropriate  supply  of  non-nitrogenous  as  well  as  proteid  nutri- 


GENERAL  CONSIDERATIONS  OF  METABOLISM  725 

ents;  and  the  condition  of  hunger  fails  to  afford  this  opportunity.  Trials 
have  been  made  to  attain  nitrogen  (proteid)  equilibrium  with  diminished 
proteid  intake.  Not  a  few  experiments  have  been  unsatisfactory  because 
the  total  nutritive  demands  of  the  body  were  not  satisfied  by  exhibition  of 
adequate  quantities  of  fats  and  carbohydrates.  It  requires  no  argument 
to  show  that  impairment  of  the  body  must  sooner  or  later  follow  any  con- 
tinued insufficiency  in  the  total  supply  of  energy  in  the  form  of  food. 
Nevertheless,  not  a  few  experiments  on  record  have  indicated  the  possibil- 
ity of  maintaining  both  nitrogenous  and  bodily  equilibrium  on  an  intake 
of  proteid  considerably  smaller  than  that  recognized  in  the  so-called  diet- 
ary standards.  Usually  this  has  been  accomplished  only  when  a  fairly 
large  amount  of  non-nitrogenous  food  was  consumed.  Kumagawa, 
weighing  48  kilos,  maintained  nitrogen  equilibrium  for  some  days  on  an 
intake  including  only  55  grams  of  proteid  and  a  total  fuel  value  of  2,480 
large  calories.  The  daily  average  nitrogen  eUmination  through  the  urine 
was  6  grams,  through  the  freces  2  grams.  The  diet  was  purely  vegetable. 
Breisacher,  in  experiments  on  himself  extending  over  thirty  days,  found 
that  an  estimated  intake  of  2,600  calories  in  the  daily  diet  sufficed  to  main- 
tain him  in  nutritive  equilibrium  with  an  average  daily  nitrogen  excretion 
of  about  8  grams.  Peschel  obtained  a  satisfactory  nitrogen  balance 
for  a  brief  period  with  7  grams  of  nitrogen  daily  in  the  food,  5.3  grams 
appearing  in  the  urine  and  1 .6  grams  in  the  fseces.  Likewise,  Caspari  and 
Glaessner  in  a  five-days'  experiment  with  two  vegetarians  noted  no  loss  of 
nitrogen  on  intakes  of  5.3  and  7.8  grams  of  nitrogen,  and  2,700  and  4,560 
calories  respectively.  More  important  are  the  experiments  which  Siven 
conducted  on  himself.  With  a  body  weight  of  60  kilos,  he  was  able,  in 
trials  extending  through  a  month,  to  estabUsh  nitrogenous  equilibrium  on 
6.26  grams  of  nitrogen  with  comparatively  low  total  intake  of  food,  amount- 
ing to  about  2,500  calories. 

Such  data  as  these  surely  warrant  the  question.  How  far  are  w^e  justified 
in  assuming  the  necessity  for  the  rich  proteid  diet  called  for  by  the  Voit 
standard  and  those  like  it?  It  is  repeatedly  stated  that  an  abundance  of 
food  is  a  necessity  for  the  maintenance  of  physical  vigor  and  muscular 
activity.  This  view  is  certainly  reinforced  by  the  customs  and  habits  of 
mankind;  but  we  may  well  query  whether  our  dietetic  habits  will  bear 
criticism,  and  in  the  light  of  modem  scientific  inquiry  we  may  even  express 
doubt  as  to  whether  a  rich  proteid  diet  adds  anything  to  our  muscular 
energy  or  bodily  strength. 

The  experiments  hitherto  reported  have  been  continued  only  for  brief 
periods;  and  recalling  the  marked  resistance  of  the  healthy  body  it  would 
be  amiss  to  draw  any  far-reaching  conclusions  from  observations  of  this 
character.  Further,  attention  must  be  given  to  the  unfavorable  effects 
which  have  been  attributed  to  a  low  proteid  diet  fed  to  dogs  for  some  time. 
Thus,  Munk  and  Rosenheim  both  noted  after  six  to  eight  weeks  a  loss  of 
the  power  of  absorption  from  the  aUmentary  tract,  loss  of  body  weight, 
strength,  and  vigor,  followed  by  death.  Jagerroos  likewise  observed  that 
there  was  after  some  months  a  striking  disturbance  of  the  intestines  on  a 
low  proteid  intake,  which  was,  however,  eventually  traced  to  a  distinct 
infection  and  probably  not  connected  with  the  diminished  quantity  of  pro- 
teid in  the  diet.  One  is  impressed,  in  the  study  of  these  animal  experi- 
ments, with  the  abnormal  if  not  unhygienic  conditions  under  which  the 


726  K'UTRITIOX 

dogs  were  kept.  The  great  monotony  in  the  diet  and  restricted  quar- 
ters to  which  they  were  subjected  makes  it  higlily  riuestiouable 
whether  the  diet  of  the  aninuUs  was  responsible  for  their  poor  heaUh 
in  the  sense  in  which  it  lias  usually  been  interpreted.  In  prolonged 
experiments  over  seven  hundred  days  on  man,  Neunuuin  has  found  70 
to  80  grams  of  proteid  i)cr  day  to  suffice  for  the  nuiintenancc  ration,  even 
with  moderate  additional  food  intake  of  90  grams  of  fat  and  300  grams 
of  carbohydrate.  He  inclines  to  the  belief  that  nitrogenous  equilibrium 
can  be  maintained  on  various  nutritive  planes.  Vegetarians  have  lived  for 
years  on  a  diet  relatively  poor  in  proteids  without  observing  any  dis- 
agreeable effects.  Jaffa's  observations  on  the  fruitarians  and  nutarians 
of  California  "showed  in  every  case  that  though  the  diet  luul  a  low  protein 
and  energy  value,  the  subjects  were  a])parcntly  in  excellent  health  and  had 
been  so  during  the  five  to  eight  years  they  had  been  living  in  this  manner. " 
In  comparing  the  income  and  outgo  of  nitrogen,  on  a  diet  composed  maiidy 
of  nuts  and  fruits,  it  was  observed  in  2  subjects  that  8  grams  of  nitro- 
gen were  sufficient  to  bring  about  nitrogen  equilibrium,  while  Avith  2 
other  subjects  the  nitrogen  required  daily  for  ecjuilibrium  was  about  10 
grams.  In  harmony  with  Siven,  Jaffa  beheves  that  after  the  body  has  suf- 
fered a  loss  of  nitrogen  there  is  at  once  an  effort  to  attain  nitrogenous 
equilibrium,  and  that  any  gain  of  nitrogenous  body  material  is  a  compara- 
tively slow  progress.  If  this  is  true,  it  is  obvious  that  the  living  substance 
of  the  tissue  protoplasm  must  be  slowly  formed  from  the  proteid  of  the 
diet.  This,  says  Jaffa,  should  serve  as  a  warning  to  anyone  contem- 
plating any  appreciable  decrease  in  the  proteid  of  the  daily  diet. 

A  further  statement  made  by  Jaffa  serves  to  illustrate  the  attitude 
taken  by  many  physiologists  on  this  question.  "Even  if  it  could  be 
proved,"  he  writes,  "by  a  large  number  of  experiments  that  nitrogen 
equihbrium  can  be  maintained  on  a  small  amount  of  protein,  it  would 
still  be  a  great  question  wdiether  or  not  it  would  be  wise  to  do  so.  There 
must  certainly  be  a  constant  effort  on  the  part  of  the  human  organism 
to  attain  this  condition,  and  with  a  low  protein  supply  it  might  be  forced 
to  do  so  under  conditions  of  strain.  In  such  a  case  the  bad  results  might 
be  slow  in  manifesting  themselves,  but  might  also  be  serious  and  lasting. 
It  has  also  been  suggested  that  when  living  at  a  fairly  high  protein  level 
the  body  is  more  resistant  to  disease  and  other  strains  than  when  the 
protein  level  is  low."  While  these  suggestions  merit  careful  considera- 
tion, it  is  equally  evident  that  there  is  another  side  to  the  question.  The 
elimination  of  the  excess  of  nitrogen  may  become  physiologically  burden- 
some and  uneconomical,  if  not  positively  harmful.  Hence,  we  may  well 
query  on  which  side  lies  the  greater  danger  without  magnifying  it  on 
the  one  hand  or  suppressing  efforts  directed  toward  the  true  proteid 
minimum  on  the  other. 

With  the  purpose  of  throwing  light  upon  the  question  of  the  proteid 
minimum  and  ascertaining  how  far,  if  at  all,  the  intake  of  proteid  food 
can  be  diminished  without  deleterious  effects,  an  extensive  series  of  ex- 
periments on  man  has  been  conducted  in  the  laboratory  of  the  writers. 
Recognizing  that  the  maintenance  of  nitrogen  and  body  equilibrium  on 
a  lower  proteid  standard  than  that  generally  adopted  would  have  little 
practical  value  and  would  not  escape  justifiable  criticism  uidess  the 
period  of  trial  was  extended  over  a  long  time,  arrangements  were  made 


GENERAL  CONSIDERATIONS  OF  METABOLISM  727 

to  realize  this  as  far  as  possil^le.  The  experiments  were  conducted  upon 
three  distinct  types  of  mdividuals:  (1)  Professional  men  who  while 
leading  active  lives  were  not  engaged  in  very  active  muscular  work. 
They  represent  the  mental  rather  than  the  physical  worker.  (2)  A 
detail  of  men  from  the  Hospital  Corps  of  the  United  States  Army,  as  repre- 
sentatives of  the  moderate  worker.  These  men,  of  different  ages  and  tem- 
peraments, took  vigorous  systematic  exercise  in  addition  to  the  routine 
work  connected  with  their  daily  life  as  members  of  the  hospital  corps. 
(3)  A  group  of  university  students  who  were  thoroughly  trained  athletes, 
and  some  of  them  with  exceptional  records  in  athletic  events.  The 
records  of  these  observations  have  already  been  published  in  Chitt(;n- 
den's  Physiological  Economy  in  Nutrition  from  which  the  data  here  pre- 
sented are  taken. 

With  reference  to  the  general  conduct  of  the  experiments  it  should  be 
emphasized  that  monotony  of  diet  was  avoided  as  far  as  possible,  in 
due  recognition  of  the  psychical  influences  liable  to  affect  secretion  and 
digestion,  and  of  the  danger  which  continued  exhibition  of  an  unvaried 
diet  may  bring,  in  the  lack  or  disproportion  of  certain  inorganic  elements 
in  the  course  of  a  long  period.  The  cooperation  of  a  large  number  of 
subjects  under  different  conditions  of  life  and  activity  and  with  widely 
varying  tastes  must  tend  to  exclude  personal  idiosyncrasies  and  thereby 
minimize  the  chance  of  misleading  conclusions.  The  professional  group 
exercised  a  free  choice  in  the  character  and  quantities  of  the  foodstuffs 
consumed.  For  the  soldiers  a  dietary  was  specially  arranged,  the  char- 
acter and  quantity  of  food  for  each  meal  being  prescribed  with  due  regard 
to  the  satisfaction  of  their  desires.  Preliminary  observations  were  made 
on  these  men  with  a  dietary  such  as  they  were  accustomed  to,  in  the  form 
of  the  ordinary  army  ration  which  has  a  high  content  of  proteid.  The 
diet  was  then  modified  very  gradually  by  the  introduction  of  various 
articles  in  place  of  meat,  until  finally  for  months  the  heavier  proteid 
foods  were  greatly  reduced  in  amount  and  replaced  in  a  measure  by 
carbohydrate  foods.  While  vegetable  foods  eventually  predominated, 
there  was  at  no  time  a  complete  change  to  a  vegetable  or  vegetarian  diet. 
The  student  athletes  likewise  lived  on  a  prescribed  diet,  with  somewhat 
greater  range  of  choice.  There  were  no  restrictions  as  to  quantity  of 
food  in  their  case. 

The  method  of  observation  consisted  in  a  daily  collection  and  meas- 
urement of  urine  and  faeces.  The  nitrogen  output  in  the  urine  was  accu- 
rately determined  throughout  the  experiment,  extending  from  six  to 
nine  months  or  longer.  At  intervals  the  daily  loss  of  nitrogen  in  the 
faeces  was  determined.  Finally  the  balance  between  income  and  outgo 
of  nitrogen  was  exactly  ascertained  several  times  for  periods  of  about 
a  week.  The  total  intake  of  food  in  terms  of  heat  units  was  approxi- 
mately estimated  without  direct  measurement.  The  statistics  on  this 
point  are  therefore  of  subordinate  value.  It  may  be  noted  that  the 
body  weight  of  some  of  the  individuals  gradually  fell  until  a  certain 
stationary  "level"  was  reached,  about  which  small  daily  fluctuations 
were  observed.  This  was  true  of  all  who  had  any  considerable  accumu- 
lation of  reserve  fat.  In  the  well-trained  men  of  slender  or  athletic  build 
these  initiatory  changes  in  weight  were  not  so  apparent,  if  they  occurred 
at  all.    One  of  the  writers  (C),  of  57  kilos  body  weight,  showed  an  aver- 


728  NUTRITION 

age  daily  nitrogen  output  of  5.7  grams  in  the  urine  for  nearly  nine  consec- 
utive months.  Nitrogen  oc[uilibrium  and  body  weight  were  maintained. 
The  other  writer  (M),  with  u  body  weight  of  70  kilos,  established  from 
an  original  weight  of  76  kilos,  likewise  maintained  health,  strength  and 
equilibrium  with  an  average  daily  output  of  G.5  grams  of  nitrogen  in  the 
urine.  A  third  subject  (U),  of  05  kilos  body  weight,  maintained  health 
without  increasing  the  total  fuel  value  of  the  food,  with  an  average  daily 
output  of  about  7.5  grams  of  nitrogen  for  many  months.  These  figures 
imply  a  daily  proteid  metabolism  equivalent  to  about  0.1  gram  of  nitro- 
gen per  kilo  of  body  weight,  or  half  of  that  which  custom  and  habit 
prescribe. 

It  should  be  said  that  these  limits  could  only  be  reached  with  main- 
tenance of  nitrogen  equilibrium,  provided  the  total  food  supply  was 
adecjuate.  Our  estimates  indicate  that  the  latter,  far  from  being  exces- 
sive, tended  to  fall  below  the  ordinarily  accepted  standard  of  3,000  large 
calories  for  a  man  of  average  body  weight  and  moderate  work.  The 
adaptation  to  the  new  standards  was  gradual  in  each  case. 

The  results  obtained  with  the  soldiers,  living  on  a  prescribed  diet  and 
exposed  to  the  strain  of  military  duties,  together  with  gymnastic  work 
and  training,  confirm  the  conclusions  arrived  at  with  the  professional 
group  from  which  some  data  are  quoted  above.  Once  accustomed  to 
a  more  sparing  proteid  diet,  less  rich  in  nitrogen,  these  subjects  had  no 
difficulty  in  maintaining  body  weight  on  the  food  provided,  and  when 
the  conditions  were  satisfactorily  adjusted  nitrogen  equilibrium  could 
readily  be  preserved.  The  members  of  the  soldier  detail  were  able  to 
live  for  five  consecutive  months  with  a  proteid  metabolism  corresponding 
to  about  8  grams  of  nitrogen  per  day  without  discomfort  or  loss  of  vigor. 
The  athletes,  as  well  as  the  physically  less  active  men,  likewise  met 
their  ordinary  requirements  for  several  months  on  an  average  daily  pro- 
teid intake  of  about  60  grams.  Moreover,  careful  dynamometer  and  other 
tests,  made  at  regular  intervals  on  the  soldiers  and  athletes,  indicated 
an  increase  in  muscular  strength  while  the  men  were  on  the  restricted 
diet.  The  summary  on  page  729  of  a  balance  experiment  lasting  one 
week  will  illustrate  the  general  character  of  the  nitrogen  results  obtained 
in  all  of  the  experiments.  The  subject  was  a  vigorous  athlete  of  63  kilos 
body  weight. 

It  is  interesting  to  compare  the  previous  dietetic  habits  of  some  of  our 
subjects  in  respect  to  the  proteid  intake.  During  two  weeks,  at  the  be- 
ginning of  the  experiment  on  the  soldiers  when  the  ordinary  army  ration 
was  used,  the  daily  output  of  urinary  nitrogen  not  infrequently  exceeded 
20  grams  and  usually  reached  over  16  grams  (equivalent  to  100  to  125 
grams  of  proteid).  The  subsequent  record  of  these  subjects  is  given 
on  page  729. 

We  believe  that  these  experiments  demonstrate  the  possibilities  of  a 
physiological  economy  corresponding  to  a  saving  of  considerable  proteid 
food.  Aside  from  its  possible  economic  or  sociological  importance  this 
may  not  be  without  physiological  significance.  The  results  are  presented 
as  a  contribution  to  the  solution  of  a  serious  problem.  If  the  data  ob- 
tained in  these  experiments,  representing  a  proteid  requirement  50  per 
cent,  lower  than  the  figures  usually  quoted  as  necessary  to  maintain 
strength  and  health,  approach  with  any  degree  of  accuracy  to  the  true 


GENERAL  CONSIDERATIONS  OF  METABOLISM 


729 


Nitrogen  Balance. 


Nitrogen 

taken  in. 

Grams. 

May  18 

8.119 

May  19 

9.482 

May  20 

10.560 

May  21 

8.992 

May  22 

9.025 

May  23 

8.393 

May  24 

7.284 

Nitrogen 


Output. 


61.855 


53.04 


61.855  grams  nitrogen. 

Nitrogen  balance  for  seven  days  = 

Nitrogen  balance  per  day  = 

Average  nitrogen  intake  per  day  = 


Weight  of 
fseces  (dry). 

Grams. 

is 


89 
24 

128 — contain 
6.40%  N. 


8 .  192  grams   nitrogen. 


61.232  grams   nitrogen. 

+  0.623  gram. 
+  0.089  gram. 

8.83    grams. 


minimal  requirement  of  the  men  under  observation,  we  believe  that  the 
physiological  needs  of  the  body  can  be  served  for  an  indefinite  period 
on  a  greatly  lessened  proteid  metabolism.  The  fact  that  the  greater 
part  of  the  nitrogen  contained  in  an  ordinary  diet,  including  120  to  150 
grams  of  proteid  per  day,  is  speedily  eliminated  lends  favor  to  the  view 
that  it  can  satisfactorily  be  replaced  by  other  foodstuffs.  As  Folin  has 
said:  "Nitrogen  enough  to  provide  liberally  for  the  endogenous  metab- 
olism and  for  the  maintenance  of  a  sufficient  supply  of  reserve  protein 


Name. 

Body  weight. 
October,  1903. 

Body  weight. 
April,  1904. 

Average  daily 
urinary  nitrogen. 
November-April. 

Metabolized 

nitrogen, 

per  kilo  of 

body  weight.* 

Kilos. 

Kilos. 

Grams. 

Gram. 

Fritz 

76.0 

72.6 

7.84 

0.106 

Oakman.  .  . 

66.7 

62.1 

7.42 

0.116 

Morris 

59.2 

59.0 

7.03 

0.119 

Broyles  . .  . 

59.4 

61.0 

7.26 

0.120 

Henderson 

71.3 

71.0 

8.91 

0.125 

Loewenthal 

60.1 

59.0 

7.38 

0.125 

Cohn 

65.0 

62.6 

8.05 

0.126 

Steltz 

52.3 

53.0 

7.13 

0.134 

Sliney 

61.3 

60.6 

8.39 

0.138 

Coffman . .  . 

59.1 

58.0 

8.17 

0.140 

Zooman . .  . 

54.0 

55.0 

8.25 

0.150 

*  In  this  calculation  the  figures  used  for  body  weight  are  those  of  April,  or 
where  there  is  much  difference  the  average  of  the  October  and  April  weights  is 
used. 


730 


NUTRITION 


is  shown  to  be  nccessarv.  But  it  ouglit  noithor  to  be  necessary  nor  advan- 
tageous for  the  organism  to  split  oii'  and  remove  hirgo  quantities  of 
nitrogen  which  it  can  neitiier  use  nor  store  up  as  reserve  material." 

In  considering  the  possible  physiological  advantages  of  some  reduction 
in  the  proteid  element  of  the  standard  diet,  it  will  be  recalled  that  many 
of  the  disorders  of  metabolism  involve  the  imperfect  katabolism  of  pro- 
teid, so  that  nitrogenous  derivatives  other  than  urea  arc  liable  to  arise. 
Lowered  proteid  intake,  especially  diminished  meat  consumption,  means 
a  decreased  metabolism  of  the  purins.  This  is  illustrated  in  the  obser- 
vations made  in  our  dietary  studies  from  which  the  following  table  is 
taken : 

AvKu.vciK  Daily  Ex(m{etion  Throxtgh  the  Urine  for  Seven  to  Nine  Months. 

PltOFESSIONAI.  GrOTTP. 


Name. 

Body 
weight. 

Total 
nitrogen. 

Uric   aoid. 

Uric   acid 
per  kilo 
of  body 
weight. 

I'liosplioric 
acid  I'jOr, 

Cliittenden..  .  . 

Mendel 

Underliill 

Kilos. 

57.0 
70.0 
05.0 
05.0 
01. 5 

Grams. 

5.09 
0.  53 
7.43 
8.99 
8.58 

Gram. 

0.392 
0.419 
0.51G 
0.  380 
0.305 

Gram. 

0.0008 
0.0000 
0. 0079 
0,0059 
0. 0059 

Grams. 

0.90 
1.40 
1.28 
1.73 

1.49 

The  diet  in  these  cases  was  very  deficient  in  purin  compounds  as  a  rule. 
But  even  among  the  other  groups  where  meat  was  more  freely  eaten, 
although  in  small  amounts,  the  daily  output  of  uric  acid  rarely  exceeded 
500  milligrams.  It  is  difficult  to  see  anything  other  than  an  advantage 
in  a  diminished  production  of  intermediary  products  of  proteid  disinte- 
gration— for  example,  amino-acids  and  uric  acid — under  conditions  where 
they  are  not  properly  converted  into  their  appropriate  end-products. 
This  involves  no  assumption  of  any  harmfulness  of  the  excess  of  ordinary 
nitrogenous  excretives  in  health.  In  disease,  however,  many  conditions 
suggest  themselves  in  which  the  clinician  may  do  well  to  consider  the 
therapeutic  value  of  the  possibilities  involved  in  the  foregoing  discussion. 
This  applies  particularly  to  disorders  in  w-hich  the  organs  of  proteid 
digestion  (gastro-intestinal  tract),  metabolism  (liver),  and  nitrogenous 
elimination  (kidneys),  are  concerned.  Furthermore,  there  is  no  lack  of 
evidence  that  temporary  proteid  starvation  is  ordinarily  not  attended  with 
any  immediate  deleterious  effects,  owing  to  a  considerable  proteid  reserve 
in  the  body;  so  that  the  physician  meeting  with  circumstances  of  disease 
complicated  by  the  difficulties  of  the  "mechanics"  of  nutrition,  for 
example,  may  readily  exchange  the  minimum  temporary  damage  or  loss 
occasioned  by  endogenous  proteid  katabolism  in  the  absence  of  food, 
for  permanent  therapeutic  gains. 

If  we  pass  to  the  data  available  regarding  the  total  food  demand  of 
the  body,  expressed  in  terms  of  energy  katabolized  daily,  statistics  of 
actual  food  consumption  show  a  fairly  wdde  range  between  1,500  and 
4,000  large  calories.  These  differences  are  conditioned  in  part  by  differ- 
ences in  the  individuals  studied,  as  well  as  by  the  variable  demand 
created  by  unlike  degrees  of  bodily  activity.    More  exact  information 


GENERAL  CONSIDERATIONS  OE  METABOLISM  731 

may  be  expected  from  the  increasing  number  of  calorimetric  observa- 
tions made  directly  on  man.  In  general  the  latter  show  a  utilization  of 
about  30  large  calories  per  kilo  of  body  weight  during  rest  and  fasting, 
increasing  somewhat  when  food  is  administered,  and  rising  to  over  twice 
this  amount  when  muscular  work  is  done.  In  cases  of  extreme  exertion 
during  many  hours  of  the  day,  the  transformation  of  energy  may  increase 
to  130  large  calories  per  kilo  of  body  weight.  Calculated  for  a  man  of 
70  kilos,  the  figures  range  from  2,100  to  9,000  large  calories,  the  latter 
representing  an  extreme,  yet  not  unreached,  figure.  To  what  extent  the 
more  usual  average  metabolism  of  3,000  calories  per  day  represents  the 
actual  needs  of  the  body  of  a  70  kilo  man  during  moderate  work  cannot 
be  conclusively  determined  at  the  present  time.  From  such  observations 
as  we  have  been  able  to  gather  in  our  experiments  of  lowered  proteid 
diet,  we  are  inclined  to  the  view  that  the  customary  standards  for  the 
total  energy  demands  represent  a  high  rather  than  a  low  limit;  for 
such  approximate  valuations  as  we  were  able  to  give  to  the  diets  used 
in  these  experiments,  and  which  are  here  mentioned  with  due  reserva- 
tion in  view  of  the  lack  of  direct  fuel  value  determinations,  indicated  a 
metabolism  of  energy  not  greatly,  if  at  all,  exceeding  40  calories* per 
kilo  of  body  weight. 

Among  the  better  classes,  the  nutritive  demands  are  certainly  more 
than  satisfied  by  the  customary  dietaries.  Whether  man  can  five  on 
different  nutritive  planes,  as  various  physiologists  have  suggested,  re- 
mains to  be  seen.  Any  complete  answer  to  such  a  question  must,  of 
course,  take  into  consideration  many  factors  more  general  in  application 
than  is  indicated  by  bodily  equilibrium  alone.  Mental  as  well  as  bodily 
efficiency,  health  and  vigor  must  remain  unimpaired.  Much  has  been 
written  about  the  relation  of  diet  to  the  development  and  characteristics 
of  races;  a  review  of  the  literature  soon  convinces  one,  however,  that 
it  is  impossible  to  form  an  unprejudiced  judgment  from  the  conflicting 
data,  or  unconfirmed  opinions.  Scientific  observation  has  not  yet  re- 
placed personal  impressions  to  a  sufficient  degree  in  the  study  of  this 
interesting  question. 

Muscular  activity  increases  the  demand  for  nutriment;  but  whether  it 
increases  the  need  for  proteid  seems  very  doubtful.  The  final  answer 
will  depend  upon  a  determination  of  endogenous  proteid  metabolism 
during  work,  measurable  perhaps  by  the  output  of  creatinin.  It  is  not 
unlikely  that  the  wear  and  tear  of  the  contractile  tissues  will  be  found 
somewhat  increased  by  maintained  activity.  With  a  surplus  of  proteid 
in  the  diet,  however,  this  does  not  make  itself  manifest  in  any  study  of 
total  nitrogen  exchange.  As  a  rule  we  eat  to  satisfy  the  demands  of  the 
appetite  without  considering  the  true  physiological  needs  of  the  body, 
or  whether  the  appetite  is  in  any  degree  proportioned  to  these.  Perhaps  the 
unwitting  use  of  an  excessive  diet  is  occasioned  by  the  modern  culinary 
methods  which  make  food  palatable  and  attractive;  and  the  danger  in 
this  direction  applies  more  particularly  to  inactive,  well-to-do  persons 
than  to  the  poorer  working  classes  with  a  larger  nutritive  demand. 

As  to  the  relative  participation  of  fats  and  carbohydrates  in  the  satis- 
faction of  the  food  requirements,  it  is  well  to  recall  the  comparative 
food  value  of  each.  One  hundred  parts  of  fat  are  isodynamic  with  230 
parts  of  a  carbohydrate,  like  starch.     Each  of  these  non-nitrogenous 


732  NUTRITION 

nutrients  is  well  utilized  and  the  combinations  are  likewise  rendered 
available  in  large  degree.  An  excess  of  fat  in  the  diet  is  liable  to  diminish 
the  utilization  of  carbohydrate  in  the  same  ration.  This  doubtless  ex- 
plains the  apparent  failure  of  the  widely  advertised  oatmeal  diet  in  dia- 
betes to  cause  sugar  excretion.  Very  large  quantities  of  fat  (300  grams 
of  butter  or  more)  are  prescribed  with  the  oatmeal.  The  absorption  of 
the  latter  is  thereby  doubtless  greatly  impaired  and  diminution  of  the 
glycosuria  is  attributal)le  nut  to  a  better  utilization  of  oat  carbohydrates, 
but  presumably  to  the  imperfect  absorption  of  the  carbohydrate,  which 
precludes  its  reappearance  as  diabetic  sugar.  On  the  other  hand,  an 
excess  of  carbohydrate  in  the  intestine,  especially  in  the  form  of  coarse 
vegetable  food,  may  become  a  severe  burden  to  the  alimentary  tract. 
The  extent  to  which  fats  and  carbohydrates  replace  each  other  is,  we 
believe,  largely  a  matter  of  convenience,  cost  and  individual  taste.  In 
general,  fats  are  expensive  and  accordingly  are  allowed  to  furnish  the 
smaller  part  of  the  energy.  Zuntz  and  Schumburg  have  lately  advocated 
a  considerable  increase  in  the  fat  foods  of  the  German  army  ration,  call- 
ing attention  to  the  large  food  value  of  fats  and  their  ready  assimilation 
without  much  digestive  work.  They  likewise  suggest  increased  employ- 
ment of  sugar,  the  refreshing  influence  of  which  on  the  fatigued  muscles 
has  lately  been  announced.  If  it  is  remembered  that  one  gram  of  fat 
is  equivalent  to  14  grams  of  milk,  9.8  grams  of  meat,  9.3  grams  of  potato, 
30  to  40  grams  of  vegetables,  it  will  be  understood  that  fats  may  become 
a  valuable  adjuvant  to  the  diet  whenever  a  decrease  in  its  bulk  becomes 
desirable.  Dietetic  habits  are  frequently  of  moment  in  this  connection. 
Individuals  accustomed  to  concentrated  diets  may  find  a  voluminous 
ration  unattractive  and  even  unendurable.  In  contrast  with  this,  others 
find  no  satisfaction  in  any  diet,  however  palatable  or  nutritive,  unless 
it  is  sufficiently  bulky.  Only  in  this  way  can  the  feeling  of  hunger  be 
dispelled. 

To  thes/i  creations  of  habit  must  be  added  certain  idiosyncrasies 
which  exL>bit  themselves  in  an  intolerance  for  certain  substances.  In 
many  cases  these  are  immediately  attributable  to  digestive  disturbances 
or  other  recognizable  disease.  Not  infrequently  they  are  of  a  more  subtle 
character.  We  see  an  illustration  in  the  appearance  of  urticaria  in  other- 
wise healthy  persons  after  eating  shell-fish,  strawberries,  etc.,  indicating 
a  susceptibility  to  minute  quantities  of  chemical  substances  insufficient 
to  affect  the  average  individual  in  a  perceptible  manner. 

Preparation  of  Food. — ^The  preparation  of  food  plays  by  no  means  a 
negligible  part  in  its  subsequent  fate  in  nutrition  and  may  contribute 
both  to  its  digestibility  and  its  palatability.  The  appearance,  flavor, 
and  odor,  stimulate  or  modify  the  activity  of  the  digestive  glands  through 
various  channels,  as  has  been  shown  so  strikingly  by  Pawlow  and  his 
pupils.  Food  which  is  repulsive  fails  to  provoke  the  proper  digestive 
response,  or  at  any  rate  calls  it  forth  more  slowly  than  an  attractive  meal 
does. 

Man  has  been  called  a  "cooking"  animal,  and  the  practice  of  sub- 
jecting foods  to  heat  is  well  nigh  universal.  The  rationale  of  the  various 
ways  of  treating  foods  by  means  of  heat  is  too  little  understood.  In 
many  cases  it  softens  the  foodstufi's  and  transforms  their  texture.  The 
connective  tissue  fibers  of  meats  are  converted  into  gelatin  by  boiUng, 


GENERAL  CONSIDERATIONS  OF  METABOLISM  733 

so  that  they  dissolve  more  readily  and  allow  the  digestive  juices  to  act 
more  directly  upon  the  muscular  fibers  themselves.  This  change  like- 
wise facilitates  the  processes  of  mastication.  Similarly,  cooking  changes 
the  tough,  firm  make-up  of  many  of  the  vegetables  into  soft  and  easily 
masticated  tissue.  In  developing  thereby  a  more  pronounced  flavor  and 
odor,  other  factors  of  value  are  added.  In  vegetable  foods  the  starch 
grains  are  ruptured  and  liberated  in  considerable  proportion  from  the 
indigestible  envelopes  of  cellulose  which  surround  them.  Further,  the 
changes  which  starchy  foods,  like  the  cereals,  undergo  by  dry  heat  are 
of  value  from  the  standpoint  of  lending  flavor  rather  than  because  of 
any  profound  chemical  changes  effected.  In  the  case  of  the  legumes, 
peas,  beans,  etc.,  we  have  a  good  illustration  of  the  importance  of  cook- 
ing for  the  proper  utilization  of  such  food  materials.  Finally,  heat 
destroys  many  toxic  substances  or  organisms  present  in  micooked  foods 
and  thus  protects  the  body  from  dangers  lurking  therein. 

A  variety  of  substances  classed  as  "food  accessories"  exert  an  influence 
quite  independent  of  any  direct  nutritive  value.  Some,  like  the  extractive 
substances  of  meat,  etc.,  are  not  entirely  devoid  of  fuel  value;  others, 
like  some  of  the  inorganic  salts,  are  indispensable,  despite  the  fact  that 
they  convey  no  energy  to  the  organism;  while  another  class  still,  includ- 
ing ordinary  condiments  such  as  pepper,  mustard,  and  other  spices, 
exert  an  indirect  influence  on  nutrition.  The  latter  class  includes  sub- 
stances which  act  directly  upon  sense  organs  exciting  the  sense  of  taste 
and  thus  inducing  a  reflex  flow  of  the  digestive  secretions.  In  so  far  as 
they  stimulate  the  appetite,  they  may  create  favorable  conditions  for 
incipient  alimentary  changes  by  the  indirect  effect  upon  the  secretory 
glands  concerned  therein.  Pawlow  has  said :  "Appetit  ist  Saft. "  The 
psychical  effect  of  various  factors  in  promoting,  or — what  is  less  famil- 
iarly recognized — in  inhibiting  indirectly  the  nutritive  processes,  is  for 
the  most  part  underestimated;  for  foodstuffs  are  not  selected,  in  the 
ordinary  course  of  events,  with  any  due  recognition  of  their  real  nutri- 
tive value,  but  rather  in  virtue  of  their  palatability  and  the  appeal  which 
they  make  to  the  senses.  Again,  the  group  of  substances  represented 
by  the  extractives  of  meat  as  they  are  obtained  in  soups,  etc.,  plays  a 
part  in  stimulating  the  secretory  glands.  They  are  rapidly  absorbed  be- 
fore the  foodstuffs  proper  are  digested,  and  in  the  blood-stream  they  act 
directly  as  secretory  stimulants,  inducing  a  flow  of  gastric  juice.  The 
question  as  to  the  effect  of  such  substances  upon  the  intermediate  pro- 
cesses of  metabolism  has  not  yet  received  the  consideration  which  it 
merits.  Heretofore  they  have  usually  been  studied  from  the  standpoint 
of  their  pharmacological  action.  Yet  taking  alcohol  as  an  illustration, 
the  more  distinctly  physiological  aspects  seem  worthy  of  attention.  Ob- 
servations in  our  laboratory  have  shown  that  it  may  noticeably  alter  the 
output  of  exogenous  uric  acid  in  man;  and  if  other  katabolic  processes 
in  the  organism  are  similarly  affected,  the  subsidiary  changes  induced  in 
intermediary  metabolism  by  such  food  accessories  as  alcohol  may  quite 
overshadow  the  influence  which  they  exert  in  the  preliminary  digestive 
changes.  It  is  impossible  to  say  in  what  degree  the  demand  for  these 
accessories  has  been  acquired  by  man;  this  much  is  e^ddent,  that  in  all 
culture  lands  the  advance  of  civilization  has  been  attended  by  increasing 
attention  to  the  factors  here  discussed.    Whether  these  subsidiary  articles 


734 


NUTRITION 


of  diet,  Including  meat  extractives,  tea,  coft'ee,  cliocolate,  alcohol,  etc., 
■which  arc  for  the  most  part  sources  of  little  or  no  energy  and  not  ])os- 
sessed  of  reparative  power  for  the  tissues  of  the  body,  are  as  necessary 
to  us  as  the  foodstuffs  themselves  is  difficult  to  say.  Common  experience 
confirms  their  agreeable  influence. 

The  inorganic  salts,  mineral  nutrients  or  inorganic  foodstuffs,  are  es- 
sential owing  to  the'  fact  that  a  lack  of  them  must  inevitably  lead  to  physi- 
ological difficulties  as  a  result  of  their  continued  loss  in  the  excretions. 
The  conservative  efforts  of  the  body  are  frequently  displayed  in  the 
marked  retention  of  some  of  these  elements;  for  example,  of  chlorine 
in  fevers.  But  unless  restitution  is  made  the  defect  inevitably  mani- 
fests itself  sooner  or  later.  From  the  quantitative  point  of  view  the 
demand  for  chlorine  and  sodium  (sodium  chloride)  is  most  cons])icuous, 
and  the  search  for  this  salt  appears  to  be  almost  instinctive  in  both  man 
and  animals.  The  pathological  symptoms  Avhich  lack  of  some  of  these 
elements,  such  as  iron  and  calcium,  develops,  is  familiar.  Occasionally 
the  difficulty  presented  apparently  involves  a  deficient  absorption  or  re- 
tention of  the  compounds.  AVe  are  inclined  to  believe  that  an  increasing 
familiarity  with  the  distribution  of  inorganic  salts  and  their  elements  in 
the  natural  foods  will  tend  to  lead  to  a  substitution  of  dietetic  methods 
of  administration  of  these  substances,  in  place  of  the  therapeutic  meas- 
ures (artificial  lime  salts,  iron  salts,  etc.)  now  employed  so  extensively. 
A  radical  change  in  diet  will  call  for  some  consideration  of  the  new  adap- 
tation of  the  inorganic  foodstuffs  accompanying  it.  Especially  is  this 
true  for  the  growing  organism.  When  the  salts  required  by  the  latter 
are  accurately  known,  a  change  from  milk  to  some  other  form  of  diet 
may  properly  suggest  the  question  whether  the  child  will  continue  to 
obtain  the  necessary  salts  in  sufficient  quantities.  Similar  considerations 
apply  to  the  convalescent  period  in  invalids.  The  following  table  (from 
Bunge)  indicates  the  range  of  variation  in  the  constituents  of  the  ash  of 
the  most  important  articles  of  diet,  arranged  according  to  the  content 
of  Ume. 

One  Hundred  Parts  of  Dried  Substance  Contain. 


CI 


Beef 

Wheat 

Potato 

Egg-white. . . 

Peas 

Human  milk 
Yolk  of  egg. 
Cow's  milk. . 


KoO 

Na.O 

CaO 

MgO 

Fe.Os 

P.Os 

l.CG 

0.32 

0.029 

0.152 

0.020 

1.83 

0.02 

O.OG 

0.  065 

0.24 

0.026 

0.94 

2.28 

0.11 

0.100 

0.  19 

0.042 

0.04 

1.44 

1.45 

0.  130 

0.13 

0.02G 

0.20 

1.13 

0.03 

0.  137 

0.22 

0  024 

0.99 

0.  58 

0.17 

0.  243 

0.05 

0.003 

0.  35 

0.27 

0.17 

0.  380 

0.00 

0.040 

1.90 

1.C7 

1.05 

1.51 

0.20 

0.003 

l.SO 

0.28 

(?) 
0.13 
1.32 
(?) 
0.32 
0.35 
1.60 


The  marked  differences  in  the  distribution  of  important  elements 
among  these  familiar  dietetic  articles  is  clearly  shown.  Thus,  the  poverty 
of  cow's  milk  in  iron  and  the  relative  abundance  of  lime  are  conspicuous. 
The  total  quantity  of  mineral  ingredients  included  in  the  ordinary  diet 
of  the  adult  and  their  distribution  has  been  compiled  by  Gautier,  as 
shown  in  the  table  on  page  735. 

To  the  17.43  grams  of  inorganic  substances  here  accounted  for,  should 
be  added  7  or  8  grams  of  common  salt  which  are  daily  contributed  directly 
to  the  food,  making  a  total  of  25  grams  of  inorganic  compounds.    It  is 


GENERAL  CONSIDERATIONS  OF  METABOLISM 


735 


estimated  that  we  excrete  somewhat  more  than  this  ({uantity  by  tlie 
various  channels  of  eUmination.  The  shght  gain  is  attributable  to  the 
sulphuric  and  phosphoric  acids  derived  from  the  oxidation  of  organic 
compounds  of  sulphur  and  phosphorus  ingested.     It  will  also  be  noted 

Inouganic  Salts  in  an  Aveijage  Day's  Ration. 


Food. 


Bread  and  pastry 

Meats 

Milk 

Eggs 

Fresh  fruits 

Fresh  vegetables. 
Dried  vegetables. 

Potatoes 

Cheese 

Sugar. 

Butter 

Wine 

Drinking-water. . 


Total  Weight. 

Inorganic  Salts. 

Grams. 

Grams. 

435 

3.15 

266 

3.40 

150 

1.05 

30 

0.03 

90 

0.45 

200 

4.15 

40 

1.20 

100 

1.20 

12 

0.80 

40 

0.00 

28 

0.00 

650 

1.65 

1,000 

0.35 

17.43 


in  the  preceding  table  that  the  preponderance  of  the  ingested  inorganic 
compounds  is  associated  with  foods  of  vegetable  origin;  this  applies 
in  particular  to  specific  elements:  Potassium,  magnesium  and  phos- 
phates. 

Composition  of  Foods  in  Their  Relation  to  Nutrition.— Broadly 
speaking,  it  is  customary  to  refer  to  the  nutritive  value  of  the  various 
foods  in  daily  use  on  the  basis  of  their  general  composition ;  that  is  to 
say,  the  content  of  nitrogen  or  protein  (N  X  6.25),  fats  (ether  extract), 
non-nitrogenous  constituents  (digestible  carbohydrates  and  insoluble 
cellulose),  inorganic  components  and  their  heat  of  combustion.  In  dis- 
cussing proteid  metabohsm  it  has  already  been  pointed  out  that  the 
nitrogenous  compounds  are  by  no  means  equivalent  or  identical  in  their 
physiological  role,  and  the  peculiar  position  of  the  purin-containing  foods 
was  emphasized.  Up  to  the  present  time,  relatively  few  data  have  been 
obtained  with  respect  to  the  purin-content  of  foods  in  common  use. 
The  great  divergence  in  the  distribution  of  purin  derivatives  is  made 
manifest  in  the  figures  compiled  by  Walker  Hall,  as  shown  in  the  table 
on  page  736. 

From  this  summary  it  is  easy  to  arrange  a  dietary  practically  free 
from  purin-containing  foods  and  yet  adapted  to  physiological  require- 
ments. For  this  diet  cereals,  milk,  butter,  eggs,  certain  green  vegetables, 
sugars,  etc.,  form  the  basis;  and  the  output  of  urinary  purins  soon  falls 
to  the  endogenous  level  thereon.  In  illustration  of  this  we  quote  from 
Rockwood  a  diet  experiment  in  which  two  subjects  subsisted  for  nearly 
two  weeks  on  a  ration  consisting  of  milk,  1,350  cc;  prepared  cereal, 
35  grams;  sugar,  20  grams;  crackers,  250  grams;  cheese,  30  grams; 
eggs,  96  grams;  apples,  90  grams;  wheat  bread,  50  grams;   butter,  15 


736 


NUTRITION 


PuRiN  Content  of  Common  Foods. 


Food. 


Fish: 

Cod... 

Plaice. 

Halibut 

Salmon 

Meats  : 

Tripe 

Mutton 

Veal 

Pork 

Beef,  ribs.  . . 

Beefsteak  . . . 

Liver 

Sweetbread. . 

Chicken 

Cereals: 

Bread,  white 

Rice 

Oatmeal.  .  .  . 
Vegetables: 

Pea  meal. . . . 

Beans 

Potatoes .... 

Onions 

Cabbage.  .  .  . 

Lettuce 

Asparagus .  . . 

Beers 

Wines 

Milk 


Average  percentage 

Purin  bodies 

of  purin  nitrogen. 

(ii-rams  per  kilo). 

0.023 

0.582 

0.032 

0.795 

0.041 

1.020 

0.046 

1.165 

0.023 

0.582 

0.038 

0.965 

0.046 

1 .  162 

0.048 

1.212 

0.045 

1.137 

0.083 

2.066 

0.110 

2.752 

0.402 

10 . 063 

0.051 

1.295 

none 

none 

0.021 

6.530 

0.015 

0.390 

0.025 

0.637 

trace 

trace 

0.003 

0.090 

none 

none 

0.009 

0.215 

0.005 

0.125 

none 

minute  trace 

minute  trace 

grams;   confectionery,  100  grams;   during  this  period  the  average  daily 
outputs  of  nitrogen  and  uric  acid  in  the  urine  were  respectively: 

A.  B. 

Nitrogen 11 .  580  grams  11 .  390  grams 

Uric  acid 0 .  305  grams  0 .  340  grams 

The  widespread  and  increasing  use  of  cereal  preparations  of  all  sorts, 
which  has  come  into  vogue  in  recent  years,  may  make  it  worth  while  to 
consider  briefly  to  what  extent  some  of  the  claims  advanced  have  justi- 
fication in  truth.  A  comparison  of  animal  foods  with  those  of  vegetable 
origin  as  sources  of  proteid  and  energy  is  afforded  by  the  following  figures 
(Milner) : 

Proteid,      Energy  per  gram, 
per  cent.        calories  (large). 

Oat  preparations 16 . 1  4 .  423 

Wheat  preparations 12.1  4 .  032 

Corn  preparations 8.6  3.894 

Rice  preparations 8.3  3.907 

Beef,  lean  round 19.5  1 .  795 

Beef,  fat  round 16 . 1  3 .  104 

Bread,  white 9.2  2 .  885 

Bread,  graham 8.9  2.872 

Cheese,  full  cream 25.9  4.674 

Potatoes 2.2  0.892 


GENERAL  CONSIDERATIONS  OF  METABOLISM  737 

Milner  has  summarized  the  essential  features  with  respect  to  modem 
cereal  preparations,  especially  the  ready-to-eat  products,  "breakfast 
foods,"  etc.,  in  these  words:  "The  difference  between  the  various  cereal 
preparations  is  principally  one  of  process  of  manufacture.  Some  con- 
tain the  whole  of  the  grain,  whereas  with  others  the  bran  and  germ  have 
been  removed  in  their  preparation.  Some  are  entirely  uncooked,  some 
are  partially  cooked,  and  some  are  wholly  cooked  and  ready  to  eat  as 
purchased.  Among  the  latter  are  the  so-called  'predigested'  or  'malted' 
preparations. 

"The  composition  of  the  different  products  depends  upon  that  of 
the  grain  from  which  they  are  made,  and  the  extent  to  which  the  bran 
and  germ  have  been  removed  in  the  manufacture.  In  general,  the  pre- 
pared product  from  any  grain  has  much  the  same  composition  as  that 
of  flour  or  meal  from  the  same  grain.  Different  brands  of  similar  nature 
when  made  from  the  same  grain  do  not  differ  in  average  composition 
any  more  widely  than  different  lots  of  the  same  brand. 

"Different  prepared  products  from  the  same  grain  show  no  marked 
differences  in  respect  to  the  amounts  of  nutrients  that  may  be  actually 
digested.  The  differences  in  actual  nutritive  value  of  the  products 
from  the  same  grain  are  therefore  on  the  average  so  small  that  they 
may  be  disregarded  in  choosing  between  them.  However,  the  oat 
preparations  contain  noticeably  larger  proportions  of  nutrients  and 
energy  than  those  of  other  grains,  and  as  they  are  when  properly 
cooked  no  less  thoroughly  digested  the  actual  nutritive  value  of  the 
oat  preparations  appears  to  be  greater  than  that  of  the  preparations 
from  other  grains. 

"The  nutritive  value  of  the  'malted'  or  so-called  'predigested'  prepara- 
tions is  no  greater  than  that  of  other  preparations  from  the  same  grains. 
In  some  instances  the  attempts  to  convert  insoluble  starch  into  more 
soluble  material  by  the  use  of  malt  have  been  to  a  small  degree  success- 
ful, and  to  that  extent  the  preparations  have  been  rendered  more  easily 
digestible;  but  just  as  much  and  even  more  is  accomplished  by  thorough 
cooking.  In  most  of  the  malted  preparations  the  quantity  of  starch 
actually  converted  is,  however,  very  small  and  in  some  cases  none  has 
been  changed. 

"The  thoroughness  of  cooking  has  quite  as  much  influence  upon  the 
actual  food  value  of  the  preparations  as  the  small  differences  in  com- 
position. If  the  cereals  are  not  thoroughly  cooked  some  of  the  nutritive 
material  will  escape  the  action  of  the  digestive  juices." 

Practical  dietetics  has  long  had  to  contend  with  a  conflict  of  opinions 
regarding  the  true  nutritive  value  of  many  familiar  food  materials.  The 
errors  are  associated  with  exaggerated  or  incorrect  ideas  regarding  the 
food  value  of  specific  dietary  articles;  and  a  prejudice  against  food 
materials  of  certain  origin  has  been  fostered  in  the  absence  of  accurate 
scientific  testimony.  These  statements  apply  to  the  medical  profession 
as  well  as  to  the  laity,  who  cannot  always  be  expected  to  arrive  at  sound 
deductions  on  the  problems  of  nutrition.  Current  notions  regarding  the 
relative  value  of  different  kinds  of  bread  furnish  an  illustration  of  what 
has  been  said  here.  Wheat  or  rye  flour  is  used  most  extensively,  though 
some  kinds  of  bread  are  prepared  from  barley  or  maize.  The  oat,  on 
the  other  hand,  will  not  yield  a  light  porous  bread.    Further  differences 

47 


738  NUTRITION 

are  brought  about  by  the  choice  of  leavening  agent  used  in  preparing  the 
dough. 

In  the  manufacture  of  the  commonly  used  "patent"  wheat  flour  by 
the  modern  process  of  milling,  the  bran  and  aleurone  layers,  together 
Vsiih  the  germ,  are  removed  by  preliminary  treatment  and  the  remainder 
of  the  kernel  is  then  ground.  The  bran,  if  included,  would  make  the 
flour  coarse;  and  the  germ  is  removed  because  it  contains  oil,  which 
acts  upon  the  other  constituents  of  the  flour  so  that  the  bread  in  baking 
is  darkened  in  color.  The  portions  removed  by  the  {)rocesses  of  refining 
are  characterized  especially  by  their  richness  in  nitrogenous  materials 
and  inorganic  salts.  There  has  been  much  controversy  regarding  the 
nutritive  value  of  the  bran;  and  it  has  been  claimed  that  valuable  parts 
of  the  wheat  are  left  in  the  waste  cortical  portions.  To  avoid  this  loss 
Graham  flour  is  prepared  by  grinding  the  whole  of  the  wheat  kernel; 
and  since  no  bolting  or  sorting  process  is  introduced  the  product  is  in 
reality  a  wheat  meal.  As  an  intermediate  product  between  the  coarse 
Graham  flour  and  the  finest  products,  the  so-called  "whole  wheat"  or 
"entire  wheat"  flour  has  arisen.  In  this  the  attempt  is  made,  with 
varying  success,  to  remove  only  the  woody  part  of  the  bran,  leaving  the 
aleurone  layer  and  the  germ  with  their  nitrogenous  and  other  ingredients 
and  removing  the  irritating  parts  of  the  bran. 

Experimental  observations  now  recorded  in  large  numbers  indicate 
how  unreliable  chemical  analysis  alone  may  be  in  determining  the  rela- 
tive nutritive  value  of  the  different  grades  of  bread  made  from  many 
kinds  of  flour.  Actual  trials  on  man  show  that  wheat  bread  is  more 
completely  utilized  than  rye  bread.  Bread  prepared  from  wheat  flour 
is  absorbed  from  the  alimentary  tract  in  larger  or  smaller  amount  ac- 
cording to  the  fineness  of  the  flour  used,  the  finest  behaving  most  favor- 
ably in  this  respect.  In  cases  where  the  flour  is  prepared  from  the  whole 
grain  there  is  always  a  considerably  larger  residue  of  unutilized  food. 
The  determining  features  are  undoubtedly  found  in  the  varying  physical 
peculiarities  of  the  types  of  bread  produced.  That  from  fine  wheat  flour 
is  far  more  porous  than  what  is  made  from  whole  or  crushed  grains,  and 
is  thus  more  readily  exposed  to  the  digestive  changes.  Judging  from  the 
relatively  large  residuum  of  undigested  material  left  after  ingestion  of  the 
coarser  kinds  of  bread,  especially  those  containing  considerable  bran, 
the  compounds  included  therein  are  protected  from  the  digestive  juices 
by  their  environment  of  cellulose  and  other  indigestible  substance  and 
thus  fail  to  contribute  the  food  value  which  their  composition  alone  dis- 
closes. 

From  digestion  trials  with  breads  Woods  and  Merrill  conclude 
that  "in  general,  the  digestibility  of  the  ration,  whether  simply  bread 
and  milk  with  a  little  butter  and  sugar,  or  a  more  varied  diet,  was  de- 
creased when  the  change  was  made  from  white  bread  to  entire-wheat 
bread,  and  still  further  decreased  when  either  was  replaced  by  Graham 
bread,  the  remainder  of  the  diet  being,  of  course,  the  same  in  all  three 
cases.  The  differences  are  sufficient  to  indicate  that,  even  though  the 
Graham  flour  contains  the  most  and  the  white  flour  the  least  total  pro- 
tein of  the  three,  the  body  would  obtain  more  protein  and  energy  from 
a  pound  of  entire  wheat  than  from  a  pound  of  Graham  flour  and  still 
more  from  a  poimd  of  white  flour  than  from  either  of  the  others.    On 


GENERAL  CONSIDERATIONS  OF  METABOLISM  739 

the  other  hand,  it  does  not  follow  that  a  larger  amount  of  digestible  nu- 
trients or  available  energy  may  not  be  obtained  from  100  pounds  of  wheat 
when  milled  as  Graham  flour  or  entire-wheat  flour  than  when  ground 
into  patent  flour,  because  100  pounds  of  cleaned  and  screened  wheat 
will  yield  100  pounds  of  Graham  flour,  about  85  pounds  of  entire-wheat 
flour,  and  only  a  little  over  72  pounds  of  standard  patent  flour.  This, 
however,  is  a  question  of  pecuniary  economy."  They  give  as  the  amount 
of  unabsorbable  nitrogen  for  fine  wheat  bread,  from  10  to  13  per  cent.; 
for  whole-wheat  bread  about  13  per  cent.;  and  for  Graham  bread  23  to 
24  per  cent,  of  the  food  nitrogen. 

On  purely  physiological  grounds  there  is  no  justification  for  the  exten- 
sive consumption  of  the  coarser  forms  of  bread  among  the  masses  of 
America  and  Europe.  To  many  persons  the  taste  of  the  coarse  grades 
of  bread  is  very  agreeable.  The  bran  is  undoubtedly  utilized  to  a  small 
extent;  but  the  justification  for  the  therapeutic  use  of  coarse  breads  is 
referable  almost  entirely  to  the  more  vigorous  intestinal  movements 
which  they  induce  by  virtue  of  a  greater  proportion  of  indigestible 
materials  acting  as  irritants. 

Experience  accumulated  in  comparing  the  availability  of  proteids  ob- 
tained from  vegetable  sources  with  those  furnished  by  animal  tissues 
has  led  to  the  inquiry  whether  these  different  types  of  proteids  exhibit 
inherent  differences  in  real  digestibility.  Not  a  few  writers  have  assumed 
this  to  be  the  case.  But  observations  made  in  our  own  laboratory,  as 
well  as  by  others,  give  no  support  to  this  view.  Oat  proteid,  for  exaihple, 
isolated  and  purified  was  found  no  less  readily  utilized  than  that  from 
lean  meat  or  milk;  and  this  corresponds  with  similar  experience  with 
other  vegetable  proteids.  When,  however,  they  are  still  mixed  with  the 
materials  naturally  associated  with  them,  vegetable  proteids  are  not 
ordinarily  utilized  to  the  same  extent  as  those  of  animal  origin. 

In  distinction  from  cereals  and  legumes,  "vegetables,"  such  as  cab- 
bage, beets,  etc.,  are  of  little  value  as  sources  of  proteid  or  fat,  although 
the  carbohydrates  which  they  contain  appear  to  be  quite  well  digested 
and  absorbed.  Bryant  and  Milner  conclude  from  their  studies  that  "the 
chief  value  of  many  vegetables,  however,  is  perhaps  aside  from  the  nu- 
trients or  energy  they  furnish;  they  add  a  pleasing  variety  and  palatabil- 
ity  to  the  diet,  supply  organic  acids  and  mineral  salts,  and  give  the  food 
a  bulkiness  that  seems  to  be  of  importance  in  its  mechanical  action  in 
maintaining  a  healthy  activity  of  the  alimentary  tract.  Possibly  the  result 
of  these  conditions  is  a  favorable  influence  upon  the  digestion  of  other 
food  eaten  with  the  vegetable;  at  least  such  an  effect  was  suggested  by 
the  results  of  some  of  the  experiments.  For  instance,  in  the  studies  with 
potatoes  and  with  apple  sauce  added  to  the  basal  ration  the  digestibility 
of  the  total  ration  including  such  material  was  noticeably  higher  than 
that  of  the  basal  ration  alone." 

Some  of  the  fallacies  frequently  met  with  regarding  these  vegetable 
products  are  well  illustrated  in  certain  popular  prejudices  with  respect 
to  mushrooms,  or  edible  fungi.  They  are  generally  regarded  as  con- 
stituting a  very  nutritious  and  sustaining  diet;  and  this  supposition  has 
given  rise  to  the  extravagant  statement  that  "a  hearty  meal  on  mush- 
rooms alone  would  be  about  as  reasonable  as  a  dinner  on  nothing  but 
beefsteak  and  might  be  expected  to  be  followed  by  similar  ill  conse- 


740  NUTRITION 

quences."  Studies  made  in  our  laboratory,  however,  have  indicated 
that  the  expression  "vegetable  beefsteak"  is  scarcely  aj^propriate  when 
applied  to  mushrooms  in  a  strictly  chemical  sense.  These  fungi  form 
no  exception  to  the  ordinary  classes  of  fresh  vegetable  foods;  indeed, 
they  take  a  decidedly  inferior  rank  in  comparison  with  many.  As  dietetic 
accessories  they  may  play  an  important  part;  but  they  cannot  be  ranked 
with  the  essential  foods. 

In  this  connection  we  may  note  the  variable  content  of  cellulose  in 
some  of  the  common  articles  of  diet. 

Cellulose  Content  of  Common  Vegetable  Foods  (Lohrisch). 

Per  cent. 

Spinach,  as  served 0 .  36 

Head  lettuce,  uncooked 0.48 

Kohlrabi,  uncooked 0 .  73 

Carrots,  uncooked 0.74 

Cabbage,  uncooked 0.79 

Cucumber,  as  served 0.11 

Potato,  dried 1 .  22 

Potato,  boiled 0.25 

Potato,  raw 0.21 

Lentils,  uncooked 3 .  39 

Oatmeal,  dry 0.24 

Rye  bread 0.15 

Graham  bread 0 .  94 

Rademann's  cellulose  bread,  dried 3.24 

Cacao  powder,  dry 2 .  29 

Agar-agar,  dry 0 .  62 

Systems  of  Diet. — From  early  times  various  systems  of  diet  and  die- 
tetic cures  have  found  favor  and  received  vigorous  advocacy  from  approv- 
ing followers.  Most  familiar  is  vegetarianism,  a  system  of  living  which 
teaches  that  the  food  of  man  should  be  derived  directly  from  the  plant 
world.  Considered  in  the  light  of  its  history,  however,  vegetarianism 
involves  something  more  than  a  mere  dietetic  program.  It  teaches  that 
the  use  of  animal  foods  is  morally  wrong  as  well  as  erroneous  with  respect 
to  the  processes  of  nutrition.  But  in  view  of  the  widespread  advocacy 
of  this  exclusive  regime,  it  may  be  worth  while  to  consider  the  physio- 
logical aspects  which  the  system  presents.  At  the  outset,  it  should  be 
noted  that  a  diversity  of  views  has  entered  into  the  so-called  vegetarian 
doctrines.  The  most  radical  reformers  have  abstained  not  alone  from 
all  food  of  animal  origin  but  also  from  tubers  and  underground  roots, 
eating  only  vegetables  and  fruits  grown  in  the  sunlight;  others  again 
reject  cereals  and  live  on  fruits,  nuts,  and  milk;  while  the  most  conser- 
vative exclude  only  fish,  flesh,  and  fowl  from  their  diet.  Among  the  latter 
groups  may  be  arranged  the  so-called  fruitarians,  who  abstain  from  all 
food  obtained  by  infliction  of  pain. 

Among  the  more  strictly  scientific  arguments  advanced  against  the 
use  of  animal  foods  are  those  relating  to  the  dangers  of  disease  lurking 
in  them.  This  applies  chiefiy  to  the  flesh  of  animals;  such  foods  as  eggs, 
milk,  and  butter,  all  derived  from  animals,  are  not  ordi'^arily  excluded 
from  the  modern  vegetarian  dietary,  but  rather  contnoute  thereto  in 
considerable  measure.  It  must  be  admitted  that  meat  may  be  the  carrier 
of  harmful  organisms,  ptomaines,  etc.;   but  this  fact  affords  no  funda- 


GENERAL  CONSIDERATIONS  OF  METABOLISM  741 

mental  source  of  objection  to  animal  foods,  since  the  dangers  here  alluded 
to  are  avoidable,  and  vegetable  foods  themselves  are  by  no  means  free 
from  similar  objections.  The  high  content  of  "extractive"  substances — 
creatin,  purin  bodies,  inorganic  salts — in  meat  is  also  referred  to  as  an 
undesirable  feature  of  any  ordinary  animal  diet.  We  have  seen  that  these 
play  a  pecuUar  role  in  metabolism,  failing  in  part  to  yield  any  energy  to 
the  organism,  and  again  becoming  partially  oxidized  to  compounds  like 
uric  acid,  which  may  have  a  significance  in  certain  pathological  conditions. 
On  the  basis  of  the  facts  now  available,  no  serious  objections  against  the 
small  quantities  of  the  meat  bases  daily  ingested  in  an  average  dietary 
can  be  formulated  for  the  healthy  individual.  A])parently  they  belong 
to  the  same  category  as  many  other  food  accessories  such  as  tea,  coffee, 
and  alcohol,  and  are  open  to  similar  criticism.  The  supposed  influence 
of  meat  extract  in  increasing  the  nutritive  value  of  vegetable  foods  has 
not  been  substantiated.  The  substances  which  lend  peculiar  character 
to  meat  act  in  the  same  stimulating  and  refreshing  manner  that  tea  and 
coffee  undoubtedly  do,  and  from  this  standpoint  must  be  looked  upon 
merely  as  pleasant  adjuncts  to  the  food.  Bunge  writes:  "That  some  or- 
ganic constituent  of  meat-extract  may  produce  an  effect  on  the  muscular 
or  nervous  system  must  be  admitted  to  be  remotely  possible;  at  pres- 
ent it  is  in  no  way  proved.  We  know,  with  regard  to  bouillon,  abso- 
lutely no  more  than  that  it  tastes  and  smells  agreeably.  This  fact, 
however,  suffices  to  explain  all  the  'enlivening'  and  'strengthening' 
virtues  which  common  experience  attributes  to  extract  of  meat  and 
bouillon,  and  to  recommend  them  as  valuable  and  pleasant  accessories 
of  our  food." 

We  are  inclined  to  believe  that  rational  objections  against  a  meat 
diet  are  applicable  with  respect  to  quantitative  aspects  rather  than  to 
the  chemical  make-up  of  such  dietaries.  In  other  words,  it  is  the  abuse 
of  meat  in  modern  dietaries  which  should  be  charged  with  any  dangers 
attaching  to  the  employment  of  this  animal  food;  and  the  disadvantages 
of  an  excessive  proteid  diet  apply  with  far  less  force  to  vegetarian  re- 
gimes, owing  to  the  proportionate  nitrogen  deficiency  of  the  ordinary  foods 
included  in  them. 

An  appeal  to  the  characteristics  of  races  or  peoples  accustomed  to 
fixed  types  of  diet  is  frequently  made  in  support  of  the  superiority  or 
undesirability  of  different  nutritive  habits.  Mental  and  physical  pecu- 
liarities of  classes  living  largely  on  rice  or  other  cereals  are  contrasted 
with  those  of  fish-  and  flesh-devouring  tribes.  It  is  widely  believed 
that  meat  eating  tends  to  develop  a  degree  of  aggressiveness  and  related 
traits  of  character,  in  distinction  from  the  more  pacific  features  of  those 
nations  accustomed  to  the  extensive  use  of  cereals  in  place  of  meats. 
This  seems  somewhat  exaggerated;  and  to  us  it  appears  doubtful  if 
temperaments  or  physical  stamina  are  so  directly  controlled  by  dietetic 
habits.  It  is  questionable,  for  example,  whether  Gautier  is  justified  in 
contending  that  by  depriving  him  of  meat  it  is  easier  to  debilitate  an 
EngHshman  or  a  Dutchman  than  a  Spaniard  or  Itahan.  The  diverse 
dietetic  customs  of  individuals  and  races  have  become  established  pri- 
marily by  virtue  of  their  pecuHar  environments,  and  the  physiological 
features  have  developed  only  in  a  secondary  way.  In  the  case  of  carniv- 
orous animals,  the  very  traits  which  are  referred  to  the  flesh  diet  are 


742  NUTRITION 

necessarily  established  in  animals  which  must  gain  their  food  by  preying 
upon  others.     Analogy  may  be  most  misleading  in  science. 

A  final  argument  in  supj)ort  of  the  vegetarian  diet  is  based  upon  the 
supposed  structural  adaptation  of  the  alimentary  canal  to  such  a  regime. 
In  reply  it  may  be  pointed  out  that  a  mixed  diet  is  admirably  utilized  in 
man  in  the  light  of  experimental  e^^dence,  There  are  no  convincing 
physiological  or  anatomical  grounds  for  recommending  an  exclusive 
diet  of  either  animal  or  vegetable  origin.  The  disadvantages  attaching 
to  the  exclusive  use  of  foodstuffs  offering  a  large  content  of  indigestible 
and  unutilizable  residues  in  the  gastro-intcstinal  tract  has  frequently 
been  urged  against  the  vegetarian.  Fruits  and  vegetables  are  extremely 
bulky  in  proportion  to  the  available  nutrients  in  them,  and  may  entail 
considerable  alimentary  waste.  In  fairness,  a  sharp  distinction  must  be 
drawn  between  vegetable  diet  and  vegetarian  diet;  and  with  progress 
in  the  processes  of  commercial  food  preparation  many  improvements 
in  adapting  plant  products  for  dietetic  uses  have  been  introduced.  The 
palatability  and  nutritive  value  of  cereals  and  nuts  in  particular  have 
been  enhanced  by  technical  processes,  so  that  many  of  the  newer  food 
products  promise  to  compete  actively  for  popular  favor  with  animal 
foods. 

If  we  attempt  to  separate  fact  from  fancy  in  an  estimate  of  the  nutri- 
tive significance  and  possibilities  of  vegetarian  diet,  there  can  be  no 
question  regarding  the  actual  possibility  of  sustaining  life  with  foods 
drawn  exclusively  from  plant  sources.  Careful  studies  of  the  metabolism 
of  indi\dduals  living  largely  or  entirely  on  such  dietaries  are  available 
in  sufficient  numbers  to  demonstrate  with  scientific  accuracy  what  famil- 
iar observations  have  long  indicated.  Nor  can  there  be  any  question 
as  to  the  possibility  of  sustained  and  vigorous  muscular  exertion  by  per- 
sons accustomed  to  a  vegetarian  regime.  This  is  no  more  than  might 
be  expected,  since  it  has  been  demonstrated  that  the  essential  source  of 
energy  liberated  in  muscular  work  is  to  be  found  in  non-nitrogenous 
foods,  the  preponderance  of  which  specially  characterizes  the  vegetarian 
diet.  There  is,  however,  no  evidence  that  the  vegetarian  utilizes  his 
food  better  or  works  more  economically.  Wliere  advantage  accrues  it 
is  referable  in  greatest  measure  to  the  moderation  in  diet  which  the  so- 
called  vegetarian  regime  tends  to  encourage.  The  appetite  is  stimulated 
to  a  lesser  degree  than  by  meats  and  meat  products,  and  this  fact  taken 
in  conjunction  with  the  usual  more  bulky  character  of  vegetable  foods 
diminishes  greatly  the  tendency  toward  overeating.  The  practice  of 
temperance  in  matters  of  diet  may  be  facilitated  by  the  introduction  of 
vegetarian  methods,  thus  contributing  therapeutic  possibilities  applicable 
in  the  treatment  of  metabolic  disorders  related  to  overnutrition  or  similar 
perversions — gout,  plethora,  obesity,  etc.  There  are  idiosyncrasies  in 
which  vegetable  as  well  as  animal  foods  meet  with  difficulties  in  the  way 
of  practical  use.  One  is  inclined  to  emphasize  the  desirability  of  using 
common  sense  in  the  application  of  dietetic  rules,  remembering  that  man 
is  well  adapted  by  nature  and  experience  to  subsist  on  a  variety  of  foods. 
On  matters  of  diet  every  man  should  be  a  law  unto  himself,  using  judg- 
ment and  knowledge  to  the  best  of  his  ability,  reinforced  by  his  own  per- 
sonal experiences.  Vegetarianism  may  have  its  virtues,  as  too  great 
indulgence  in  flesh  foods  may  have  its  serious  side;  but  there  would  seem 


GENERAL  CONSIDERATIONS  OF  METABOLISM  743 

to  be  no  sound  physiological  reason  for  the  complete  exclusion  of  any 
one  class  of  foodstuffs,  under  ordinary  conditions  of  life. 

Diet  "Fads"  and  "Cures." — Aside  from  the  l^roader  systems  of  diet 
already  considered  and  many  dietetic  "fads"  which  have  been  exploited 
in  a  popular  way,  a  goodly  number  of  diet-cures,  involving  either  exten- 
sive use  or  omission  of  certain  types  of  food  materials,  have  received 
the  advocacy  of  the  medical  profession  at  times  and  thus  found  their 
way  into  the  literature  of  nutrition.  In  illustration  of  some  of  the  types 
here  referred  to,  we  quote  actual  dietaries  which  amply  represent  the 
characteristic  features. 

Dietary  of  a  Fruitarian. — ^The  subject  was  a  man  aged  sixty-three 
years,  weighing  124  pounds.  He  had  lived  upon  a  fruitarian  diet  for  up- 
ward of  twenty  years,  and,  while  he  had  at  times  used  cooked  vegetables 
and  cereals,  he  believed  that  a  diet  of  ripe  and  sweet  fruits  with  nuts 
agreed  with  him  best.  During  the  experimental  period  of  twenty  days 
the  subject  walked  from  4  to  8  miles  a  day,  besides  working  a  little  at 
gardening.  His  average  daily  food  intake,  consisting  almost  exclusively 
of  fresh  fruits  and  nuts,  contained  proteids,  40  grams;  fat,  54  grams; 
starch,  sugar,  etc.,  286  grams;  crude  fiber,  25  grams;  with  a  total 
fuel  value  of  1,700  large  calories.  The  articles  of  diet  used  were 
cottage  cheese,  honey,  apples,  bananas,  cantaloupe,  four  varieties  of 
grapes,  scarlet  haws,  pears,  pomegranates,  persimmons,  oranges,  straw- 
berries, watermelon,  dried  figs,  olive  oil,  almonds,  and  peanut  butter. 
Though  the  data  fall  far  below  the  tentative  dietary  standards,  the 
individual  was  apparently  able  to  satisfy  his  nutritive  demands 
(Jaffa). 

Dietary  of  a  Vegetarian. — I.  The  subject,  accustomed  to  only  light 
exercise,  was  a  healthy  man,  aged  thirty-eight  years,  weighing  61  kilos, 
who  was  under  observation  in  our  laboratory  for  many  months,  during 
which  he  abstained  from  meat,  fish,  and  eggs.  His  average  daily  output 
of  nitrogen  in  the  urine  was  8.5  grams.  A  typical  day's  ration,  selected 
from  a  period  in  which  he  was  actually  in  nitrogen  equilibrium,  is  the 
following: 

Breakfast. — Oatmeal,  237  grams;  butter,  10  grams;  sugar,  35 
grams;    milk,  60  grams;    coffee,  210  grams. 

Lunch. — Macaroni,  142  grams;  cheese,  10  grams;  bread,  71  grams; 
sweet  potatoes,  119  grams;    milk,  250  grams. 

Dinner. — Bread,  80  grams;  butter,  20  grams;  mashed  potato,  176 
grams;  string  beans,  77  grams;  apple  pie,  82  grams;  milk,  250 
grams. 

Total  nitrogen  in  the  food 10 .0  grams. 

Total  nitrogen  in  the  urine 8.5  grams. 

The  estimated  fuel  value  of  food  was  over  2,000  calories. 

II.  Another  individual  of  medium  stature,  observed  by  Caspari  and 
Glaessner,  after  he  had  been  accustomed  to  a  diet  entirely  composed  of 
plant  products  for  many  years,  maintained  nutritive  equilibrium  upon 
rations  like  the  following: 


744  NUTRITION 

Nitrogen,  Fat,  Fuel  value, 

grams.  grams.  calories. 

20  grams,  coffee 0 .  34  82 

46  grams,  sugar 182 

330  grams,  dates 1 .  49  927 

113  grams,  nuts 3.09  64.9  782 

154  grams,  oil 154.0  1,457 

1,005  grams,  potatoes 3.02  988 

30  grams,  carrots 0 .  33  ....  136 


Total 8.27  218.9  4,554 

This  case  is  of  interest  in  view  of  the  extensive  introduction  of  fat  into 
the  dietary  and  the  complete  exchision  of  butter,  milk,  cheese,  or  eggs. 
The  food  utilization  was  not  as  good  as  in  case  of  subject  I,  living  almost 
entirely  on  cooked,  rather  than  raw  products. 

Dietary  in  "Proteid-Fat"  Cures. — The  chmination  of  carbohydrates 
from  the  dietary,  with  substitution  of  fats  and  proteids,  has  been  recom- 
mended by  clinicians  for  the  dietetic  treatment  of  certain  maladies,  prin- 
cipally diabetes  and  obesity.  Without  discussing  here  the  disadvantages 
of  such  a  selection  as  is  usually  made,  with  its  preponderance  of  meat, 
we  quote  a  typical  recommendation  by  F.  A.  Hoffman: 

Morning. — Milk,  200  grams;    cream,  50  grams;   two  eggs;   butter; 
meat,  100  grams. 

Noon. — Meat,  200  grams;   with  peas  or  green  vegetables. 

Afternoon. — Milk,  200  grams;   cream,  50  grams. 

Evening. — Four  eggs;   ham. 

The  total  fuel  value  is  estimated  at  2,200  large  calories,  and  an  increase 
in  the  proteid  content  is  made  possible  by  addition  of  preparations  of 
pure  proteid  such  as  "plasmon"  and  "nutrose."  Many  of  the  dietaries 
now  advised  in  tuberculosis  resemble  the  above  in  various  ways,  with 
eggs  added  in  larger  quantity.  In  numerous  instances,  the  phthisical 
patient  is  not  noticeably  injured  thereby;  nevertheless,  it  is  doubtless 
wise  to  sound  a  warning  of  possible  danger  in  this  high  proteid  nutrition 
in  such  cases. 

Dietary  in  "Hypernutrition"  Cures. — As  illustration  of  a  typical 
dietary  recommended  in  the  "rest  cure"  introduced  into  medical  practice 
by  Weir  Mitchell,  the  following  maximal  intake  continued  for  four  weeks 
has  been  adopted  by  Burkart.  It  should  be  remembered  that  the  patients 
are  inactive  for  the  most  part  during  the  period  of  treatment. 

Quantity,       Proteid,  Fat,      Carbohydrate,  Calories. 


grams. 

grams. 

grams. 

grams. 

Milk 

.  .  .       2.064 

70.4 

75.0 

101.0 

1,296.0 

Meat 

352 

59.8 

7.0 

502.2 

Eggs 

212 

26.7 

487.6 

White  bread 

30 

2.0 

2i.6 

79.5 

Zwieback 

325 

18.0 
8.6 
1.0 

180.0 

42.0 

3.0 

852.0 

Potatoes 

200 

199.4 

Vegetable 

100 

Butter 

20 

ie.e 

50.0 

145.3 

Sweets 

100 

3.0 

0.5 

15.0 

80.0 

195.5  99.1  412.6  3,642.0 


GENERAL  CONSIDERATIONS  OP  METABOLISM  745 

To  the  preceding  list  may  be  added  such  further  extreme  types  of 
dieting  as  are  represented  in  the  so-called  milk-cure,  whey-cure,  grape- 
cure,  etc.,  in  which  a  moderate  diet  is  used  containing  a  large  propor- 
tion of  the  foods  suggested  by  the  names  applied.  Whatever  theraj^eutic 
value  they  have  is  doubtless  associated  with  a  degree  of  moderation  in 
eating  which  they  induce,  as  well  as  with  minor  influences  such  as  the 
mild  diuretic  and  laxative  effects  incidental  to  the  grape  regime. 

Artificial  Food  Preparations. — Modern  times  have  witnessed  the  in- 
troduction of  an  almost  endless  number  of  food  products  prepared  on 
a  commercial  scale  by  modifying  the  natural  foods  in  various  ways. 
The  prevailing  preferences  and  methods  have  been  altered  from  time 
to  time,  in  accordance  with  the  changing  attitude  toward  the  products  of 
the  period.  A  few  years  ago  the  use  of  various  types  of  "  predigested " 
foods  was  hailed  as  an  important  advance  in  feeding  methods.  This  was 
especially  true  of  numerous  albumose  (proteose)  and  peptone  prepara- 
tions, which  found  their  way  into  practice.  The  early  favorable  reception 
which  these  products  received  has,  however,  not  been  continued.  Experi- 
ment has  shown  that  they  can,  under  appropriate  conditions,  replace  true 
proteids  in  the  diet  without  apparent  disadvantage  during  brief  periods 
of  observation,  and  with  maintenance  of  nitrogenous  equilibrium.  But 
in  view  of  the  manifold  provision  in  the  alimentary  tract  for  the  proper 
and  complete  digestion  of  proteid  compounds,  the  unpalatable  character 
of  most  of  these  predigested  materials  and  the  unfavorable  symptoms 
(diarrhoeas,  etc.)  which  larger  doses  of  concentrated  soluble  foods  may 
induce,  their  popularity  has  gone.  In  place  of  them  a  variety  of  native 
proteids,  some  of  them  in  the  form  of  soluble  salts,  like  the  casein  de- 
rivatives, has  been  brought  into  prominence.  Similar  considerations 
apply  to  the  carbohydrate  and  fat  foods,  all  of  them  being  combined 
with  alcoholic  fluids  to  form  widely  used  stimulant  or  "tonic"  prepara- 
tions. It  is  true  that  most  of  these  are  readily  assimilated;  yet  it  can 
scarcely  be  questioned  that  any  therapeutic  value  which  they  may  exhibit 
is  attributable  to  their  nutritive  properties  in  minor  degree  only.  Too 
frequently  the  "food-tonic"  habit  is  induced  in  ways  both  irrational 
and  unadvised.  At  present  the  field  for  artificial  food  preparations  is 
more  generally  restricted  to  infant  nutrition. 

Artificial  Nutrition. — The  cases  in  which  ordinary  methods  of  nutri- 
tion cannot  be  applied  because  of  some  temporary  or  permanent  dis- 
ability of  the  ordinary  paths  of  alimentation  are  sufficiently  familiar  to 
the  physician.  Artificial  modes  of  nourishment  in  such  instances  have 
long  been  practiced  in  the  form  of  feeding  through  a  stomach  tube,  or 
of  rectal  feeding.  It  is  in  this  latter  process  that  the  modern  soluble 
food  preparations  promise  to  be  of  some  value.  Views  regarding  the 
ideal  composition  of  nutritive  enemata  are  somewhat  at  variance.  The 
practice,  however,  is  sufficiently  well  established  to  assure  its  usefulness. 
Subcutaneous  injection  of  soluble  foodstuffs  has  lately  been  advocated, 
especially  by  v.  Leube  in  the  use  of  fats.  This  author  claims  to  have 
achieved  a  satisfactory  absorption  of  liquid  fats  from  under  the  skin, 
olive  oil  being  employed.  It  is  doubtful  whether  any  satisfactory  utiliza- 
tion occurs  in  this  way.  For  proteids  the  experience  on  record  is 
unfavorable,  as  might  be  expected,  if  a  more  complete  break-down  is  essen- 
tial to  their  proper  metabolism.    In  the  case  of  carbohydrates  studies 


746  NUTRITION 

in  our  laboratory  have  shown  that  compounds  like  glycogen,  dextrin, 
inulin,  and  isolichenin  are  absorbed  from  beneath  the  skin,  but  excreted 
again  in  part  unchanged  in  the  urine,  owing  presunuibly  to  the  lack  of 
appropriate  digestive  enzymes  to  convert  them  into  "physiological" 
sugars  during  their  passage  into  and  through  the  circulation.  The 
variable  fate  of  diifercnt  sugars  has  been  previously  noted  and  although 
over  50  grams  of  dextrose  can  be  introduced  subcutaneously  in  man  with- 
out excretion  of  the  sugar,  the  practical  difficulties  encountered  in  infus- 
ing any  considerable  quantities  of  nutriment  in  this  way  are  at  present 
almost  insuperable. 

The  increasing  scientific  and  intelligent  interest  in  the  subject  of  nutri- 
tion is  full  of  promise  for  the  future,  v.  Leyden  has  well  said:  "The 
healthy  and  orderly  conduct  of  our  daily  life  is  intimately  associated 
with  three  important  factors:  nutrition,  work,  sleep.  A  measured  par- 
ticipation in  these  closely  interdependent  things  will  preserve  health, 
prolong  life,  and  perfect  the  valuable  habits  of  regularity,  moderation, 
and  self-control.  Nutrition  should  therefore  be  looked  upon  as  an  im- 
portant function — as  a  duty  of  man  toward  himself." 


PART  IX. 
CONSTITUTIONAL  DISEASES. 


CHAPTER  XXIX. 

DIABETES  MELLITUS. 
By  THOMAS  B.  FUTCHER,  M.  B. 

Definition, — ^A  disorder  of  carbohydrate  and  fat  metabolism  charac- 
terized usually  by  progressive  loss  in  weight,  thirst  and  polyuria,  and  by 
the  persistent  excretion  of  glucose  in  the  urine  while  the  individual  is  on  a 
diet  containing  only  moderate  amounts  of  carbohydrates,  or,  in  certain 
instances,  even  when  no  carbohydrates  are  ingested. 

Historical. — Salomon  and  Hirsch  have  given  the  best  historical  ac- 
counts of  the  disease.  Hippocrates  made  no  reference  to  it  in  his  writings. 
Celsus,  in  the  first  century,  described  a  disease  characterized  by  polyuria, 
wasting,  and  bodily  weakness.  Aretaeus  (circa  150  A.  D.)  was  the  first  to 
use  the  term  diabetes  (Sta/Jiyriys,  a  syphon).  He  noted  the  thirst,  diuresis, 
and  the  striking  emaciation.  The  writings  of  Galen  indicate  that  he  was 
familiar  with  the  main  symptoms  of  the  disease.  The  ancient  Hindoo 
physicians  of  India  are  credited  with  having  been  familiar  with  the  sweet 
taste  of  diabetic  urine.  This  characteristic  is  said  by  Hirsch  to  have  been 
described  in  the  Ayur  Veda  of  Susruta,  written  in  the  sixth  century.  In 
a  Cingalese  treatise  of  the  fifteenth  century,  diabetic  urine  is  referred  to  as 
"modu  mehe"  or  honey  urine.  Notwithstanding  these  references  to  the 
sweetness  of  the  urine,  the  credit  for  pointing  out  this  characteristic  is 
universally  attributed  to  Thomas  Willis,  who  described  it  in  his  "  Pharma- 
ceutice  Rationahs,"  published  first  in  1674.  On  page  71  of  Pordage's 
translation  of  this  treatise,  which  appears  in  the  1684  edition  of  this 
author's  complete  works,  the  following  statement  occurs: — "But  as  to 
what  several  Authors  say,  that  the  Drink  is  little  or  nothing  changed, 
there  is  no  truth  in  their  suggestion;  because  in  all  People  (that  I  ever 
happened  to  know,  and  I  believe  it  to  be  so  in  all)  their  Urin  was  very 
different  not  only  from  the  Drink  that  they  took  in,  but  also  from  any 
other  humors  that  are  usually  generated  in  our  Bodies,  being  exceedingly 
sweet,  as  if  there  had  been  Sugar  and  Honey  in  it."  It  was  not  until  1776, 
a  century  later,  that  Matthew  Dobson,  of  Liverpool,  demonstrated  that 
the  urine  contained  saccharine  matter,  by  evaporating  down  two  quarts 
of  diabetic  urine  and  obtaining  a  cake  of  sugar  weighing  2  oz.,  2  dr.,  2  scr. 

747 


748  CONSTITUTIOXAL  DISEASES 

He  noted  that  tlie  urine  lost  its  sweet  taste  when  it  fermented,  and  also 
stated  that  the  blood  serum  was  sweet. 

Rollo's  atlvocacy,  in  1797,  of  a  meat  diet  in  the  treatment  of  diabetes, 
marks  an  epoch  in  its  history.  He  was  also  the  first  to  give  a  detailed  and 
intelligent  account  of  the  disease.  In  1849,  Claude  Bernard  demon- 
strated that,  in  animals,  puncture  of  a  point  in  the  floor  of  the  fourth  ven- 
tricle near  the  tip  of  the  calamus  scriptorius  and  between  the  nuclei  of 
the  pneumogastric  and  auditory  nerves,  causes  a  transitory  glycosuria. 
In  1857,  he  discovered  the  glycogenic  function  of  the  liver.  A  great  ad- 
vance in  our  knowledge  of  the  disease  was  furnished,  in  1889,  by  Min- 
kowski and  V.  jNIcring,  who  demonstrated  that  conijilctc  extirpation  of  the 
])ancreas  in  various  animals  regularly  caused  a  ))ermanent  diabetes.  In 
1900,  Opie  and  others  pointed  out  the  association  between  degeneration 
of  the  islands  of  Langerhans  of  the  pancreas  and  the  existence  of  glyco- 
suria. The  investigations  of  Otto  Cohnheim,  published  in  1903  and  1904, 
and  jiurporting  to  show  that  the  carbohydrates  of  the  system  are  normally 
burnt  up  by  the  interaction  of  glycolytic  bodies  formed  in  the  ])ancreas  and 
muscles,  promise,  if  eventually  confirmed,  to  go  far  toward  elucidating 
many  hitherto  obscure  points  in  the  metabolism  in  diabetes  mellitus. 

Etiology. — I.  Predisposing  Factors. — Although  diabetes  is  not  a  very 
common  disease,  a  study  of  its  inridcnce  seems  to  indicate  that  it  is  on  the 
increase  in  the  United  States,  even  allowing  for  the  greater  accuracy  in 
diagnosis,  and  in  the  reporting  of  deaths  in  recent  years.  The  United 
States  Census  for  1850  gave  0.9;  for  1860,  1.2;  for  1870,  2.1;  for  1880, 
2.8;  for  1890,  5.5;  and  for  1900,  9.3  deaths  from  diabetes  per  100,000 
population.  In  the  census  year  1900,  there  were  4,672  deaths  from  the 
disease  in  the  United  States,  of  which  2,650  were  in  males  and  2,022  in 
females.  In  this  year  the  ratio  of  deaths  from  diabetes  to  the  total  number 
of  deaths  was  1  to  222.  Statistics  recently  published  by  Tyson  gave  the 
ratio  of  deaths  in  Philadelphia,  for  1900,  as  1  to  402.  In  1870,  the  ratio 
was  less  than  half  this,  namely  1  to  850,  thus  indicating  a  marked  increase 
in  the  prevalence  of  the  disease.  In  Greater  New  York  City,  the  death- 
rate  from  diabetes  in  1900  was  10.3,  and  in  1902,  12.96,  per  100,000  popu  • 
lation.  In  Baltimore,  the  death-rate  from  the  disease  in  1900  was  8. .3,  and 
in  1903,  6.5,  per  100,000.  The  incidence  of  diabetes  in  Baltimore  is 
further  indicated  by  the  fact  that  in  the  seventeen  years  since  the  opening 
of  the  Johns  Hopldns  Hospital,  ending  May  15,  1906,  there  were  259 
cases  under  treatment  in  the  medical  wards  and  medical  section  of  the 
dispensary,  out  of  a  total  of  106,000  medical  patients.  Of  these,  159  were 
in-patients  in  the  medical  wards  among  19,685  medical  admissions 
or  0.8  per  cent,  of  the  total.  The  more  recent  statistics  are  opposed 
to  the  view  that  diabetes  is  much  less  frequent  in  the  United  States  than 
m  Europe.  The  report  of  the  Registrar  General  for  England  and  Wales, 
for  1900,  gave  8.6,  and  for  1903,  8.5,  deaths  from  diabetes  per  100,000 
population,  while  the  rate  in  the  United  States  for  1900  was  9.3.  Accord- 
ing to  Saundby,  writing  in  1897,  the  death-rate  from  the  disease  per  100, 
000  population  varies  considerably  for  the  different  European  cities  and 
countries.  In  Paris  the  death-rate  is  14;  in  Malta,  13;  in  Copenhagen, 
7;  in  Vienna,  4;  in  Norway,  2;  in  Prussia,  2;  and  in  Italy,  1.5. 

Race. — The  statement  that  diabetes  is  very  uncommon  in  the  colored 
race  does  not  seem  to  be  altogether  borne  out  by  facts.    In  the  Johns 


DIABETES  MELLITUS  749 

Hopkins  Hospital  series  of  259  cases,  there  were  26  in  negroes,  or  10.03 
per  cent.  Among  the  159  ward  cases,  tliere  were  143  whites  and  16  colored 
patients,  or  a  ratio  of  9  to  1.  The  ratio  of  white  to  colored  admissions  in 
the  medical  wards  during  this  period  has  been  about  4  to  1.  Thus,  1  out 
of  every  10  cases  of  diabetes  occurred  in  the  colored  race,  while  1  out  of 
every  5  medical  admissions  was  a  colored  patient.  Expressed  in  terms  of 
susceptibility,  it  would  appear  then  that  in  Baltimore  the  white  population 
is  only  twice  more  liable  to  the  disease  than  the  colored.  The  Urn'ted 
States  Census  report  for  1900,  on  the  other  hand,  gave  only  48  deaths 
from  the  disease  in  the  colored  race  out  of  a  total  of  4,672  deaths  from 
diabetes.  Of  these  28  were  in  males  and  20  in  females.  All  authorities 
agree  that  the  Hebrew  race  is  particularly  susceptible.  Frerichs  states 
that  of  his  400  cases,  102  were  Jews.  Wallach  clearly  demonstrated  its 
greater  frequency  among  the  Hebrews  of  Frankfurt.  From  1872  to  1890 
there  were  171  deaths  from  diabetes  in  that  city.  The  proportion  of 
deaths  from  diabetes  to  the  deaths  from  all  causes  was  six  times  greater 
amongst  the  Jews  than  amongst  the  rest  of  the  inhabitants.  The  factors 
occasioning  this  greater  susceptibility  in  Hebrews  are  not  well  understood. 
It  has  been  variously  ascribed  to  greater  instability  of  the  nervous  system, 
fondness  for  sweets,  and  over-eating  and  sedentary  habits  amongst  the 
better  classes,  particularly.  Diabetes  is  very  common  among  the  educa- 
ted and  commercial  classes  in  India,  and  Rose  and  Sen  have  shown  that 
it  is  the  Hindoos  who  chiefly  suffer.  The  disease  is  said  to  be  very  un- 
common in  China  and  Japan. 

Heredity,  undoubtedly,  is  a  factor  in  many  cases.  Several  brothers  and 
sisters  may  be  affected.  While  one  or  other  parent  may  have  the  disease, 
they  often  escape,  and  an  uncle,  aunt  or  cousin  may  suffer  from  it.  Rich- 
ard Morton,  who  termed  the  disease  hydrops  ad  matulam,  or  dropsy  of  the 
chamber-pot  (Phthisiologia,  1689),  records  a  family  in  which  four 
children  were  affected,  one  of  whom  recovered  on  a  milk  diet  and  diascor- 
dium.  Pleasants  found  only  6  cases,  or  5 . 3  per  cent,  with  a  family  history 
of  diabetes,  in  the  first  112  diabetics  in  Osier's  clinic  at  the  Johns  Hopkins 
Hospital,  and  reported  a  family  in  which  two  brothers,  two  sisters,  an 
uncle,  and  a  grand-uncle  had  the  disease.  Of  particular  value  is  the  series 
reported  by  Fitz  and  Joslin  in  which  especial  inquiry  was  made  and  in 
which  heredity  was  found  to  play  a  role  in  23.8  per  cent.  Naunyn  ob- 
tained a  family  history  of  diabetes  in  35  out  of  201  private  cases  and  in 
only  7  of  157  hospital  cases.  Obesity  is  often  a  feature  in  these  hereditary 
cases. 

The  possibility  of  one  person  contracting  the  disease  from  another  by 
injection,  was  first  suggested  by  Schmidt,  in  1890.  Amongst  2,320  cases, 
he  recorded  26  instances  in  which  the  disease  appeared  in  apparently 
healthy  persons,  living  in  intimate  association  with  diabetics.  These 
were  chiefly  married  females  who  contracted  diabetes  after  nursing 
husbands  suffering  from  the  disease.  These  are  the  cases  of  so-called 
"conjugal  diabetes."  Oppier  and  Kiilz,  in  1896,  reported  47  married 
couples  amongst  3,489  diabetic  patients  or  1  to  93 . 3,  or  1 .  08  per  cent. 
Senator,  in  the  same  year,  stated  that  amongst  770  of  his  cases  of  diabetes, 
there  were  9  instances,  or  1 .  19  per  cent.,  in  which  a  man  and  wife  suffered 
from  the  disease.  For  several  years  the  writer  has  had  a  husband  and 
wife,  both  diabetic,  under  his  care.    The  wife  was  shown  to  be  diabetic  in 


750  CONSTITUTIONAL  DISEASES 

1899,  and  sugar  was  first  detected  in  tlic  husband's  urine  in  1902.  Both 
patients  are  rather  obese.  When  one  chniinates  the  influence  of  heredity, 
worry,  obesity,  and  dietetic  conditions  in  these  cases,  Httle  evidence 
remains  to  support  the  hypotiiesis  that  diabetes  can  actually  be  contracted 
by  one  individual  from  another. 

No  age  is  exempt  from  the  disease,  but  most  authors  agree  that  the 
largest  number  of  cases  occin*  in  the  sixth  decade,  that  is,  between  fifty  and 
sixty  years  of  age.  The  incitlencc  as  to  decades  in  the  Johns  Hopkins 
Hospital  series  of  259  cases  is  shown  in  the  following  analysis: — 


1-10 

11-20 

21-30 

31-40 

41-50 

51-60 

61-70 

71-80 

4 

14 

25 

43 

68 

75 

25 

5 

It  will  be  seen  that  the  largest  number  of  cases — 75,  or  28.9  per  cent. — 
occurred  in  the  sixth  decade.  These  figures  agree  closely  with  those  of 
Frerichs,  Scegen,  and  Pavy,  all  of  whom  found  the  largest  number  of 
cases  in  the  sixth  decade,  their  percentages  being  26,  30,  and  30.7  respect- 
ively. Wegeli,  in  an  analysis  of  102  cases  in  children  under  sixteen 
years,  found  the  age  distribution  to  be  as  follows:  under  one  year, 
3;  one  to  five  years,  26;  five  to  ten  years,  31;  ten  to  sixteen  years,  42. 
Stern  mentions  a  case  in  which  a  child  was  apparently  born  with  glycos- 
uria, and  in  which  recovery  took  place  in  eight  months. 

Diabetes  is  decidedly  more  common  in  the  male  sex.  The  proportion 
of  males  to  females  affected  is  about  four  to  three.  In  our  series  of  259 
cases  there  were  151  males  and  108  females.  Of  the  4,672  deaths  from  the 
disease  in  the  United  States  in  1900,  2,650  were  in  males  and  2,022  in 
females.  This  disproportion  is  not  so  marked  in  childhood  and  extreme 
old  age,  when  the  figures  are  more  nearly  equal.  The  incidence  of  the 
disease  in  the  two  sexes  in  the  colored  race  is  indicated  by  the  United 
States  Census  figures  for  1900.  Out  of  48  fatal  cases  in  negroes  for  that 
year,  28  were  in  males  and  20  in  females,  practically  the  same  ratio  as  in 
whites.  Statistics  at  the  Johns  Hopkins  Hospital,  on  the  contrary,  show 
a  striking  preponderance  of  the  disease  in  females  in  the  proportion  of 
two  to  one.  Of  the  26  cases  in  the  wards  and  the  out-patient  department, 
17  were  in  females  and  9  in  males. 

In  spite  of  the  fact  tliat  the  disease  is  often  seen  in  its  severest  form 
among  the  poorer  classes,  it  is  undoubtedly  more  common  in  those  of 
good  social  jposiiion.  Not  infrequently  the  onset  of  the  disease  is  preceded 
by  a  history  of  fright,  severe  nervous  strain,  mental  worry,  and  irritation. 

Obesity  plays  a  very  important  role.  Diabetes  occurs  very  frequently 
in  persons  who  become  very  stout  during  middle  life.  Frerichs  had  59 
cases  of  obesity  among  400  diabetic  patients,  or  15  per  cent.  It  occurred 
in  30  per  cent,  of  Seegen's  and  in  45  per  cent,  of  Bouchard's  cases. 
Women  are  liable  to  become  stout  at  the  climacteric  period,  and  are 
particularly  prone  to  become  diabetic  at  this  time.  Diabetes  occurring 
in  fat  individuals  is  termed  "lipogenous  diabetes."  When  diabetes  occurs 
in  obese  persons  of  middle  age  it  is  usually  of  a  mild  type,  and  the  progno- 
sis is  more  favorable,  the  glycosuria  disappearing  on  a  rigid  diet.  The 
obesity  usually  precedes  the  glycosuria  by  several  years.  The  fat  diabetic 
is  more  commonly  met  with  in  private  than  in  hospital  practice.  Occasion- 
ally obesity  develops  rapidly  in  young  persons  before  the  twentieth  year. 


DIABETES  MELLITUS  751 

These  subjects  may  also  develop  diabetes,  which  is  always  of  a  grave  type 
and  rapidly  leads  to  a  fatal  termination. 

Universally  admitted  as  this  connection  between  obesity  and  glycosuria 
is,  the  nature  of  the  relationship  between  fat  and  carbohydrate  exchange 
is  not  at  all  well  understood.  Von  Noorden  is  of  the  opinion  that  the 
obesity  is  an  early  symptom  of  the  diabetic  condition,  and  that  it  develops 
long  before  glucose  makes  its  appearance  in  the  urine.  Owing  to  the 
belief  that  the  obesity  is  caused  by  the  diabetic  condition,  he  has  given  it 
the  name  "  diabetogenous  obesity."  He  believes  that  in  every  case  of 
true  diabetes,  not  only  the  oxidation  of  carbohydrates,  but  also  their  con- 
version into  fat,  is  restricted.  He  says  that  it  is  conceivable  that  there 
are  cases  in  which  at  first  the  power  to  burn  up  the  sugar  in  the  organism 
is  alone  interfered  with,  while  the  conversion  of  carbohydrates  into  fat 
still  goes  on.  Under  these  circumstances  the  working  or  muscle-cells  of 
the  body  are  richly  bathed  in  a  nutritive  sugar  solution;  nevertheless 
they  are  starved  because  they  cannot,  or  at  least  can  only  with  difficulty, 
seize  upon  the  sugar  molecule,  owing  to  deficient  powers  of  oxidation.  As 
a  consequence  there  occurs  a  sort  of  tissue-hunger,  which  excites  reflexly  a 
sharper  appetite  and  leads  to  the  ingestion  of  a  greater  quantity  of  food. 
The  latter  results  directly  in  an  increased  deposit  of  fat.  According  to 
von  Noorden,  such  persons  are  diabetic,  only  they  do  not  excrete  sugar 
externally  through  the  urine,  but  into  the  easily  accessible  layer  of  adipose 
tissue. 

We  might  suppose  that  the  prolonged  excessive  use  of  carbohydrate 
food  would  favor  the  development  of  diabetes.  There  seems  no  satisfac- 
tory evidence  favoring  this  view,  however.  Cantani  stated  that  the 
majority  of  his  Italian  patients  subsisted  largely  on  farinaceous  food.  He 
believed  the  diet  was  an  important  etiological  factor.  In  Ceylon,  also, 
where  diabetes  is  common,  large  quantities  of  saccharine  food  are  taken. 
The  Chinese,  on  the  other  hand,  rarely  suffer  from  diabetes,  although  their 
diet  consists  chiefly  of  carbohydrates. 

The  metabolic  disturbances  underlying  gout  seem  to  favor  the  occur- 
rence of  diabetes.  Grube,  of  Neuenahr,  found  that  16  out  of  177  diabetic 
patients  suffered  from  gout,  and  23  had  gouty  parents  (hereditary  alter- 
nating gout).  This  proportion  is  probably  unduly  high  owing  to  the  fact 
that  the  waters  at  Neuenahr  are  especially  recommended  for  the  mild 
cases  of  diabetes  occurring  in  gouty  patients.  Von  Noorden  says  that 
the  connection  between  the  two  diseases  may  manifest  itself  in  various 
ways.  The  patient  may  suffer  from  typical  attacks  of  gout  in  middle 
life,  and  later  the  attacks  cease  and  glycosuria  appears.  On  the  other 
hand,  cases  are  observed  in  which  attacks  of  gout  alternate  with  glycos- 
uria (diabetes  alternans).  In  a  third  group,  gouty  symptoms  and  glycos- 
uria are  present  at  the  same  time.  In  all  these  cases  the  diabetes  is  of  a 
mild  type  and  is  compatible  with  a  long  life. 

In  occasional  instances,  diabetes  may  be  traced  to  a  syphilitic  infection. 
The  cases  are  undoubtedly  rare.  Feinberg  reported  3  cases  of  diabetes 
and  1  of  glycosuria  which  he  attributed  to  a  syphilitic  infection.  Where 
syphilis  plays  a  part,  the  lesion  is  most  probably  a  local  one,  and  most 
likely  to  be  situated  in  the  region  of  the  medulla.  Nutritional  changes 
in  the  brain  and  pancreas  from  syphilitic  arterial  disease  must  be  con- 
sidered as  a  possible  cause  for  the  diabetic  manifestations. 


752  CONSTITUTIOXAL  DISEASES 

In  certain  cases  the  diabetic  symptoms  have  begun  shortly  after  one 
of  the  infectious  diieases.  Cases  have  followed  typhoid  fever,  scarlet 
fever,  cholera,  diphtheria,  and  rheumatic  fever.  There  seems  no  satis- 
factory evidence  sui)porting  the  view  that  malaria  is  a  contributory  cause. 
Williamson  thought  influenza  jilayed  a  part  in  G  out  of  100  cases  in  which 
special  in(|uirv  was  made  into  the  previous  history. 

In  rare  instances  diabetes  appears  to  be  induced  by  prrgnanci/.  The 
disease  may  manifest  itself  only  during  the  pregnant  period,  being  absent  in 
the  intervals.  It  is  an  occasional  accompaniment  of  Ba.tedoios  disease. 
JNIore  often  a  transitory  glycosuria  occurs.  Lowered  tolerance  to  car- 
bohydrates in  this  disease  has  been  demonstrated  by  numerous  observers. 
Falkcnberg  has  reported  cases  in  which  glycosuria  has  followed  extirpa- 
tion of  the  thyroid.  Marie,  Fraenkel,  Striunpell,  and  others,  have  observed 
it  in  acrovicgali/.  A  transitory  glycosuria  occasionally  supervenes  after 
attacks  of  gall-stone  colic.  It  may  occur  after  the  administration  of  a 
general  ana\stlietic,  and  in  other  forms  of  narcosis.  Asphyxia,  occasioned 
by  carbon  monoxide  or  carbon  dioxide  poisoning,  may  cause  a  glycosuria, 
or  even  a  true  diabetes.  In  this  connection  also  may  be  mentioned  the 
glycosurias  following  the  administration  of  certain  drugs,  such  as  amyl- 
nitrite,  strychnine,  curare,  and  methyldcljihinin. 

Glycosuria  in  Lesions  of  the  Central  Nervous  System. — Although  isolated 
observations  had  previously  called  attention  to  an  association  between 
certain  lesions  of  the  nervous  system,  and  glycosuria  or  diabetes,  it  was 
Claude  Bernard,  who,  in  1849,  first  demonstrated  this  relation  by  his 
celebrated  "piqiire"  experiment.  He  showed  that  by  puncturing  a  point 
in  the  floor  of  the  fourth  ventricle,  situated  between  the  centres  for  the 
pncumogastric  and  auditory  nerves,  a  hyperglyca?mia,  polyuria,  and  a 
transitory  glycosuria  occurred,  lasting  six  hours  in  the  rabbit,  and  about 
forty-eight  in  the  dog.  Although  this  experiment  has  not  been  confirmed 
in  man,  it  is  not  surprising  that  certain  injuries  to  the  central  nervous 
system  cause  sugar  to  appear  in  the  urine.  Thus  glycosuria  or  a  true 
diabetes  may  follow  severe  trauma.  Ebstein  obtained  a  history  of  external 
injury  in  6  out  of  116,  and  Williamson  in  6  out  of  100  cases  of  diabetes. 
Ebstein  collected  50  cases  of  traumatic  diabetes  from  his  own  clinic  and 
from  the  literature.  In  one-half  of  these,  the  head  was  the  seat  of  the 
injury.  Glycosuria  is  more  liable  to  follow  trauma  in  this  situation.  In 
other  cases,  injuries  to  the  neck,  liver,  kidney  region,  and  pubes,  have  been 
followed  by  it.  Ebstein  thinks  that  individual  predisposition  is  a  large 
factor  in  determining  the  occurrence  of  diabetes  in  these  cases.  Glycos- 
uria may  also  develop  in  the  course  of  a  traumatic  neurosis. 

Glycosuria  or  a  true  diabetes  may  occur  in  organic  lesions  of  the  brain, 
without  Bernard's  "diabetic  centre"  being  necessarily  involved.  Glycos- 
uria is  not  infrequent  after  cereJjral  hemorrhage.  It  rarely  appears  earlier 
than  two  hours  after  the  apoplexy,  and  usually  clears  up  within  six  days. 
Naunyn  knows  of  only  one  instance  where  the  glycosuria  has  passed  over 
into  a  true  diabetes — a  case  reported  by  Meyer.  A  true  diabetes  may  be 
occasioned  by  a  tumor  of  the  pons,  medulla,  or  cerebellum.  Osier  cites  a 
case,  seen  with  Reiss  at  the  Friedrichshain,  Berlin,  of  a  woman  with 
anomalous  cerebral  symptoms  and  diabetes,  in  whom  at  postmortem  a 
cysticercxis  in  the  fourth  ventricle  was  foimd.  Ebstein  reported  4  cases 
in  which  there  was  a  coincident  occurrence  of  ejrilepsy  and  diabetes,  but 


DIABETES  MELLITUS  753 

attributes  the  two  diseases  to  the  same  cause.  Similar  observations  have 
been  made  by  Naunyn,  Jacobi,  and  Lallier.  Naunyn  observed  a  case  in 
chronic  encephalomalacia.  Observers  agree  in  the  comparative  frequency 
of  glycosuria,  or  a  mild  diabetes,  in  general  paresis.  Bond  reports  having 
found  it  in  10  per  cent.,  and  Strauss  in  9  per  cent,  of  their  cases.  Glycos- 
uria is  an  occasional  accompaniment  of  tabes  dorsalis  and  multiple  scler- 
osis. Tumors  of  the  vagus  and  involvement  of  the  nerve  secondary  to  a 
caseated  lymph-gland  have  been  associated  with  a  glycosuria.  The  latter 
is  sometimes  seen  in  severe  cases  of  sciatica,  but  in  this  connection  it  must 
be  remembered  that  neuralgias  are  not  uncommon  in  diabetes.  Isolated 
instances  of  disease  of  the  abdominal  sympathetic  ganglia  accompanied  by 
glycosuria  have  been  reported. 

Experimental  Pancreatic  Diabetes. — Since  Thomas  Cawley,  in  1788, 
recorded  a  case  of  diabetes  in  which  the  pancreas  was  atrophied  and  con- 
tained calculi,  changes  in  the  gland  have  been  from  time  to  time  reported 
by  clinicians  and  pathologists  in  this  disease.  In  1877,  Lancereaux,  on 
the  strength  of  numerous  clinical  observations,  described  a  special  form  of 
diabetes  under  the  name  of  diabete  pancreatique  ou  diabete  maigre,  in 
which  emaciation  was  the  striking  feature,  in  contradistinction  to  diabete 
gras,  in  which  the  subject  remains  well  nourished,  and  in  which  the  pan- 
creas was  not  thought  to  be  involved.  A  great  advance  in  our  knowledge 
of  the  relationship  between  the  pancreatic  functions  and  diabetes  resulted 
from  the  publication  by  Minkowski  and  von  Mering,  in  1889,  of  the  results 
obtained  from  the  extirpation  of  the  pancreas  in  animals.  These  results 
have  since  been  amply  confirmed.  Our  knowledge  concerning  experi- 
mental pancreatic  diabetes  may  be  briefly  summarized  as  follows: 
The  complete  extirpation  of  the  pancreas  in  dogs,  cats,  pigs,  carnivorous 
birds,  frogs,  and  turtles,  is  regularly  followed  by  a  permanent  glycosuria; 
and  in  dogs,  particularly,  the  train  of  symptoms  is  almost  identical  with 
those  of  severe  diabetes  in  man,  and  in  a  comparatively  short  time  ter- 
minates in  death  of  the  animal.  This  result  is  not  due  to  cessation  of  the 
flow  of  pancreatic  juice  into  the  intestinal  canal,  because  diabetes  does 
not  follow  when  the  duct  is  ligatured  or  when  the  juice  escapes  externally 
through  a  cutaneous  fistula.  When  about  one-tenth  of  the  gland  is  left 
behind  with  power  to  functionate,  the  glycosuria  is  slight  and  occurs  only 
when  carbohydrates  are  ingested.  When  more  than  one-tenth  of  the  gland 
is  left  behind  in  a  functionating  condition,  diabetes  does  not  result.  That 
the  diabetes  is  not  a  result  of  injury  of  the  sympathetic  nervous  system, 
as  some  have  claimed,  is  shown  by  the  fact  that  when  the  pancreas  is  only 
partially  extirpated,  and  the  remaining  portion,  with  the  vessel  intact, 
is  transplanted  into  the  abdominal  wall,  diabetes  does  not  occur.  If 
later  this  engrafted  portion  be  removed  diabetes  quickly  supervenes.  It 
should  be  emphasized  here  that  in  experimental  pancreatic  diabetes 
the  deposition  of  the  glycogen  in  the  liver  and  muscles  is  interfered 
with.  The  animals  may  be  given  abundance  of  starchy  material  wih- 
out  more  than  traces  of  glycogen  being  found  in  these  organs.  There 
is  always  a  hyperglycsemia,  however,  the  amount  of  sugar  in  the  circu- 
lating blood  reaching  as  high  as  0.5  per  cent,  within  twenty-four  hours. 
Minkowski  and  von  Mering  formulated  the  following  hj^otheses :  either 
some  substance  which  has  an  inhibitory  action  on  sugar  conversion  col- 
lects in  the  blood  after  extirpation  of  the  pancreas,  or  else,  after  this  oper- 

48 


75i  CONSTITUTIONAL  DISEASES 

ation,  some  substance  is  wanting  or  function  abolished  which,  under  nor- 
mal conditions,  serves  to  facilitate  the  conversion  of  carbohydrate  bodies, 

Lepine,  of  Lyons,  in  1892,  was  the  first  to  advance  the  view  that  dia- 
betes in  man,  and  after  extirpation  of  the  pancreas  in  animals,  is  due  to  the 
failure  of  the  pancreas  to  j^roduce  a  "glycolytic  ferment,"  which  occurs 
as  an  internal  secretion.  This  hyjxithesis  was  based  on  the  following  ex- 
periments: When. a  quantity  of  blood  of  a  normal  dog  is  divided  into  two 
equal  parts,  one  of  which  is  heated  to  54°  C,  and  both  then  placed  in  a 
thermostat  at  39°  C,  it  is  found  that  the  amount  of  sugar  in  the  vmheated 
specimen  is  much  less  than  in  the  other.  That  is,  the  ferment  is  destroyed 
in  the  latter,  and  glycolysis  does  not  occur.  When  the  blood  of  a  pan- 
creatized  dog,  or  of  a  human  diabetic,  was  treated  in  the  same  way,  the 
difference  in  the  amount  of  sugar  in  the  heated  and  unheated  blood  was 
much  less,  indicating  the  absence  of  the  glycolytic  ferment.  These  very 
suggestive  exj)eriments  were  not  subsequently  confirmed  by  the  work  of 
such  investigators  as  ]\Iinkowski,  Ivraus,  and  Seegen. 

Diabetes  and  Organic  Diseases  of  the  Pancreas. — It  is  not  surprising, 
considering  the  foregoing  experimental  results,  that  pancreatic  lesions 
in  man  are  often  followed  by  diabetes.  Lesions  of  no  other  single  organ 
so  frequently  give  rise  to  the  disease,  and  evidence  is  steadily  accumu- 
lating to  lead  us  to  believe  that  many  cases  of  diabetes,  apparently  unac- 
companied by  any  organic  lesion,  are  actually  due  to  pancreatic  disease 
made  out  only  on  microscopic  examination.  Most  of  the  published  sta- 
tistics, showing  the  percentage  of  cases  of  diabetes  with  involvement  of 
the  pancreas,  are  altogether  unreliable  in  the  light  of  recent  knowledge, 
owing  to  the  fact  that  microscopic  examinations  were  in  the  majority  of 
instances  omitted.  According  to  Naunyn,  a  pancreatic  calculus  has  been 
the  most  frequent  lesion.  Others  would  consider  atrophy  of  the  gland, 
chronic  interstitial  pancreatitis,  the  commonest  pathological  change.  In 
the  case  of  a  calculus,  it  must  be  remembered  that  there  is  always  an  asso- 
ciated pancreatitis.  Diabetes  may  occur  when  cancer  involves  the  whole 
or  greater  part  of  the  gland.  It  is  an  interesting  fact  that  diabetes  is  absent 
in  many  of  these  cases.  Hansemann,  and  Bard  and  Pic  attribute  the 
absence  of  the  glycosuria  to  the  assumption  of  the  pancreatic  function  of 
the  cancer-cells.  It  is  surprising  that  glycosuria  does  not  occur  oftener 
in  acute  hemorrhagic  pancreatitis  with  complete  destruction  of  the  gland. 
Seitz  collected  100  such  cases,  in  not  a  single  one  of  which  did  glycosuria 
occur.  This  may  be  accounted  for  by  the  early  death  in  most  of  these  cases. 
Benda  and  Stadelmann  reported  a  case  with  glycosuria.  Sugar  in  the 
urine  occasionally  occurs  in  patients  with  pancreatic  cysts. 

The  Association  Between  Diabetes  and  Lesions  of  the  Islands  of  Lan- 
geraans. — The  year  1900  marks  a  new  epoch  in  our  knowledge  of  the 
etiology  of  diabetes.  In  that  year  Opie^  published  from  Welch's  labor- 
atory a  pathological  study  on  interstitial  pancreatitis  in  which  he  for  the 
first  time  demonstrated  a  connection  between  disease  of  the  islands  of 
Langerhans  and  diabetes.  His  results  were  published  more  in  detail  in 
the  following  year.^  These  groups  of  cells  were  first  described  by 
Langerhans,  in  1869.    They  are  composed  of  columns  of  cells  having  no 

^The  Journal  of  the  Boston  Society  of  Medical  Sciences,  Vol.  IV,  p.  251,  June, 
1900. 

'The  Journal  of  Experimental  Medicine,  1901,  pp.  398-428  and  pp.  527-540. 


DIABETES  MELLITUS  755 

communication  with  the  ducts  of  the  gland,  but  being  in  intimate  relation 
with  a  rich  capillary  network.  They  are  about  the  size  of  a  kidney  glo- 
merulus, measuring  0.2  mm.  in  diameter.  The  islands  are  situated  for 
the  most  part  in  the  centres  of  the  ordinary  gland  acini,  and  arc  quite  dis- 
tinct, structurally  and  functionally,  from  them.  They  are  distributed 
throughout  the  whole  gland,  but  are  more  numerous  in  the  tail  than  in  the 
body  or  head.  In  tissues  treated  two  or  three  days  with  Miiller's  fluid 
they  appear,  under  low  magnification,  as  conspicuous  points  of  a  bright- 
yellow  color.  With  high  magnification,  they  are  found  to  be  composed  of 
small,  irregular,  polygonal  cells  having  a  round  nucleus  and  homogeneous 
protoplasm. 

Opie  described  two  forms  of  chronic  interstitial  pancreatitis — an 
interlobular  and  an  interacinar  type.  In  the  former,  the  development  of 
fibrous  tissue  is  most  conspicuous  between  the  lobules,  while  that  within 
the  lobules  and  between  the  acini  is  much  less  marked.  In  the  latter,  on 
the  other  hand,  the  interlobular  connective  tissue  is  not  specially  increased, 
whereas  the  connective  tissue  between  the  individual  acini  is  markedly 
augmented.  Here,  also,  the  connective  tissue  may  invade  the  individual 
acini  when,  as  would  be  expected  from  their  situation,  the  islands  of 
Langerhans  are  likely  to  be  involved.  In  his  first  series  Opie  reported 
11  cases  of  the  interlobular  and  3  of  the  interacinar  type.  Of  the  11  cases 
only  1  was  accompanied  by  diabetes.  In  this  case,  the  connective  tissue 
had  invaded  the  individual  acini  and  had  caused  atrophy  of  the  islands 
of  Langerhans.  Of  the  3  cases  of  interacinar  pancreatitis,  2  had  diabetes, 
and  the  islands  were  extensively  destroyed.  In  the  third  case  it  was 
thought  that  the  absence  of  diabetes  was  due  to  the  patient  having  died 
of  typhoid  fever  before  the  islands  had  had  time  to  become  extensively 
involved.  The  most  suggestive  case  of  all  was  a  girl,  aged  seventeen, 
who  had  suffered  from  diabetes  for  two  years.  The  autopsy  revealed 
no  gross  lesions  to  account  for  the  disease.  The  pancreas,  macroscopic- 
ally,  looked  perfectly  normal.  On  microscopic  examination,  however, 
it  was  found  that  the  islands  of  Langerhans  were  completely  destroyed 
throughout  the  whole  gland,  with  practically  no  involvement  of  the 
ordinary  secreting  cells  of  the  pancreas.  In  stained  sections,  the  islands 
stood  out  conspicuously  as  red  areas  of  hyaline  degeneration — granular 
atrophy  of  Hansemann — a  few  nuclei  still  being  seen,  without  any  of  the 
original  island-cells  being  visible.  Later,  Opie  observed  2  cases  of 
diabetes  with  identical  changes.  This  hyaline  degeneration  of  the  islands 
appears  to  be  the  characteristic  lesion  in  cases  of  pancreatic  diabetes  in 
which  they  are  not  destroyed  secondarily  to  an  interstitial  pancreatitis. 

Ssobolew,  working  independently,  published,  in  1901,  practically  identi- 
cal observations  on  the  relationship  between  disease  of  the  islands  and 
diabetes.  In  view  of  the  intimate  association,  in  his  series,  between 
involvement  of  the  islands  of  Langerhans  and  diabetes,  Opie  was  led  to 
conclude  that  there  was  a  very  intimate  connection  between  the  functions 
of  these  islands  and  carbohydrate  metabolism.  Laguesse  and  Schafer  had 
previously  suggested  that  the  islands  furnish  an  internal  secretion  in  the 
same  manner  that  the  thyroid  and  adrenal  glands  do.  Owing  to  the 
small  size  of  the  islands,  and  the  almost  utter  impossibility  of  isolating 
them  from  the  rest  of  the  gland  substance,  it  has  been  practically  impos- 
sible  to   produce  experimental  evidence  favoring  this  view,  although 


756  CONSTITUTIOXAL  DISEASES 

Ssobolew  claims  to  have  done  so.  Occurring  as  ductless  glands,  and 
being  surrounded  by  a  rich  capillary  network,  it  is  extremely  probable 
that  these  islands  secrete  some  substance — we  may  call  it  a  "glycolytic 
ferment"  after  Lepine — which  enters  the  circulating  blood,  and  which  is 
necessary  for  the  })ro])er  combustion  of  the  carbohydrates  in  the  system. 
Opie's  observations  have  been  confirmed  by  numerous  observers,  among 
them,  by  Joslin  in  this  country,  and  in  Gernuiny  by  Sauerbeck,^  who  has 
published  the  best  review  of  oiu'  knowledge  on  the  islands  since  Opie's 
comnnmication.  Sauerbeck  fui'uished  a  very  important  contribution  to 
the  subject  by  finding  that  ligature  of  the  pancreatic  duct  in  rabbits  is 
eventually  followed  by  diabetes,  contrary  to  the  view  previously  held. 
Until  about  the  thirtieth  day  after  the  operation  the  islands  of  Langerhans 
are  well  preserved.  On  or  about  this  day,  however,  they  begin  to  dis- 
appear and  their  disappearance  is  marked  by  the  simultaneous  occurrence 
of  sugar  in  the  urine. 

The  theory  that  pancreatic  diabetes  is  dependent  upon  disease  of  the 
islands  of  Langerhans,  while  generally  accepted,  has  certain  strong 
opponents,  among  them  Hansemann  of  Berlin.  There  is  every  reason  to 
believe,  however,  that  very  many  of  the  cases  of  diabetes  in  which  at 
autopsy  no  gross  lesion  is  observable,  will  be  shown  to  reveal  degenerative 
changes  in  the  islands  of  Langerhans  when  examined  microscopically. 
Although  it  is  probable  that  all  cases  of  diabetes  are  not  due  to  organic 
changes  in  these  islands,  we  must  keep  in  mind  the  possibility  of  a  func- 
tional distvu'bance  in  the  cases  where  organic  changes  are  not  demonstra- 
able.  It  is  quite  likely  that  many  of  the  cases  of  the  so-called  endogenous 
diabetes — that  is,  those  without  any  attributable  exciting  cause,  and  without 
evident  pathological  lesions — are  due  to  organic  or  functional  disease  of 
the  islands  of  Langerhans.  The  recent  work  of  Otto  Cohnheim  on  the 
combustion  of  carbohydrates,  to  be  referred  to  later,  tends  to  support  this 
view. 

At  this  point  also  must  be  mentioned  the  interesting  group  of  cases  of 
"bronze  diabetes,"  occurring  as  a  late  manifestation  of  the  remarkable 
affection  known  as  hcemoehromatosis.  The  latter  condition  is  character- 
ized by  a  peculiar  pigmentation  of  the  skin  and  viscera,  associated  with  a 
form  of  hypertrophic  cirrhosis  of  the  liver  and  extensive  sclerotic  changes 
in  the  pancreas,  and  accompanied  in  the  late  stages  by  a  persistent  glycos- 
uria. Hanot  and  Chauffard  first  described  these  cases,  in  1882,  and,  in 
1886,  Hanot  suggested  the  name  diabete  bronze  for  this  type  of  diabetes, 
and,  as  he  considered  the  liver  changes  secondary  to  the  diabetic  condition, 
he  gave  the  name  cirrhose  pigmentaire  diabetique  to  this  form  of  cirrhosis. 
The  true  nature  of  the  affection  was  first  revealed  in  1889  by  von  Reck- 
linghausen, who  described  the  disease  under  the  name  of  hsemochromato- 
sis.  He  showed  that  the  pigmentation  of  the  skin  and  viscera  is  due  to  the 
deposition  of  an  iron-containing  pigment,  hemosiderin,  and  a  non-iron- 
containing  pigment,  htemofusein,  in  the  tissues. 

According  to  the  latest  conception  of  the  disease,  hsemochromatosis  is 
to  be  considered  as  a  primary  affection  of  the  blood  in  which  the  red  cells 
^re  made  more  vulnerable,  causing  them  to  disintegrate  more  readily  and 
to  give  up  their  hsemoglobin.    The  hsemosiderin  possesses  a  brown  color 

,  1  Ergebnisse  der  Allgemeinen  Pathologie  und  Pathologischen  Anatomic,  Achter 
jatrgang,  II,  Abteilung,  1902.    Published  in  1904. 


DIABETES  MELLITUS  757 

and  is  deposited  mainly  in  the  cells  of  the  liver,  pancreas,  lymphatic  and 
sweat  glands.  The  hsemofuscin,  on  the  other  hand,  is  finer,  of  an  ochre- 
yellow  color,  and  is  present  in  the  smooth  muscle  fibers  of  the  stomach, 
intestines,  blood-  and  lymph  vessels,  and  occasionally  in  those  of  the 
urinary  bladder,  ureter  and  vas  deferens.  Iless  and  Zurhelle  have  recently 
made  very  careful  studies  of  two  cases  of  "bronze  diabetes,"  that  is,  two 
cases  of  hsemochromatosis  which  had  advanced  to  the  diabetic  stage. 
As  a  result  of  their  chemical  and  histological  studies  they  incline  to  the 
view  that  the  cirrhosis  of  the  liver  and  the  formation  and  deposition  of  the 
pigment  are  dependent  upon  some  common  cause.  They  hold  that  some 
toxic  substance,  possibly  alcohol,  causes  disturbances  in  metabolism 
which  bring  about  the  above  changes.  A  lipeemia,  which  was  present  in 
one  of  their  cases,  is  explained  in  the  same  way.  Their  investigations 
also  go  to  show  that  a  sharp  distinction  between  hsemosiderin  and  hBemo- 
fuscin  cannot  be  made.  They  claim  to  have  found  them  side  by  side  in 
the  same  cell  with  gradual  transitions  from  one  into  the  other.  The 
hsemoglobin  of  the  blood  is  in  all  likelihood  their  common  source.  As 
a  result  of  the  local  deposition  of  the  pigment  in  the  liver  and  pancreas,  a 
chronic  interstitial  inflammation  occurs,  producing  in  the  case  of  the  liver, 
a  hypertrophic  pigmentary  cirrhosis,  and,  in  the  case  of  the  pancreas, 
an  interstitial  pancreatitis  of  a  pigmentary  type.  In  the  early  stages  or 
early  years  of  this  affection  sugar  does  not  appear  in  the  urine,  and  it  is 
only  when  the  changes  in  the  pancreas  become  so  advanced  that  pre- 
sumably the  islands  of  Langerhans  are  largely  or  completely  destroyed 
that  diabetes  develops.  Whenever  hsemochromatosis,  either  with  or 
without  diabetes,  is  suspected,  the  correctness  of  the  diagnosis  intra 
vitam  will  be  made  much  more  probable  by  removal  of  portions  of  the 
pigmented  skin  and  the  finding  of  iron-containing  pigment  in  the  cells  of 
the  sweat  glands,  by  the  potassium  ferrocyanide  test,  and  of  the  ochre- 
yellow  haemofuscin  in  the  muscle  fibers  of  any  bloodvessels  that  may  be 
present. 

Naunyn,  Grube,  Laache,  and  Fleiner,  have  drawn  attention  to  the 
frequency  in  the  association  between  arteriosclerosis  and  diabetes.  Nutri- 
tional changes  in  the  pancreas,  due  to  sclerosis  of  the  pancreatic  arteries, 
has  been  suggested  as  the  assignable  cause.  Fleiner  reported  a  case  of 
diabetes  in  a  patient  with  general  arteriosclerosis  in  which  there  was  a 
diffuse  interstitial  pancreatitis  with  marked  thickening  and  obliteration 
of  the  branches  of  the  pancreatic  artery. 

Diabetes  and  Organic  Diseases  of  the  Liver. — When  one  considers  what 
an  important  part  the  liver  plays  in  carbohydrate  metabolism — being  the 
great  glycogen  reservoir — it  would  be  natural  to  expect  that  organic 
lesions  of  the  liver  would  frequently  be  the  cause  of  diabetes.  Clinical 
experience,  however,  teaches  us  that  the  most  extensive  disease  of  the 
liver,  such  as  carcinoma  and  cirrhosis,  may  occur  without  even  a  glycosuria 
occurring.  Naunyn  seems  to  be  the  strongest  advocate  of  what  he  terms  a 
"liver  diabetes,"  that  is,  where  the  diabetes  is  due  to  the  organic  change 
in  this  gland.  He  describes  personal  observations  of  cases  of  diabetes 
attributed  to  cirrhosis  of  the  liver  and  to  the  liver  disturbances  accom- 
panying gall-stones.  He  also  draws  attention  to  the  frequency  with 
which  he  has  met  the  glycosuria  in  individuals  with  enlarged  livers, 
caused  by  passive  engorgement  secondary  to.  cardiac  disease.     There  does 


758  CONSTITUTIOXAL  DISEASES 

not  seem  to  be  sufficient  evidence  at  the  present  time  to  justify  the  opinion 
that  a  true  "hver  diabetes"  exists.  Until  a  larger  number  of  cases  of 
diabetes  with  organic  disease  of  the  liver  and  without  microscopic  evi- 
dence of  disease  of  the  islands  of  Langerhans  are  reported,  we  must  sup- 
port this  contention. 

Renal  Diabetes. — The  only  cases  known  to  be  definitely  of  renal  origin 
are  those  of  "phloridzin  diabetes,"  experimentally  produced  by  the  ad- 
ministration of  phloriilzin.  The  latter  is  a  glycoside  obtained  from  the 
bark  of  the  trunk  and  root  of  a])ple,  pear,  ])lum,  and  cherry  trees.  In 
1886,  von  Mering  discovered  that  when  phloridzin  is  administered  by 
mouth  or  subcutaneously  in  man  or  animals,  a  temporary  glycosuria 
results.  The  amount  of  sugar  may  reach  18  per  cent,  in  dogs.  The 
glycosuria  continues  in  animals  fed  on  nitrogenous  diet,  or  in  men  when 
fasting,  indicating  that  the  sugar  is  in  part  manufactured  from  proteids. 
An  important  fact  is  that  no  hyperglycjemia  exists.  That  the  glycosuria 
results  from  the  phloridzin  causing  certain  changes  in  the  renal  cells 
rendering  them  more  permeable  to  glucose,  is  indicated  by  the  fact  that 
there  is  no  increase  of  glucose  in  the  blood;  by  failure  of  a  hyperglycsemia 
to  occur  after  ligaturing  the  ureters  or  excising  the  kidneys;  and  by  the 
observation  of  Zuntz,  who  found  that  when  phloridzin  is  injected  into  one 
renal  artery,  glucose  is  excreted  by  the  corresponding  kidney  immediately, 
while  it  does  not  appear  in  the  urine  of  the  opposite  kidney  until  half  an 
hour  later,  that  is,  until  after  it  reaches  that  kidney  through  the  general 
circulation. 

Considerable  doubt  exists  as  to  whether,  clinically,  the  "renal  diabetes" 
of  Jacobi  actually  occurs.  The  instances  of  diabetes  occurring  in  the 
course  of  chronic  nephritis  are  usually  cited  in  support  of  the  view  that  a 
renal  diabetes  actually  exists.  Klemperer  records  a  very  suggestive  case 
in  which  a  patient  with  chronic  nephritis  excreted  0 .  35  per  cent,  of  glucose. 
There  was  no  accompanying  hyperglycsemia,  nor  did  the  latter  occur  even 
after  the  individual  was  fed  on  bread  and  glucose  and  excreted  as  much 
as  150  grams  of  sugar  daily.  In  fact  the  blood  showed  a  h^^oglycsemia. 
Naunyn  reports  3  cases  of  diabetes  in  chronic  nephritis,  and  inclines  to 
the  view  that  cases  of  renal  diabetes  occur,  but  admits  that  the  question 
is  still  an  open  one.  He  cites  the  cases  of  glycosuria  accompanying  renal 
hemorrhages  and  chyluria,  in  support  of  the  "renal  diabetes"  hypothesis. 

Adrenalin  Glycosuria. — There  is  no  clinical  or  pathological  evidence 
showing  that  diabetes  bears  any  intimate  relationship  to  disease  of  the 
adrenal  glands.  In  rare  instances,  glycosuria  has  been  found  in  associa- 
tion with  lesions  of  these  glands.  Experimentally,  however,  it  has  been 
shown  that  adrenalin,  the  active  principle  of  the  gland,  has  a  powerful 
influence  on  carbohydrate  metabolism.  In  1901,  F.  Blum  reported  the 
results  of  his  experiments  in  connection  with  adrenal  diabetes.  He  found 
that  the  subcutaneous  injection  of  an  aqueous  extract  of  the  adrenal  gland 
produced  glycosuria  in  22  out  of  25  dogs  experimented  upon.  This 
observation  was  later  confirmed  by  Suelzer  and  Croftan.  Herter,  in  1902, 
published  his  experiments  with  adrenalin  chloride.  He  used  a  1  to  1,000 
aqueous  solution  of  adrenalin  chloride  in  his  research.  Subcutaneous, 
intravenous,  and  intraperitoneal  injections  of  the  drug  in  dogs  were  almost 
invariably  followed  by  glycosuria.  Peritoneal  injections,  other  things 
being  equal,  produced  the  most  marked  glycosuria,  an  excretion  of  10 


DIABETES  MELLITUS  759 

per  cent,  or  more  of  sugar  not  being  uncommon.  The  glycosuria  lasts 
usually  a  little  over  twenty-four  hours.  In  order  to  ascertain  whether  the 
more  marked  glycosuria  following  intraperitoneal  injection  was  due  to 
the  direct  action  of  the  drug  on  the  pancreatic  gland,  the  pancreas  was 
exposed  in  a  number  of  normal  dogs,  and  adrenalin  chloride  solution 
was  applied  directly  to  the  presenting  surface  of  the  gland.  It  was  shown 
that  a  marked  glycosuria  followed  the  application  of  very  small  quantities 
of  adrenalin  to  the  gland — quantities  which,  when  applied  locally  to  other 
parts  of  the  body,  gave  rise  either  to  no  sugar  excretion  or  only  a  trivial 
glycosuria.  The  problem  now  to  determine  was  just  how  this  glycosuria 
is  produced.  It  was  first  shown  that  it  was  not  due  to  vascular  disturb- 
ances. Owing  to  adrenalin  chloride  being  a  very  active  reducing  sub- 
stance, Herter  thought  that  the  glycosuria  resulted  from  interference  with 
oxidation  within  the  pancreatic  cells.  Accordingly  local  applications  to 
the  pancreas  of  other  reducing  substances  were  made.  Solutions  of 
potassium  cyanide  constantly  produced  a  glycosuria.  Similar  results  were 
obtained  with  sulphurous  acid,  ammonium  sulphide,  sulphuretted 
hydrogen,  illuminating-gas,  carbon  monoxide,  and  other  reducing  agents. 
Negative  results  were  regularly  obtained  with  non-reducing  substances 
such  as  sodium  chloride,  sodium  hydroxide,  ferric  chloride,  hydrochloric 
acid,  bromine  water,  etc. 

Herter  concluded  that  adrenalin  chloride  and  the  other  reducing  sub- 
stances cause  glycosuria  by  their  power  of  removing  oxygen  from  the 
pancreatic  cells,  thus  interfering  with  their  function.  Histological  exam- 
ination of  the  pancreatic  gland  at  the  height  of  the  glycosuria  showed  no 
recognizable  lesion.  He  did  not  think  that  the  glycosuria  was  due  to  loss 
of  function  of  the  islands  of  Langerhans,  although,  later,  he  found  that  fatal 
doses  of  adrenalin  produced  marked  granular  degeneration  of  the  cells 
composing  the  islands.  Herter  considered  the  experiments  of  clinical  im- 
portance in  that  they  probably  threw  considerable  light  on  certain  forms  of 
human  glycosuria.  He  suggests  that  the  forms  of  glycosuria  following 
conditions  of  asphyxia,  as  after  epileptiform  seizures  and  carbon  monoxide 
poisoning,  may  be  due  to  interference  with  oxidation  in  the  pancreas. 

View  that  Diabetes  is  Produced  by  a  Circulating  Toxin. — In  1900,  Hans 
Leo  published  the  results  of  his  experiments  which  led  him  to  believe  that 
diabetes  was  due  to  some  unknown  toxin.  The  urine  from  diabetic  pa- 
tients was  found  to  cause  glycosuria  in  dogs  when  administered  by  mouth 
and  subcutaneously.  This  result  was  obtained  with  fermented  as  well  as 
with  unfermented  urine.  Leo  was  unable  to  determine  the  true  nature  or 
source  of  this  toxin.  That  it  was  not  of  the  nature  of  a  ferment  he  con- 
cluded from  the  fact  that  it  was  soluble  in  water  and  alcohol,  was  not 
precipitated  by  oxalic  acid,  and  not  destroyed  by  heat.  No  proof  has 
since  been  advanced  to  support  Leo's  view. 

It  is  of  interest  to  note  that  Hofmeister  has  produced  a  so-called  "hun- 
ger-diabetes" in  dogs  by  cutting  off  all  food  for  several  days.  If  a  dog 
weighing  two  to  three  kilograms  be  then  given  10  to  30  grams  of  starch,  a 
glycosuria  reaching  3.84  per  cent,  and  a  total  excretion  of  30  per  cent,  of 
the  ingested  starch  results.  So  far  as  we  know,  an  analogous  condition 
does  not  occur  in  man;  but  Naunyn  makes  the  suggestion  that  some  of 
the  glycosurias  occurring  in  various  cachetic  diseases  may  be  an  expres- 
sion of  a  hunger  diabetes. 


760  CONSTITUTIONAL  DISEASES 

II,  Disturbances  of  Metabolism  in  Diabetes. — The  immediate  cause  of 
diabetes  is  the  development  of  a  hyperglycivmia;  that  is,  an  excess  of  ghi- 
cose  in  the  circulating  blood.  The  explanation  for  the  occurrence  of  this 
bypcrglvcaMuia  is  the  prol)lem  which  has  occupied  the  attention  of  so 
many  investigators  and  one  which  is  still  in  need  of  a  solution. 

As  the  metabolic  disturbances  in  diabetes  have  to  do  mainly  with  the 
warehousing  of  the  carbohydrates,  they  will  probably  be  best  appre- 
ciated by  first  reviewing  the  fate  of  the  carbohydrates  in  normal  metab- 
olism. 

The  hexoses  mainly  concern  us  in  a  discussion  of  both  normal  and 
pathological  carbohydrate  metabolism.  The  hexoses,  in  general  terms, 
may  be  described  as  carbohydrates,  the  molecules  of  which  contain  the 
carbon  atoms  to  the  number  of  six  or  multiples  thereof,  and  the  hydrogen 
and  oxygen  atoms  in  the  proportion  in  which  they  form  water.  They  are 
classified  according  to  the  number  of  carbon  atoms  they  contain,  as  fol- 
lows : 

1.  The  monosaccharides,  or  cjlycoses,  having  the  general  formula  CgHiz 
Og.  These  include  grape-sugar,  also  called  dextrose  or  glucose  (dextro- 
rotatory) ;  fruit-sugar  or  levulose  (levo-rotatory) ;  galactose  and  mannose 
(both  dextro-rotatory) .  All  these  ferment  and  reduce  alkaline  copper-sul- 
phate solutions. 

2.  The  disaccharidcs,  or  saccharoses,  possessing  twelve  atoms  of  carbon 
in  the  molecule,  and  having  the  formula  C12H22O11.  These  are  formed 
by  the  combination  of  two  molecules  of  a  monosaccharide  with  the  loss  of 
a  molecule  of  water.  They  include  cane-sugar  or  saccharose;  milk-sugar 
or  lactose;  and  maltose.  With  the  exception  of  cane-sugar,  all  reduce 
alkaline  copper-sulphate  solutions.  All  are  dextro-rotatory,  but  do  not 
ferment  wdthout  being  split  up  by  dilute  mineral  acids,  etc. 

3.  The  polysaccharides,  or  amyloses:  these  are  the  anhydrides  of  a 
combination  of  many  molecules  of  monosaccharides,  and  possess  the  gen- 
eral formula,  (C6Hio05)n.  They  include  starch,  glycogen,  and  dextrin, 
(all  dextro-rotatory);  inulin  (levo-rotatory) ;  cellulose;  and  animal  gum 
(inactive).  They  do  not  reduce  alkaline  copper-sulphate  solutions  and 
do  not  ferment  w'ithout  being  previously  split  up. 

Normal  Carbohydrate  Metabolism. — The  carbohydrates  in  the  food 
undergo  a  series  of  changes  during  digestion,  as  a  result  of  the  action  of  the 
diastatic  ferments  in  the  saliva,  pancreatic  juice,  and  succus  entericus. 
Possibly  some  changes  also  occur  in  the  process  of  absorption.  Starch, 
the  most  abundant  article  in  our  dietary,  is  eventually  converted  into 
maltose,  or  maltose  and  dextrin,  after  passing  through  a  series  of  inter- 
mediate stages.  The  maltose  and  dextrin  are  further  converted  into  dex- 
trose by  the  sugar-splitting  enzymes  of  the  intestinal  mucous  membrane. 
Cane-sugar,  the  sugar  for  ordinary  sweetening  purposes,  is  hydrolized 
into  dextrose  and  levulose,  and  milk-sugar  probably  undergoes  a  similar 
change  to  dextrose  and  galactose,  although  of  this  we  are  not  so  certain. 
According  to  our  present  knowledge  we  may  say  that  the  carbohydrates 
of  our  food  are  eventually  absorbed  in  the  form  mainly  of  dextrose  (glu- 
cose) or  dextrose  and  levulose.  These  sugars  are  absorbed  directly  into 
the  portal  capillaries  and  not  into  the  lymphatics.  As  a  result  of  car- 
bohydrate digestion  the  portal  vein  conveys  to  the  liver  a  stream  of  sugars 
consisting  mainly  of  dextrose,  but  also  of  smaller  quantities  of  levulose 


DIABETES  MELLITUS  761 

,and  galactose,  and  there,  by  a  jjrocess  of  dehydration,  the  liver-cells  con- 
vert them  into  glycogen  as  follows:  CJIigOg — H2(>=Q,HioC)5.  After  the 
ingestion  of  carbohydrates,  the  surplus  that  is  not  required  for  the  imme- 
diate use  of  the  economy  is  stored  up  in  the  liver  as  glycogen.  According 
to  the  generally  accepted  view  of  {physiologists,  this  glycogen  is  recon- 
verted into  glucose,  probably  by  the  action  of  a  special  enzyme  produced 
by  the  liver-cells.  This  glucose  reaches  the  general  circulation  by  the 
hepatic  veins,  and  is  conveyed  to  the  tissues,  where  it  is  oxidized,  produc- 
ing heat  and  energy.  This  glycogenic  function  of  the  liver  was  first  dem- 
onstrated by  Claude  Bernard,  in  1857,  and  is  generally  accepted  by  modern 
physiologists,  though  it  has  been  vigorously  opposed  in  certain  quarters. 

Pavy  and  his  followers  differ  from  most  physiologists  in  their  views 
concerning  the  method  of  absorption  of  carbohydrates.  He  thinks  that  in 
health  a  considerable  portion  of  the  carbohydrates  ingested  is  converted  by 
the  villi  of  the  intestinal  mucous  membrane  into  fat  and  carried  thence  by 
the  lacteals  to  the  blood.  Another  portion  is  split  up,  being  incorporated 
with  nitrogenous  material  and  carried  away  in  the  form  of  proteid.  These 
changes  are  affected  by  the  same  cells  of  the  villi.  Pavy  thinks  that  only 
the  carbohydrates  not  thus  assimilated  as  fat  or  proteid-carbohydrate 
pass  to  the  liver  and  are  there  converted  into  glycogen  in  the  manner 
described.  "The  office  of  the  liver,"  according  to  Pavy,  "is  thus  supple- 
mentary to  the  assimilative  work  performed  elsewhere.  If  the  latter  work 
is  efficiently  performed  none  is  left  for  the  liver  to  accoinplish.  It  is  the 
sugar  that  is  permitted  to  reach  the  portal  vein  that  is  taken  up  by  the 
liver  and  it  may  happen  that  none  reaches  it  in  health." 

Glucose  and  glycogen  are  formed  not  alone  from  carbohydrates,  but  a 
certain  amount  is  manufactured  from  ingested  and  sometimes  from  body 
proteid.  Evidence  favoring  this  view  was  advanced  by  Claude  Bernard, 
who  showed  that  the  liver  of  an  animal  kept  under  conditions  ordinaril^i 
favoring  the  disappearance  of  the  glycogen,  such  as  fasting,  exercise,  etc.,! 
still  contains  glycogen  when  fed  on  an  exclusive  proteid  diet.  Furthei? 
evidence  is  afforded  by  the  fact  that  severe  diabetics  often  excrete  sugar 
when  on  a  similar  diet.  According  to  Minkowski,  45  grams  of  carbohy- 
drate is  formed  out  of  every  100  grams  of  proteid  decomposed  in  the  body. 
The  general  belief,  however,  is  that  in  normal  metabolism  carbohydrates 
are  probably  not  manufactured  from  the  ingested  proteids.  In  the 
disordered  metabolism  of  diabetes,  on  the  other  hand,  both  the  proteids  of 
the  food  and  particularly  the  body  proteids  yield  considerable  quantities 
of  glucose. 

The  liver  is  capable  of  storing  up  glycogen  to  the  extent  of  14  per  cent,  of 
its  own  weight.  The  amount  it  contains  depends  on  several  factors.  Pro- 
longed fasting,  continuous  physical  exertion,  and  high  temperature, 
rapidly  deplete  its  supply  of  glycogen.  The  latter  is  greatest  in  amount 
on  a  diet  rich  in  carbohydrates.  The  liver  is  not  the  only  seat  for  the 
storage  of  glycogen,  however.  The  other  great  reservoir  is  the  muscular 
system;  and  it  is  estimated  that  the  quantity  in  the  muscles  practically 
equals  that  stored  in  the  liver.  When  conditions  favor  the  depletion  of 
the  supply  of  glycogen  it  is  found  that  the  muscles  give  up  their  supply 
much  less  readily  than  does  the  liver.  The  source  of  the  muscle  glycogen 
is  not  definitely  known,  but  presumably  it  is  formed  from  the  glucose 
brought  to  the  muscles  by  the  circulating  blood. 


762  CONSTITUTIOXAL  DISEASES 

It  has  been  clearly  shown  that  the  amount  of  glucose  in  the  circulating 
blood  normally  varies  within  cjuite  narrow  limits,  namely,  between  0.1 
and  0 . 2  per  cent.  This  is  remarkable  because  we  would  expect  that  when 
carbohydrates  are  ingested  in  large  quantities  the  blood  would  contain 
more  glucose  than  when  they  are  taken  in  smaller  amounts.  This  is  not 
the  case,  however,  for  the  percentage  of  sugar  in  the  circulating  blood 
remains  in  normal  individuals  constantly  within  the  narrow  percentage 
limits  mentioned  above.  This  naturally  leads  us  to  consider  the  fate  of 
the  carbohydrates  under  conditions  which  may  be  considered  as  normal 
variations. 

(a)  In  Ordinary  Nutniion. — In  a  healthy  person,  on  a  usual  mixed 
diet  and  taking  a  moderate  amount  of  exercise,  the  carbohydrates  are 
always  on  hancl  and  are  always  in  demand.  By  their  combustion,  pre- 
sumably for  the  most  part  in  the  muscles,  they  produce  heat  and  energy. 
Owing  to  the  fact  that  normally  there  is  no  loss  of  sugar  in  any  of  the 
excretions,  excepting  in  the  urine  in  the  minutest  traces,  and  owing  to  the 
interposition  of  the  two  carbohydrate  reservoii's,  the  liver  and  muscles,  the 
percentage  of  glucose  in  the  circulating  blood  remains  practically  con- 
stant. After  a  meal  the  excess  of  carbohydrates  is  temporarily  stored  up 
in  the  liver  as  glycogen. 

(6)  When  the  Supply  of  Carbohydrates  is  Insufficient  and  the  Demand 
Excessive. — For  a  few  hours  or  days  under  these  conditions  the  glycogen 
in  the  liver  and  muscles  is  called  upon,  and  makes  up  for  the  deficiency  of 
the  carbohydrate  intake.  In  this  way  the  percentage  of  glucose  in  the 
circulating  blood  is  kept  within  normal  limits.  Eventually  the  glycogen 
is  entirely  used  up,  yet  the  blood  contains  the  normal  amount  of  glucose. 
This  has  been  thought  by  some  to  be  due  to  the  conversion  of  the  body- 
fat  into  glucose.  This  view  has  few  adherents,  how^ever,  and  the  phenom- 
enon is  more  likely  explained  by  the  conversion  of  the  body-proteids  into 
glucose. 

(c)  When  Carbohydrates  are  Ingested  in  Excess  of  the  Needs  of  the 
Body. — ^The  fate  here  depends  on  circumstances.  Within  certain  limits, 
the  excess  in  carbohydrates  can  be  stored  up  in  the  liver  and  muscles  as 
glycogen.  The  limit  of  this  storage  capacity  is  eventually  reached,  for  von 
Noorden  states  that  the  human  organism  is  capable  of  storing  up  only 
about  300  grams  of  glycogen.  Results  will  now  vary  according  to  whether 
the  carbohydrates  are  ingested  in  moderate  excess  over  a  considerable 
interval,  or  in  enormous  quantities  in  a  short  period  of  time.  In  the 
former  case  the  excess  of  carbohydrates  is  converted  into  fat  which  is 
deposited  in  the  connective  tissues,  and  no  hyperglycsemia  occurs.  When, 
however,  there  is  a  sudden  ingestion  of  an  enormous  amount  of  carbohy- 
drates, the  liver  and  muscles  cannot  store  it  all  up  as  glycogen,  nor  can 
the  organism  convert  it  all  into  fat.  An  excess  of  glucose  accumulates  in 
the  circulating  blood.  When  the  blood  contains  more  than  0.2  per  cent, 
of  glucose  a  hyperglyceemia  exists,  which  always  results  in  the  appearance 
of  glucose  in  the  urine. 

The  form  of  glycosuria  produced  in  the  manner  just  described  is  known 
as  alimentary  glycosuria.  This  may  be  considered  a  physiological  pro- 
cess, and  must  not  be  confused  with  true  diabetes.  The  quantity  of  sugar 
that  can  be  ingested  without  its  appearing  in  the  urine  is  designated  by 
Hofmeister  as  the  assimilation  limit.     This  varies  in  normal  persons 


DIABETES  MELLITUS  763 

according  to  the  individual  and  acconiing  to  the  sugar  ingested.  Von 
Noorden  states  that  the  sugar  that  appears  in  the  urine  is  the  same  as 
that  ingested.  This  statement  must  be  accepted  with  reservations.  The 
glycosuria  thus  produced  is  known  as  glycosuria  e  saccharo.  The  assimila- 
tion limit  for  normal  individuals  on  a  fasting  stomach  is  stated  by  von 
Noorden  to  be  as  follows:  For  milk-sugar,  120  grams;  for  cane-sugar, 
150  to  200  grams;  for  fruit-sugar,  200  grams;  for  grape-sugar,  200  to  250 
grams.  When  the  sugars  are  taken  after  a  light  meal  the  limit  is  higher. 
It  is  well  to  emphasize  here  that,  in  a  healthy  person,  sugar  never  appears  in 
the  urine  after  the  ingestion  of  even  enormous  quantities  of  starch.  Diges- 
tion and  absorption  take  so  much  time  that  a  sudden  flooding  of  the  blood 
with  carbohydrates  cannot  take  place.  When  a  glycosuria  does  occur 
after  the  ingestion  of  starch  it  is  called  glycosuria  e  amylo.  It  should 
always  lead  the  physician  to  suspect  that  a  true  diabetic  condition  exists, 
for  it  means  that  the  assimilation  limit,  or  power  to  warehouse  carbohy- 
drates, is  lowered. 

Manner  in  Which  the  Carbohydrates  are  Oxidized  in  the  System. — ^We 
have  until  a  recent  date  been  almost  entirely  in  the  dark  as  to  how  and 
where  the  glucose  of  the  blood  is  ultimately  burnt  up.  At  one  time  it  was 
thought  that  it  was  oxidized  in  the  lungs.  Subsequently,  the  body  tissues, 
particularly  the  muscles,  have  been  held  to  be  the  seat  where  the  carbohy- 
drates are  oxidized,  yielding  energy  and  heat,  and  resulting  in  the  produc- 
tion of  carbonic  acid  and  water.  Lepine  and  Barral  held  that  this 
"glycolysis"  was  affected  through  the  agency  of  a  glycolytic  ferment  pro- 
duced by  the  pancreas  as  an  internal  secretion.  Arthus  denied  the  exist- 
ence of  such  a  ferment  in  the  circulating  blood,  and  held  that  the  enzyme 
is  merely  a  postmortem  product  resulting  from  the  disintegration  of  the 
red  blood  corpuscles. 

Otto  Cohnheim,^  in  1903  and  1904,  published  the  results  of  experi- 
ments which,  if  ultimately  confirmed,  seem  destined  to  solve  the  mystery 
of  carbohydrate  metabolism,  and  to  throw  much  light  on  the  etiology  of 
diabetes  rnellitus.  By  means  of  a  specially  constructed  press,  he  obtained 
quantities  of  juice  from  the  pancreas  and  muscles  of  cats  and  dogs.  With 
each  of  these  juices  he  first  experimented  separately.  Each  juice  when 
added  to  a  solution  of  glucose  was  inactive.  When,  however,  muscle- 
juice  and  glucose-solution  were  mixed  together,  and  then  the  juice  of  the 
pancreas  added,  there  was  a  rapid,  and  eventually,  a  complete  conversion 
of  the  glucose  into  carbonic  acid  and  alcohol.  Cohnheim  holds  that  the 
ingested  carbohydrates  are  burnt  up  in  the  muscles.  He  suggested  two 
possible  explanations  for  the  remarkable  results  above  noted.  One  is 
based  on  Ehrlich's  side-chain  theory.  According  to  this  view,  the  pan- 
creas and  muscles  provide  complementary  and  intermediate  bodies,  both 
of  which  are  necessary  for  normal  carbohydrate  metabolism.  His  second 
explanation  is  in  accord  with  Pawlow's  findings  regarding  the  relationship 
between  trypsinogen,  the  proteid  enzyme  of  the  pancreas,  and  proteid 
digestion.  Pawlow  found  that  trypsinogen  itself  was  inactive  on  proteids, 
but  when  it  came  into  contact  with  the  "enterokinase"  of  the  intestinal 
juice  it  was  converted  into  trypsin  and  then  caused  rapid  digestion  of  the 
proteids.  Cohnheim  believes  that  both  the  pancreas  and  the  muscles  pro- 
duce substances  which  are  necessary  for  normal  carbohydrate  metabohsm. 

» Zeitschrift  fiir  Physiologische  Chemie,  Bd.  XXXIX,  p.  338,  vmd  Bd.  XLII, 
p.  401. 


;64  CONSTITUTIONAL  DISEASES 

He  at  first  thought  that  these  substances  were  of  the  nature  of  enzymes  oi 
ferments.  According  to  this  hyi)othesis,  he  held  that  the  muscles  jn-o- 
duced  a  proenzyme  which  reciuircs  the  action  of  a  ferment,  produced  by 
the  pancreas  and  contained  in  its  internal  secretion,  before  it  can  become 
active  on  carbohydrates.  Cohnheim  in  his  second  communication  gave 
the  results  of  his  experiments  as  to  the  nature  of  the  glycolytic  body  pro- 
duced by  the  pancreas.  He  found  that  it  withstands  boiling,  is  soluble  in 
water  and  96  per  cent,  alcohol,  but  insoluble  in  ether  For  these  reasons, 
he  believes  that  the  glycolytic  agent  of  the  pancreas  is  really  not  a  ferment, 
but  a  body  very  closely  allied  in  its  characteristics  to  such  other  well- 
known  constituents  of  internal  secretions  as  adrenalin,  iodothyrin,  and 
secretin.  An  interesting  feature  is  that  an  excess  of  this  body  hinders,  and, 
when  present  in  large  quantities,  absolutely  prevents,  carbohydrate  com- 
bustion. The  most  active  sugar  destruction  occurs  when  muscle  and 
pancreas  are  mixed  together  in  the  proportion  of  75  grams  of  the  former 
to  0.8  grams  of  the  latter.  When  more  than  0.8  grams  of  pancreas  is 
added  the  activity  diminishes,  and  ceases  when  2  grams  is  reached. 
Cohnheim  suggests  two  explanations  for  this  remarkable  finding.  The 
first  is,  that  the  pancreas  produces  two  substances,  one  of  which  favors 
and  the  other  hinders  sugar  combustion.  For  various  reasons  he  sets 
this  aside  as  a  possible  explanation.  The  second  is  based  on  the  obser- 
vation of  Neisser  and  Wechsberg,  that  the  destruction  of  bacteria  by  a 
bacterial  serum  is  due  to  the  combined  action  of  amboceptors  and  comple- 
ments, and  that  an  excess  of  amboceptors  destroys  the  bactericidal  action 
of  the  serum.  By  analogy,  he  suggests  that  by  adding  an  excess  of  pan- 
creas juice  to  a  mixture  of  sugar  solution  and  muscle  juice,  an  over 
abundance  of  amboceptors  is  provided,  thus  destroying  the  glycolytic 
action  of  the  two  juices. 

Rahel-Hirsch,  whose  researches  were  published  practically^  at  the  same 
time  as  Cohnheim 's,  reached  almost  identical  results.  He  found,  further, 
that  liver  juice,  preserved  in  toluol,  itself  caused  an  appreciable  destruc- 
tion of  glucose  in  solution,  but  that  the  destruction  was  much  more 
marked  after  pancreas  juice  was  added. 

Claus  and  Embden,  in  a  pviblication  which  appeared  early  in  1905, 
stated  that  they  failed  to  confirm  Cohnheim 's  results.  They  believed 
that  the  sugar  destruction  in  Cohnheim 's  and  Kahel-Hirsch's  experi- 
ments was  dependent  upon  bacterial  action  and  due  to  their  failure  to 
prevent  bacterial  growth  in  the  added  pancreas  juice.  Cohnheim  claimed 
that  their  failure  to  confirm  his  results  was  due  to  defective  chemical 
technicjue.  In  INIarch,  1906,  he  published  his  results  of  a  reinvestigation 
of  his  former  work,  and  states  that  they  entirely  confirmed  his  early 
experiments.  His  theory  is  an  extremely  suggestive  one.  According  to 
his  view,  the  sugar  of  the  blood  is  burnt  up  in  the  muscles  through  the 
agency  of  a  glycolytic  substance  which  results  from  the  interaction  of 
bodies  produced  in  the  pancreas  and  muscles.  The  bearing  of  this  con- 
ception on  carbohydrate  metabolism  in  diabetes  will  be  considered  under 
the  theories  as  to  the  causation  of  diabetes. 

Having  reviewed  the  main  features  of  carbohydrate  metabolism  in 
health,  it  is  now  in  order  to  see  what  variations  occur  in  diabetes  mellitus. 
Hyperglycemia,  or  excess  of  glucose  in  the  blood,  is  the  most  constant  and, 
striking  evidence  of  disordered  metabolism  in  the  disease.     Naunyn 


DIABETES  MELLITUS  765 

states  that  he  knows  of  no  case  of  diabetes  in  man  without  a  hypergly- 
csemia,  with  the  exception  of  Klemperer's  case  of  diabetes  in  chronic 
nephritis,  where  the  glucose  in  the  blood  was  said  to  be  subnormal.  It 
will  be  recalled  that  this  case  was  cited  by  Klemperer  as  evidence  in 
favor  of  a  "renal  diabetes."  In  phloridzin  diabetes,  which  is  a  true  renal, 
diabetes,  there  is  no  hyperglycfemia,  and  often  the  glucose  in  the  blood  is 
decidedly  below  normal.  The  great  problem  is  to  ascertain  why  this 
hyperglycaemia  occurs.  Whereas  the  blood  normally  contains  about  0.1 
per  cent,  of  glucose,  with  0.2  per  cent,  as  the  maximum  normal  amount, 
in  diabetes  the  glucose  may  reach  O.G  per  cent,  according  to  determina- 
tions made  by  Pavy  and  by  Seegen.  Naunyn  found  0 . 7  per  cent,  in  one 
case.     This  is  among  the  highest  percentages  recorded. 

Another  very  striking  and  almost  constant  metabolic  disturbance  in 
diabetes  is  the  failure  of  the  liver  to  store  up  glucose  in  the  form  of  glyco- 
gen (zooamylon),  a  condition  to  which  Naunyn  has  given  the  term 
"dyszooamylie."  The  amount  of  glycogen  in  the  liver  is  usually  reduced, 
or  it  may  be  entirely  absent.  Naunyn  says  that  the  evidence  at  hand  is  not 
sufficient  to  decide  the  question  as  to  whether  the  deficiency  of  the  liver  in 
glycogen  is  due  to  failure  of  the  liver-cells  to  convert  glucose  into  glycogen, 
or  mere  failure  of  the  liver-cells  to  store  it  up  when  received.  This  poverty 
in  glycogen  is  also  a  striking  feature  in  the  experimental  glycosuria  follow- 
ing medullary  puncture  and  extirpation  of  the  pancreas.  It  is  an  interest- 
ing fact  that  a  diabetic  can  store  up  glycogen  in  his  liver  from  ingested 
levulose,  whereas  there  is  no  conversion  from  ingested  glucose.  This 
failure  of  the  liver-cells  to  store  up  glycogen  is  very  closely  related  to  the 
production  of  the  hyperglycsemia.  Why  this  power  is  lost  is  not  yet 
understood.  The  fact  that  it  occurs  after  extirpation  of  the  pancreas  in 
animals  suggests  the  possibility  that  some  ferment,  contained  in  an  inter- 
nal secretion  of  the  pancreas,  is  necessary  to  enable  the  liver-cells  to  form 
glycogen  from  ingested  carbohydrates. 

The  metabolic  disturbance  in  diabetes  does  not  in  itself  cause  an  in- 
crease in  the  destruction  of  body  proteids.  The  diabetic  nearly  always 
excretes  a  marked  excess  of  nitrogen  in  the  form  of  urea.  This  increase 
is  due,  however,  in  large  part  to  the  excessive  ingestion  of  proteids,  and 
must  be  considered  physiological.  The  healthy  individual  would  excrete 
proportionally  large  amounts  of  nitrogen  if  his  diet  were  increased  to 
the  same  extent.  The  condition  becomes  pathological  only  when  the 
amount  of  nitrogen  in  the  urine  exceeds  that  taken  in  the  food;  in  other 
words,  when,  in  addition  to  the  albumin  in  the  food,  that  of  the  tissues 
also  is  decomposed.  This  occurs  in  diabetics  when  so  much  sugar  is 
excreted  that  after  the  subtraction  of  its  heat- value  from  the  heat- value  of 
the  food,  the  latter  is  found  to  be  insufficient.  This  waste  of  nitrogen  is 
the  greater  the  more  the  food  value  is  depreciated  by  glycosuria.  It  is 
very  large  as  long  as  the  diabetic  is  left  to  himself  to  ingest  the  carbohy- 
drates which  are  useless  to  him,  but  becomes  slight  or  ceases  when  the 
diet  consists  largely  of  proteids  and  fat.  In  the  severe  cases  of  diabetes 
with  rapid  emaciation  there  is  often  a  marked  increase  in  the  excretion  of 
nitrogen,  owing  to  the  consimiption  of  the  body  proteids. 

It  is  not  alone  the  metabolism  of  the  carbohydrates  that  is  disturbed  in 
diabetes.  It  is  only  in  the  last  few  years  that  students  of  this  disease  are 
awakening  to  the  fact  that  there  is  also  a  marked  disturbance  in  fat 


766  CONSTITUTIOXAL  DISEASES 

metabolism.  There  is  now  practically  conclusive  evidence  that  the  power 
of  the  tissues  to  oxidize  the  fat  of  the  food  and  body  is  markedly  lowered. 
In  the  last  five  years  evidence  has  gradually  accumulatetl  to  show  that 
/?-oxybutyric  acid  and  its  derivatives,  diacctic  acid  and  acetone,  arise  as 
a  result  of  the  incomplete  oxidation  of  fat.  This  is  the  generally  accepted 
view  as  to  their  origin  at  the  present  time.  It  will  naturally  be  inferred 
that,  in  the  regulation  of  the  iliet  of  diabetics,  we  must  not  only  consider 
the  carbohydrates,  but  we  must  pay  more  attention  to  the  prescribing 
of  the  amount  and  kind  of  fat  than  we  have  been  accustomed  to  do  here- 
tofore. 

Diabetes  is  sometimes  considered  among  the  auto-intoxications.  We 
have  no  proof  that  an  excess  of  glucose  in  the  circulating  blood  is  capable 
in  itself  of  producing  any  toxic  symptoms.  Diabetic  coma,  the  most 
serious  complication  of  the  disease,  however,  is  definitely  due  to  an  acid 
auto-intoxication,  as  we  shall  sec  later  on. 

Theories  of  Diabetes  MellitUS.— The  results  of  researches  published 
up  to  the  present  do  not  warrant  any  dogmatic  statements  as  to  the  cause 
or  causes  of  the  hyperglycemia  in  diabetes.  We  can  conceive  of  its  being 
occasioned  in  at  least  two  ways:  (1)  By  over-production  of  glucose. 
(2)  By  under-consumption  of  glucose  in  the  tissues. 

1.  Theory  of  Over-Production. — There  is  no  evidence  to  show  that 
the  diabetic  individual  forms  any  more  sugar  from  a  certain  amount  of 
food  than  does  a  healthy  person  from  the  same  amount  of  food.  We  have 
instances  of  over-production  in  those  cases  of  glycosuria,  or  true  diabetes, 
resulting  from  irritation  or  injury  to  the  nervous  system,  of  which  the 
medullary  puncture  is  a  type.  In  these  cases,  however,  the  over-produc- 
tion of  glucose  is  a  temporary  one,  and  results  merely  from  an  over- 
production of  glucose  from  the  stored-up  glycogen  in  the  liver.  Two 
explanations  are  given  for  the  h^'perglycjemia  in  these  cases.  One  is  that 
the  injury  to  or  disease  of  the  nervous  system  causes  a  centripetal  nerve- 
impulse  to  be  sent  out  to  the  liver,  causing  its  cells  rapidly  to  part  with 
their  glycogen  in  the  form  of  glucose.  The  other  is  that  vasomotor 
disturbances  are  produced  which  result  in  increased  vascularity  of  the 
liver.  In  this  way  a  greater  amount  of  some — as  yet  undetermined — 
ferment  in  the  blood  reaches  the  liver,  causing  a  more  rapid  conversion 
of  glycogen  into  glucose.  Naunyn  believes  that  the  hyperglycemia  is 
directly  dependent  on  the  fact  that  the  liver  and  muscles  of  the  diabetic 
are  unable  to  store  up  glycogen  in  the  same  way  that  they  do  in  health. 
The  glucose  derived  from  the  ingested  carbohydrates  and  proteids  goes 
to  the  liver,  and,  instead  of  being  there  temporarily  stored  up  as  glycogen 
until  required  by  the  system,  as  occurs  in  health,  it  presumably  passes 
directly  into  the  blood  after  a  meal,  causing  a  hyperglyctemia  and  con- 
sequent glycosuria.  This  naturally  does  not  necessarily  mean  an  over- 
formation  of  glucose.  Von  Noorden  denies  the  over-production  of  sugar, 
but  advances  no  conclusive  evidence  to  support  his  contention. 

2.  Theory  of  Under-Consumption  and  Deficient  Oxidation. — In 
health,  the  glucose  of  the  blood  is  consumed  mainly  in  the  tissue-cells, 
particularly  those  of  the  muscles.  Normally  arterial  blood  contains  more 
glucose  than  venous  blood,  which  is  evidence  in  favor  of  the  above  con- 
tention. If  the  tissue  cells  of  diabetic  individuals  fail  to  consume  glucose 
we  would  expect  to  find  less  difference  between  the  percentage  of  glucose 


DIABETES  MELLITUS  767 

in  arterial  and  venous  blood  in  diabetic  than  in  healthy  persons.  Chau- 
veau  and  Kaufmann  estimated  the  sugar  in  the  blood  of  the  crural  artery 
and  vein  in  healthy  and  in  diabetic  dogs.  They  found  the  difference  to  be 
the  same  in  both  animals,  and  conclude  that  the  capacity  for  consuming 
sugar  is  not  lost  in  diabetes. 

A  healthy  individual  on  a  mixed  diet  gives  out  less  carbonic  acid  than 
he  receives  of  oxygen,  the  ratio  being  on  an  average  9  to  10.  I^his  is  ex- 
pressed by  the  fraction  0.9,  and  is  called  the  respiratory  cjuotient.  If 
there  were  an  under-consumption  of  glucose  in  the  tissues  we  would  expect 
the  quotient  to  be  much  reduced.  Voit  and  Leo  have  shown  that  there  is 
no  such  reduction.  Von  Noorden,  who  is  a  vigorous  supporter  of  the 
under-consumption  theory,  lays  great  stress  on  an  observation  of  Wein- 
trand  and  Laves,  who  found  that  the  addition  of  small  quantities  of 
carbohydrates  to  the  dietary  of  diabetics  raises  the  respiratory  quotient 
much  less  than  in  health.  He  considers  that  this  is  evidence  that  the 
glucose  is  not  properly  consumed  in  the  tissues  of  diabetics.  Another 
evidence  in  favor  of  under-consumption  is  that  carbohydrates  are  not 
converted  into  fats  as  in  health. 

Lactic  and  glycuronic  acids  are  considered  by  most  physiologists  to  be 
intermediate  products  in  the  combustion  of  glucose  in  the  system.  Gly- 
curonic acid,  like  glucose,  is  found  in  minute  traces  in  normal  urine. 
Mayer  has  found  the  glycuronic  acid  excretion  considerably  increased  in 
diabetes,  and  as  he  has  also  found  it  increased  in  conditions  of  suboxida- 
tion  he  thinks  he  has  demonstrated  conclusively  that  diabetes  is  due  to 
deficient  oxidation  in  the  tissues. 

The  evidence  so  far  provided  does  not  warrant  us  in  asserting  definitely 
that  diabetes  results  from  over-production  and  not  under-consumption  of 
glucose  or  vice  versa.  In  the  opinion  of  the  writer,  however,  the  evidence 
points  much  more  strongly  toward  the  view  that  the  hyperglycsemia  is  due 
rather  to  under-consumption  of  glucose  from  a  lowering  of  the  powers 
of  the  tissues  to  oxidize  carbohydrates,  than  to  an  over-production  of 
glucose. 

Pavy,  it  will  be  recalled,  thinks  that  normally  the  ingested  carbohy- 
drates are  converted  by  the  intestinal  villi  largely  into  fat  and  into  a 
proteid-carbohydrate,  and  that  only  a  smaller  quantity  reaches  the  liver 
as  glucose.  In  diabetes  he  thinks  that  this  function  of  the  villi  is  largely 
abolished;  and  that  consequently  a  much  larger  quantity  of  sugar 
reaches  the  liver  and  general  circulation,  resulting  in  a  hyperglycsemia. 

Cantani  holds  that  the  sugar  found  in  the  diabetic  individual  is  not 
ordinary  glucose,  but  a  paraglucose  which  the  tissues  are  not  capable  of 
utilizing.  Consequently  it  accumulates  and  a  hyperglycsemia  results. 
His  view  has  not  received  substantiation. 

Theory  Based  on  the  View  that  a  Normal  Glycolytic  Ferment  or  Body  is 
Lacking  in  Diabetes. — Lepine  was  the  first  to  advance  the  hypothesis  that 
diabetes  resulted  from  the  failure  of  the  pancreas  to  produce  a  glycolytic 
ferment  which  was  necessary  to  the  liver  in  order  for  it  to  perform  its  glyco- 
genic functions.  The  observations  of  Opie  and  Ssobolew  on  the  relation- 
ship  between  disease  of  the  islands  of  Langerhans  of  the  pancreas  and 
diabetes,  and  the  recent  important  investigations  of  Otto  Cohnheim  and 
Rahel-Hirsch  on  the  combustion  of  carbohydrates,  have  afforded  evidence 
strongly  supporting  the  view  that  the  pancreas,  pancreas  and  muscles. 


768  CONSTITVriOXAL  DISEASES 

or  pancreas  and  liver,  prodnce  a  glycolytic  body  "which  is  necessary  for 
carbohydrate  metabolism,  the  absence  of  which  leads  to  failure  in  the 
combustion  of  glucose  antl  consequent  hyperglycannia.  Their  work 
has  already  been  given  in  detail,  and  only  the  essential  points  will  be 
recalled  here  to  elucidate  the  theory  under  discussion.  Opie  showed 
that  in  diseases  of  the  pancreas  accompanied  by  diabetes,  the  islands 
of  Langerhans  were  practically  always  diseased  and  presumably  ren- 
dered functionless.  He  also  found  that  in  certain  cases  of  diabetes 
the  pancreas  macroscopically  appeared  normal,  but  microscopically 
revealed  degeneration  of  the  islands  of  Langerhans  as  the  only  patho- 
logical change. 

Cohnheim,  in  1903,  found  that  muscle  juice  of  cats  and  dogs  when  added 
to  a  solution  of  glucose  had  no  effect  on  the  latter.  When,  however,  the 
expressed  juice  of  the  pancreas  was  added  to  the  mixture  of  muscle  juice 
and  glucose  there  was  a  ra])id  breaking-up  of  the  glucose  into  alcohol  and 
carbonic  acid.  He  concludetl  that  in  normal  animals  a  glycolytic  ferment 
or  body  results  from  the  interaction  of  substances  produced  by  the  pan- 
creas and  muscles,  and  that  this  is  necessary  for  the  combustion  of  glucose. 
Opie's  observations  on  the  pancreas  suggest  very  strongly  that  the  pan- 
creatic part  of  the  glycolytic  body  is  produced  by  the  islands  of  Langer- 
hans, and  Ssobolew  claims  to  have  shown  that  this  is  the  case. 

The  work  of  these  observers  is  extremely  suggestive,  and  constitutes  one 
of  the  most  important  contributions  to  our  knowledge  of  the  etiology  of 
diabetes  that  has  ever  been  made.  It  seems  to  afford  an  explanation  for 
the  development  of  diabetes  after  extirpation  of  the  pancreas.  Some  ob- 
servers claim  to  have  found  no  disease  of  the  islands  of  Langerhans  in 
certain  cases  of  diabetes.  In  these  cases  two  possibilities  present  them- 
selves. The  islands  may  not  be  organically  but  functionally  diseased. 
On  the  other  hand  the  muscles  may  be  at  fault. 

The  evidence  thus  afforded  seems  to  justify  us  in  strongly  suspecting 
that  in  health  the  pancreas  and  muscles  (and  possibly  other  tissue-cells)  pro- 
duce substances  tohich,  by  their  interactio7i  on  each  other,  yield  a  glycolytic 
body — call  it  a  glycolytic  ferment  if  tve  will — ivhich  is  necessary  for  the 
proper  combustion  of  the  glucose  in  the  body.  This  body  may  be  necessary 
also  for  the  normal  glycogenic  function  of  the  liver  to  be  carried  on.  Its 
absence  would  lead  to  an  under-consumption  of  glucose  with  a  resultant 
hyperglycaemia.  It  must  not  be  forgotten  that  Cohnheim's  results  have 
not  been  confirmed  by  some  of  the  workers  who  have  repeated  his  experi- 
ments. Consequently,  any  explanation  as  to  the  etiology  of  diabetes 
based  upon  them  is  still  in  the  hypothetical  stage.  If  Cohnheim's  work 
be  correct  it  must  necessarily  add  additional  support  to  the  view  that  the 
hyperglyctemia  in  diabetes  is  due  rather  to  deficient  consumption  or 
lowered  oxidation  than  to  over-production  of  glucose. 

One  seems  justified  in  predicting  that  in  the  future  it  will  be  shown  that 
a  much  larger  percentage  of  cases  of  diabetes  is  due  to  pancreatic  disease 
than  was  formerly  believed.  The  recent  advances  in  our  knowledge  of 
the  physiology  and  pathology  of  the  gland  seem  to  warrant  this  pre- 
diction. 

It  is  quite  probable  that  all  cases  of  diabetes  cannot  definitely  be 
attributed  primarily  to  disordered  metabolism — the  cases  of  "pure" 
diabetes  of  Xaunyn — or  to  pathological  lesions  in  the  pancreas.    A  com- 


DIABETES  MELLITUS  769 

paratively  small  number  are  due  primarily  to  functional  or  organic 
disease  of  the  central  nervous  system,  as  noted  in  the  consideration  of  the 
etiology. 

Pathology. — The  etiology  and  pathology  of  diabetes  mellitus  are  so 
clearly  related  that  it  is  almost  impossible  to  discuss  one  without  the  other. 
In  the  section  on  etiology  those  morbid  lesions  which  were  believed  to  be 
the  cause  rather  than  the  result  of  the  diabetes  have  already  been  con- 
sidered. Thus  the  organic  lesions  of  the  nervous  system,  liver,  and 
pancreas  which  are  so  important  in  the  etiology  of  diabetes,  have  been 
fully  discussed.  In  order  to  prevent  repetition,  these  will  not  be  fully  con- 
sidered here.  The  morbid  changes  not  already  considered,  and,  partic- 
ularly, those  which  are  regarded  as  the  result  of  the  disease,  will  now  be 
briefly  considered. 

The  blood  always  shows  a  hyperglycaemia.  The  only  exceptions  to  this 
rule  are  the  cases  of  phloridzin  diabetes  and  the  other  rare  instances  of 
so-called  "renal"  diabetes  which  have  been  described  by  Kemperer  and 
Naunyn.  In  these  cases  there  is  a  hypoglycsemia.  The  blood  is  often 
concentrated.  The  specific  gravity  may  be  increased  or  diminished, 
according  to  the  water  content.  In  cases  with  marked  polyuria,  in  which 
the  watery  constituents  of  the  blood  are  depleted,  the  red  cells  may  be 
6,000,000  per  cmm.  or  more.  The  latter  react  differently  from  those  of 
normal  blood  with  certain  aniline  dyes.  Bremer  found  that  smears  of 
diabetic  blood,  heated  for  six  to  ten  minutes  at  135°  C.  and  immersed 
for  one  to  two  minutes  in  a  1  per  cent,  aqueous  solution  of  congo-red, 
remained  unstained,  while  smears  of  normal  blood  take  the  red  stain. 
The  red  cells  of  diabetic  blood  also  stain  differently  with  eosin  and  methy- 
lene blue.  The  leukocytes  are  usually  normal  in  number,  or  increased 
only  in  proportion  to  the  concentration.  The  writer  has  observed  a 
leukocytosis  of  from  18,000  to  25,000  in  diabetic  coma.  The  leukocytes 
contain  glycogen.  The  alkalinity  is  reduced,  particularly  in  coma.  This 
is  occasioned  by  the  presence  of  /?-oxybutyric  and  diacetic  acids.  Ace- 
tonsemia  may  occur.  Lipcemia  occasionally  occurs.  The  fat  may  be  de- 
tected in  the  form  of  numerous  minute  dancing  granules  in  the  serum  in 
thick  preparations  of  fresh  blood.  The  separated  serum  has  a  decided 
milky  appearance.  Fraser,  in  1903,  reported  a  case  in  a  diabetic  with 
a  fatal  coma.  The  percentage  of  fat  in  the  blood  was  16.44  per  cent. 
Fischer  recorded  a  case  with  18.12  per  cent.,  the  highest  ever  reported. 
According  to  Becquerel  and  Rodier,  blood  normally  contains  from  0.16  to 
0.325  per  cent,  of  fat.  Exudates  in  the  serous  sacs  may  be  turbid  with  fat. 
The  lipajmia  has  been  attributed  to  the  over-ingestion  of  fats,  to  fatty 
degeneration  of  the  viscera,  and  to  deficient  lipolysis.  In  Fraser's  case, 
the  appearance  of  the  lipsemia  was  coincident  with  a  marked  reduction 
in  the  sugar  of  the  blood,  and  he  thinks  that  the  fat  may  be  derived  from 
the  glucose.  The  fat  droplets  take  the  characteristic  stains  with  Sudan 
III  and  osmic  acid. 

No  characteristic  changes  are  to  be  found  in  the  gastro-intestinal  tract. 
Frerichs  frequently  found  a  thick  layer  of  a  fungus  growth  in  the  mucous 
membrane  of  the  fauces  and  oesophagus.  Occasionally  the  stomach  has 
been  found  dilated.  Swelling,  redness,  and  ecchymoses  of  the  gastric 
mucosa,  have  been  noted.  Tuberculous  ulceration  of  the  intestine  may 
occur  where  there  is  pulmonary  tuberculosis. 

49 


770  CONSTITUTIONAL  DISEASES 

The  heart  may  be  hypertro[)hiod,  but  this  is  rare.  The  myocardium  is 
often  pale  and  soft.  In  old-standino-  cases,  advanced  fatty  degeneration 
of  the  muscle-fibers  is  common.  Pericarditis  and  endocarditis  rarely 
occur.    Arteriosclerosis  is  rather  common. 

Of  the  pulmonary  lesions,  tuberculosis  is  probably  the  most  common. 
The  tissues  of  the  diabetic  seem  to  furnish  a  specially  good  medium  for  the 
growth  of  the  tubercle  bacillus.  Acute  bronchopneumonia  and  lobar 
pneumonia  may  occur,  and  either  may  terminate  in  gangrene.  The 
writer  has  seen  one  case  of  bronchopneumonia  terminate  in  abscess 
formation.  Ch'ohe,  Kiihne,  and  Ehrlich,  have  shown  the  cells  of  the 
pneumonic  exudate  to  be  rich  in  glycogen.  A  chronic  non-tuberculous 
interstitial  ])neumonia  has  been  described.  So-called  fatty  emboli  of  the 
pulmonary  arteries  occur  in  coma,  but  are  of  no  pathological  significance. 

The  liver  is  usually  somewhat  enlarged,  and  fatty  degeneration  is  com- 
mon. The  form  of  cirrhosis  designated  by  Hanot  as  cirrhose  jncjvien- 
iaire  diahetique,  which  is  one  of  the  lesions  of  htemochromatosis  in  which 
diabetes  may  develop  as  a  late  manifestation,  has  already  been  described. 
Poverty  of  the  liver  in  glycogen  is  a  striking  feature.  The  jxmcreatic 
lesions  have  been  described.  There  are  no  changes  in  the  gland  that  are 
regarded  as  secondary  to  the  disease. 

The  kidneys  are  often  enlarged.  The  most  characteristic  change  is  a 
hyaline  degeneration  of  the  epithelial  cells  of  Henle's  loop,  described  by 
Armanni  and  sometimes  spoken  of  as  the  lesion  of  Armanni.  The 
affected  cells  present  a  swollen,  transparent  appearance,  as  if  transformed 
into  large  hyaline  vesicles.  The  nuclei  stain  well  and  are  pushed  to  the 
periphery.  Cantanniand  others  have  confirmed  Armanni's  observations. 
Ehrlich  and  Frerichs  have  described  a  glycogenic  degeneration  of  the 
same  cells  as  are  involved  in  Armanni's  lesion.  The  degeneration  can  be 
demonstrated  macroscopically  by  treating  the  kidney  section  with  Lu- 
gol's  solution,  the  affected  portion  taking  on  a  red  color.  Straus  holds 
that  the  hyaline  changes  described  by  Armanni  and  the  glycogenic 
changes  described  by  Ehrlich  and  Frerichs,  are  really  of  the  same  nature. 
In  some  cases  he  has  demonstrated  the  hyaline  changes  without  finding 
glycogen  present.  In  such  cases,  he  thinks  that  the  glycogen  has  been 
present  at  one  time,  but  has  disappeared  before  death,  leaving  only  the 
hyaline  changes.  Ebstein  has  described  a  necrosis  of  the  renal  epithelial 
cells,  similar  to  the  coagulation  necrosis  of  Weigert  in  other  diseases. 
Interstitial  and  parenchymatous  nephritis  may  occur,  but  there  is  no  reason 
to  believe  that  diabetes  is  the  cause  of  the  nephritis  in  these  cases.  A 
cystitis  occasionally  occurs.  It  has  been  attributed  to  irritation  by  the 
saccharine  urine,  but  it  is  more  likely  due  to  bacterial  infection. 

Of  the  lesions  of  the  nervous  system  not  already  described,  Saundby 
states  that  congestion  and  oedema,  and  thickening  of  the  membranes  of 
the  brain,  may  occur.  Williamson,  Sandmeyer,  and  Kalmus,  have  des- 
cribed a  degeneration  of  the  posterior  columns  of  the  cord  similar  to  the 
sclerosis  of  these  tracts  in  tabes  dorsalis.  Williamson  states  that  the 
lesion  is  best  seen  with  the  naked  eye,  when  the  affected  portions  appear 
much  paler  than  does  the  healthy  white  matter.  These  changes  are 
attributed  to  the  action  of  some  toxic  agent.  The  peripheral  nerves, 
particularly  those  of  the  lower  extremities,  may  be  the  seat  of  an  inter- 
stitial inflammation,  with  secondary  degeneration  of  the  axis  cylinders  of 


DIABETES  MELLirUS  771 

the  nerve  fibers.  This  neuritis  may  be  the  cause  of  definite  cHnical 
symptoms. 

Symptoms. — Various  writers  have  been  disposed  to  recognize  certain 
chnical  types  of  the  disease.  Thus  acute  and  chronic  cases  are  described. 
The  acute  cases  generally  occur  in  children  and  young  adults,  the  emacia- 
tion being  marked  and  the  course  very  rapid.  The  chronic  cases  usually 
occur  in  persons  who  develop  the  disease  after  the  fortieth  year,  and  in 
middle-aged  and  elderly  obese  individuals.  The  acute  cases,  however, 
may  occur  in  the  aged.  Osier  reports  a  man  aged  seventy-three  years  in 
whom  the  entire  course  of  the  disease  was  less  than  three  weeks. 

There  are  the  mild  and  the  severe  cases.  According  to  Naunyn,  if  the 
glucose  disappears  with  the  patient  on  a  non-carbohydrate  diet,  the  case 
belongs  to  the  former  type.  If,  on  the  other  hand,  he  continues  to  excrete 
glucose,  the  case  is  a  severe  one,  for  it  means  that  sugar  is  being  produced 
from  the  body  proteids.  Further,  we  have  the  fat  or  lipogenous  (diabete 
gras)  and  the  emaciated  (diabete  maigre)  cases.  Lancereaux  believed 
the  latter  were  caused  by  lesions  of  the  pancreas.  Exogenous  and  en- 
dogenous cases  have  been  described.  The  former  embrace  the  cases  in 
which  there  is  some  external  exciting  cause.  The  latter,  according  to 
Striimpell  and  others,  include  those  in  which  there  is  no  apparent  external 
etiological  factor,  or  any  evident  organic  lesion,  but  in  which  the  disease 
is  thought  to  be  due  to  some  developmental  abnormality.  We  have  also 
the  neurotic  cases  due  to  injuries  or  functional  disorders  of  the  nervous 
system.  There  is  no  fundamental  difference  in  any  of  these  cases,  and  no 
satisfactory  classification,  along  the  lines  indicated,  seems  possible. 

Although  the  disease  is  usually  accompanied  by  a  certain  group  of 
symptoms  which  especially  characterize  it,  and  which  may  be  so  abrupt 
in  their  onset  that  the  patient  can  state  the  date  of  their  appearance  with 
considerable  accuracy,  yet  these  may  for  a  long  time  remain  in  abeyance, 
and  may  even  never  become  a  prominent  feature.  Thus  the  polyuria, 
thirst,  increased  appetite,  emaciation,  and  weakness,  may  not  be  suffi- 
ciently marked  to  attract  the  patient's  attention.  The  first  intimation  of 
there  being  anything  wrong  may  be  a  gradual  failure  in  vision.  An  ocu- 
list is  consulted  who,  finding  a  commencing  or  well-developed  cataract  or 
a  retinitis,  suspects  diabetes,  and  orders  an  examination  of  the  urine, 
which  results  in  his  suspicions  being  confirmed.  On  the  other  hand,  the 
patient  may  consult  the  family  physician  for  an  obstinate  general  or 
localized  pruritus  as  the  first  symptom,  with  the  same  results.  Similarly, 
a  furunculosis,  a  severe  neuralgia,  or  impotence,  may  cause  the  patient  to 
seek  advice.  Occasionally  general  weakness,  nervousness,  slight  change 
in  temperament,  mental  hebetude,  and  inability  to  apply  himself  to 
business,  may  antedate  the  characteristic  symptoms.  Too  often,  un- 
fortunately, the  cause  of  such  symptoms  is  not  discovered  sufficiently 
early,  and  the  disease  gets  a  firm  foothold  and  has  seriously  impaired  the 
general  health  before  it  is  finally  recognized. 

Polyuria  is  the  symptom  most  frequently  first  complained  of  by  the 
diabetic.  In  the  acute  cases,  the  patient  asserts  positively  that  the  quan- 
tity of  urine  suddenly  became  greater,  and  that  he  is  obHged  to  get  up 
frequently  at  night  to  pass  urine.  The  increase  in  the  quantity  of  urine  is 
referable  to  the  hyperglycsemia.  Owing  to  the  increased  quantity  of 
glucose  in  the  blood,  the  latter  becomes  hyperisotonic,  and  the  fluids  of  the 


772  COXSTITUTIOXAL  DISEASES 

tissues  arc  absorbed  into  the  circulation  more  rapidly  than  in  the  nornial 
individual,  and  consequently  more  water  is  secreted  by  the  kidneys.  The 
amount  of  urine  may  reach  10  to  20  liters  (5  to  10  quarts)  daily  in  the 
severest  cases,  although  it  is  rare  to  see  cases  in  which  more  than  10  liters 
is  voided  in  the  twenty-four  hours.  The  amount  of  uriiie  in  the  majority 
of  cases  ranges  between  2  and  5  liters.  The  quantity  usually  bears  a 
direct  relationship  to  the  percentage  of  sugar  excreted.  In  certain  cases 
it  is  well  to  remember  that  there  may  be  no  increase  in  the  urine  even 
when  glycosuria  is  present. 

Thirst,  or  polydi})sia,  may  be  extreme,  and  may  be  complained  of  as 
early  as,  but  more  often  very  soon  aftt-r,  the  polyuria.  It  is  indirectly 
traceable  to  the  hyjierglycaniiia,  and  directly  to  the  dessication  of  the 
tissues  already  described.    It  bears  a  definite  relationshij)  to  the  polyuria. 

Increased  appetite  (bulimia  or  polyphagia)  is  a  frequent  symptom, 
particularly  in  the  very  acute  cases.  In  the  milder  forms,  and  in  the 
advanced  stages  of  the  severe  type,  this  symptom  may  be  wanting.  There 
may  even  be  loss  of  desire  for  food.  Notwithstanding  the  enormous 
amount  of  food  eaten,  ])rogressive  emaciation  is  the  rule,  es])ecially  in  the 
young  individual.  The  increased  a]:)])ctite  and  the  emaciation  are  largely 
dependent  upon  the  same  cause — the  failure  of  the  diabetic  organism 
fully  to  utilize  the  carbohydrates  of  the  food.  The  nutritive  changes  in 
diabetes  are  interesting  and  deserve  some  consideration.  An  individual 
doing  light  work  requires  about  40  calories  for  each  kilo  body-weight 
daily,  although  the  recent  work  of  Chittenden  seems  to  indicate  that  this 
caloric  requirement  is  too  high.  Thus  a  person  of  average  weight 
would  require  food  to  yield  2,400  calories  for  his  nutritive  needs.  Let  us 
su})pose  this  individual  to  be  suffering  from  diabetes  and  to  be  taking  a 
mixed  diet  including  proteids,  fats,  and  carbohydrates,  in  the  following 
proportions  with  their  caloric  ecjuivalents:  160  grams  of  albumin,  yielding 
656  calories;  110  grams  of  fat,  yielding  1,023  calories;  and  240  grams  of 
carbohydrates,  yielding  984  calories.  This  diet,  therefore,  would  provide 
a  total  of  2,663  heat  units,  or  263  more  than  would  be  required  by  the 
individual  were  he  perfectly  healthy.  Let  us  suppose,  however,  that  he  is 
excreting  140  grams  of  sugar  daily.  He  would  therefore  lose  each  day 
nutritive  material  to  the  value  of  140X4.1=574  calories.  The  food  of  this 
diabetic  consequently  would  have  the  value  of  only  2,663 — 574  =2,089 
calories.  As  the  estimated  nutritive  need  was  2,400,  there  Avas  a  daily 
deficit  of  2,400 — 2,089=311  calories.  The  body,  therefore,  in  order  to  meet 
the  requirements  of  energy  and  heat  production,  must  have  consumed  of 
its  own  substance  to  the  value  of  311  calories.  The  tissues  drawn  on  for 
fuel  material  to  make  up  for  this  caloric  deficit  are,  of  course,  the  albumin- 
ous and  fatty.  By  estimating  the  amount  of  nitrogen  in  the  food  and  in 
the  urine  and  faeces,  it  is  possible,  accurately,  to  determine  the  exact 
proportion  of  body-fat  and  albumin  consumed  daily  to  make  up  for  the 
caloric  loss  resulting  from  the  failure  of  the  organism  to  utilize  all  the 
ingested  carbohydrates  OAAing  to  a  considerable  quantity  being  eliminated 
in  the  urine  as  glucose.  Tliis  consumption  of  his  own  body-fat  and  albumin 
necessarily  occasions  a  progressive  loss  in  weight,  and  the  hypothetical 
case  illustrates  how  the  emaciation  is  brought  about.  The  latter  will  con- 
tinue unless  the  diet  is  so  regulated  as  to  prevent  a  loss  of  sugar  in  the 
urine.     Von  Noorden  explains  the   polyphagia  in  the   following  way; 


DIABETES  MELLITUS  773 

"The  sufferer  from  this  disease  whose  diet  is  not  regulated  by  medical 
advice,  swallows  great  quantities  of  food,  including  much  carbohydrate. 
The  'stomach  hunger'  is  momentarily  stilled,  but  quickly  returns,  for 
'tissue  hunger'  is  not  satisfi(Ml.  The  inordinate  appetite  of  the  diabetic 
disappears  only  when  the  useless  carbohydrates  are  cut  off  and  their 
place  sup})lied  by  albumin  and  fat.  When  this  is  done  the  emaciation 
of  the  patient  comes  to  a  halt,  with  relief  of  the  polyphagia." 

The  face  is  often  of  a  deep  red  color.  The  skin  of  the  entire  body  in 
the  majority  of  cases  is  dry  and  harsh.  This  is  due  to  the  fact  that  the 
sweat,  as  is  the  case  with  nearly  all  the  secretions,  with  the  exception  of 
the  urine,  is  diminished  in  amount.  The  skin  may  be  moist,  however.  In 
cases  complicated  by  pulmonary  tuberculosis,  sweats  may  occur,  and  they 
have  been  known  to  alternate  with  polyuria.  The  nails  are  often  brittle, 
and  the  hair  thin  and  dry.  There  may  be  some  irritability  of  temper. 
There  is  a  strong  tendency  for  the  individual  to  become  morose  or  even 
hypochondriacal.  Some  complain  of  extreme  drowsiness  during  work- 
ing hours.  The  temperature  in  uncomplicated  cases  is  usually  subnormal. 
The  pulse  is  generally  increased  in  frequency,  with  the  pulse-tension 
above  normal. 

The  mouth  is  dry,  due  to  the  thirst  and  to  the  diminished  salivary  secre- 
tio'ii.  The  saliva  is  less  alkaline  than  in  health,  and  that  collected  from 
Steno's  duct  is  usually  acid  in  reaction.  Frerichs,  von  Noorden,  and 
Mosler,  found  the  saliva  almost  without  exception  free  from  sugar.  Fre- 
richs demonstrated  sugar  in  one  out  of  nine  cases.  The  tongue  is  usually 
dry  and  red,  and  often  has  a  glossy  appearance  resembling  that  in  psori- 
asis linguae.  The  digestion,  notwithstanding  the  enormous  quantities 
of  food  taken,  is,  as  a  rule,  good.  Obstinate  constipation  is  the  rule.  The 
eye-sight,  owing  to  the  ocular  complications,  is  often  defective.  Pain  in 
the  lumbar  region  is  often  an  annoying  symptom  even  early  in  the  disease. 
Cramps  in  the  calves  of  the  legs  occasionally  cause  much  discomfort. 
Owing  to  the  lowered  vitality  of  the  tissues,  and  owing  to  the  latter  being 
richer  in  sugar  than  normally  and  consec]uently  being  a  better  nutritive 
medium  for  the  growth  of  organisms,  wounds  heal  less  readily  and  are 
much  more  liable  to  become  infected.  In  patients  with  secondary  lesions 
of  the  cord  or  peripheral  nerves  of  the  lower  extremities  a  sensation  of  a 
"giving  away"  of  the  knees  may  be  complained  of.  This  occasionally 
occurs,  however,  even  without  nervous  manifestations. 

Loss  of  sexual  desire  and  power  in  men  is  common,  and  may  be  an 
early  feature.  It  may  reach  the  grade  of  actual  impotence.  Sexual  power 
may  return,  according  to  Seegen,  with  improvement  in  the  patient's  other 
symptoms  while  under  treatment.  Occasionally  increased  sexual  desire 
and  power  persist  throughout  the  disease.  In  severe  cases  of  diabetes  in 
women  the  sexual  desire  is  much  impaired,  but  in  mild  cases  in  elderly 
women  it  is  said  to  be  often  increased.  Amenorrhoea  is  not  uncommon, 
and  may  occur  early  in  the  disease. 

The  Urine. — The  amount  of  urine  has  been  considered  under  polyuria. 
It  is  usually  extremely  pale  and  clear.  The  quantity  and  pallor  generally 
bear  a  direct  relationship  to  the  percentage  of  sugar  present.  Occasion- 
ally one  sees  diabetic  urine  of  quite  deep  color.  In  these  cases  there  is 
little  or  no  polyuria.  It  often  has  a  suggestive  greenish  tint,  and  may,  when 
shaken,  have  a  syrupy  consistency.  It  has  a  sweet  taste,  and  in  severe  cases 


774  CONSTITUTIONAL  DISEASES 

with  threatening  coma,  may  have  a  sweetish,  fruity  odor,  owing  to  the 
presence  of  acetone.  The  specific  gravity  usually  ranges  between  1,025 
and  1,045.  A  jiale  urine  with  a  specific  gravity  above  1,025  should  always 
lead  one  to  suspect  the  presence  of  sugar.  In  rare  instances  diabetic  urine 
with  sugar  demonstrable  may  have  a  specific  gravit}^  of  1,015  or  even 
lower.  A  specific  gravity  above  1,050  is  rare.  Naunyn  has  seen  a  case 
with  1,000.  The  highest  si)ecific  gravity  recorded  was  in  two  cases  re- 
ported by  Bouchardat  and  Prout,  in  each  of  which  it  was  1,074.  Very 
high  specific  gravities — 1,070  or  over — always  suggest  fraud. 

The  most  characteristic  feature  is  the  presence  of  sugar  and  the  diag- 
nosis is  largely  dependent  upon  this.  This  is  almost  invariably  grape- 
sugar  (glucose,  dextrose).  Normal  urine  contains  glucose  in  quantities 
not  demonstrable  by  the  ordinary  tests.  In  rare  instances  levulosuria  may 
occur  either  with  glycosuria  or  alone.  Authentic  cases  have  been  reported 
by  Seegen,  Kiilz,  and  ]\Iay.  Kiilz  and  Vogel  have  frequently  noted 
pentosuria  in  human  diabetes,  and  in  experimental  diabetes  in  animals, 
even  after  prolonged  fasting,  showing  that  the  pentose  originates  in  the 
animal  body.  The  amount  of  sugar  excreted  varies  considerably  at 
different  periods  of  the  day.  The  period  of  minimum  output  is  in  the 
late  night  or  early  morning  hours.  According  to  Naunyn  there  are  two 
periods  of  maximum  output;  one  in  the  late  morning  hours,  the  other 
about  six  o'clock  in  the  afternoon,  occasionally  lasting  until  midnight. 
The  amount  of  sugar  usually  begins  to  increase  about  one  and  a  half  to 
two  hours  after  a  meal.  The  percentage  of  sugar  should  be  determined 
from  a  sample  of  urine  taken  from  the  mixed  twenty-four  hour  amount. 
Knowing  the  total  amount  of  urine,  it  is  then  easy  to  calculate  the  total 
amount  of  sugar,  in  grams  or  grains,  excreted  daily.  This  is  the  only 
satisfactory  way  of  following  the  progress  from  day  to  day  or  from  week 
to  week.  Variations  in  the  percentage  of  glucose  excreted  at  different 
periods  of  the  day  are  much  less  marked  in  the  severe  than  in  the  mild 
cases,  and  in  the  former,  the  sugar  of  the  night  urine  may  exceed  that  of 
the  day.  In  the  latter,  the  variations  are  often  quite  marked  and  the 
urine  of  the  early  morning  hours  may  be  free  from  sugar.  The  percentage 
of  glucose  varies  greatly.  In  the  majority  of  cases  it  ranges  about  3  per 
cent.  In  the  severe  cases  it  reaches  5  per  cent,  or  over.  It  is  very  rare  to 
meet  with  more  than  8  or  9  per  cent,  although  Naunyn  reported  a  case 
with  11  per  cent.,  and  Higgins  and  Ogden  a  case  of  traumatic  diabetes 
with  20  per  cent,  of  glucose.  The  total  output  of  sugar  for  the  twenty-four 
hours  may  be  only  a  few  grams  in  the  mild  cases.  In  some  cases  the 
quantity  of  sugar  may  be  enormous.  It  is  not  unusual  to  see  cases  with  a 
daily  excretion  of  500  grams  (15  oz.).  Charcot  reported  a  case  with 
1,100  grams  (35  oz.),  Lecorhe  a  case  with  1,200  grams  (38  oz.),  and 
Dickinson,  a  case  cited  by  Naunyn  Avith  the  enormous  output  of  1,500 
grams  (48  oz.). 

Many  factors  influence  the  sugar  output.  Diet  is  the  most  important 
one.  Carbohydrates  cause  a  marked  increase,  whereas  a  diet  consisting 
exclusively  of  proteids  and  fat  will  cause  the  sugar  to  disappear  in  mild 
cases  and  will  reduce  it  to  a  minimum  in  the  severe  cases.  Acute  febrile 
diseases  and  septic  infections  often  cause  a  marked  reduction.  It  is  not 
unusual  in  diabetes  with  pulmonary  tuberculosis  accompanied  by  high 
fever,  to  see  the  sugar  almost  entirely  disappear  in  the  terminal  stages. 


DIABETES  MELLITUS  775 

The  onset  of  coma  manifestations  with  the  appearance  of  /?-oxybutyric 
acid  in  the  urine  is  not  infrequently  attended  by  a  markerl  reducticjn 
in  the  sugar  excretion.  The  following  are  the  most  satisfactory  tests  for 
glucose : 

Fehling's  Test. — Two  separate  solutions  are  necessary  unless  one  uses 
the  Haines  or  Purdy  modification.  The  copper  solution  contains  34.65 
grams  of  pure  crystallized  copper  sulphate  to  the  liter  of  distilled  water. 
The  alkaline  solution  is  prepared  by  dissolving  173  grams  of  Rochelle 
salt  in  350  cc.  water,  adding  GOO  cc.  of  a  caustic-soda  solution  of  a  specific 
gravity  of  1.12,  and  diluting  with  distilled  water  to  1  liter.  For  the 
qualitative  sugar  test,  equal  quantities  of  the  two  solutions  are  mixed 
together,  then  boiled,  and  the  suspected  urine,  after  being  freed  from  albu- 
min, added  a  few  drops  at  a  time  and  then  again  heated.  If  glucose  be 
present  either  the  yellow  hydroxide  of  copper  or  the  red  cuprous  oxide 
will  be  precipitated.  If  reduction  does  not  follow  boiling,  set  aside  for  a 
while  and  a  precipitation  may  occur  on  cooling,  when  only  traces  of  sugar 
are  present. 

Although  the  Fehling's  test  requires  considerable  experience  in  order 
to  secure  absolute  accuracy  as  a  quantitative  method  of  determining  the 
amount  of  sugar,  it  is  probably  the  least  expensive  and  most  accurate  of 
the  methods  available  for  the  general  practitioner  where  mere  approxi- 
mate results  are  desired.  This  quantitative  method  is  dependent  upon  the 
fact  that  10  cc.  of  the  copper  sulphate  solution  is  reduced  by  0.05  grams 
of  glucose.  The  determination  is  cai*ried  out  as  follows:  10  cc.  each  of 
the  copper  and  alkaline  solutions  are  mixed  in  a  small  flask  and  30  cc.  of 
water  added.  If  the  urine  has  a  specific  gravity  approximately  of  1,030 
the  urine  is  diluted  five  times,  if  over  1,030,  ten  times.  A  graduated  bu- 
rette is  filled  with  the  diluted  urine.  The  Fehling's  solution  is  boiled,  and 
then  the  diluted  urine  is  added  at  first  about  1  cc.  at  a  time  and  later  in 
smaller  quantity  as  the  end  reaction  is  approached.  The  solution  is  boiled 
after  each  addition  of  urine.  The  end  reaction  consists  in  the  disappear- 
ance of  the  blue  color  immediately  after  boiling.  The  ability  accurately 
to  determine  this  point  comes  with  experience.  To  determine  whether  the 
color  has  disappeared,  allow  the  copper  suboxide  to  settle  a  little  below 
the  meniscus  formed  by  the  surface  of  the  liquid.  If  this  layer  is  not  blue 
on  holding  it  on  a  level  with  the  eye,  the  whole  procedure  is  repeated  add- 
ing 0.1  cc.  less  urine;  if  now,  after  the  copper  suboxide  has  settled,  the 
supernatent  liquid  has  a  blue  color,  the  titration  is  comjjleted.  Three  or 
four  estimations  should  be  made  in  order  to  accurately  determine  the  end 
reaction.  Once  the  amount  of  urine  required  to  reduce  the  0.05  grams 
of  copper  sulphate  in  the  10  cc.  of  Fehling's  copper  solution  has  been 
ascertained,  the  calculation  of  the  percentage  is  easy.  Let  us  take  an 
example  for  illustration  and  suppose  that  the  urine  has  been  diluted  ten 
times,  and  that  8.5  cc.  of  diluted  urine  Avas  necessary  to  complete  the  end 
reaction.  We  therefore  know  that  the  8.5  cc.  of  urine  used  contain  0.05 
grams  of  sugar  and  the  percentage  is  therefore  (8.5  :  0.05  ::  100  :  x)  =  0.58. 
This  would  be  the  percentage  if  the  urine  had  not  been  diluted.  Since  the 
urine  was  diluted  ten  times  the  percentage  of  sugar  in  the  undiluted  urine 
would  therefore  be  0.58  X  10  =  5.8. 

Trommer's  test,  in  which  a  dilute  copper  sulphate  solution  and  a 
solution  of  caustic  soda  or  potash  are  used,  while  reliable  in  experienced 


776  CONSTITUTIOXAL  DISEASES 

hands,  is  subject  to  too  many  fallacies  to  be  used  by  the  general  prac- 
titioner.   Excess  of  uric  acid  or  creatinin  will  give  a  similar  reaction. 

Fermeniaiion  Teni. — This  is  the  most  reliable  single  test  we  have.  It  is 
best  carried  out  by  using  one  of  the  fermentation  tubes  designed  for  bac- 
teriological purposes,  or  one  of  the  special  tubes  such  as  Einhorn's 
saccharimeter  (made  especially  for  urinary  work)  by  which  also  the  per- 
centage of  sugar  can  be  roughly  estimated.  When  yeast  is  added  to 
diabetic  urine  and  the  mixture  is  kept  at  22°  to  28°  C.  for  twenty-four 
hours,  the  sugar  is  decomposed  and  carbonic  acid  is  given  off.  By  measur- 
ing the  gas  given  off  from  10  cc.  of  diabetic  urine  (as  is  possible  with 
Einhorn's  saccharimeter),  it  is  possible  to  determine  the  percentage  of 
sugar.  While  this  method  is  not  absolutely  accurate,  for  the  purpose  of 
following  the  progress  from  week  to  week  it  is  sufficiently  so  for  the 
general  practitioner.  As  the  yeast  itself  may  cause  a  small  evolution  of 
gas,  a  control  test  with  normal  urine  should  always  be  made.  The 
determination  of  the  percentage  of  sugar  by  noting  the  reduction  in  the 
specific  gravity  after  complete  fermentation  cannot  be  recommended. 

Bismuth  Tcsi. — This  is  best  performed  with  Nylander's  modifica- 
tion of  Almen's  original  solution.  Nylander's  solution  is  made  by  dissolv- 
ing 4  grams  of  Rochelle  salt  in  100  parts  of  10  per  cent,  caustic  soda 
solution  and  adding  2  grams  of  bismuth  subnitrate  and  digesting  in  a 
water-bath  until  as  much  of  the  salt  is  dissolved  as  possible.  To  10  cc.  of 
urine  add  1  cc.  of  Nylander's  solution  and  boil  two  or  three  minutes.  If 
glucose  be  present  the  urine  becomes  yellowish,  yellowish-brown  and 
finally  black  from  a  deposition  of  metallic  bismuth.  A  simple  modifica- 
tion is  to  render  10  cc.  of  suspected  urine  alkaline  with  caustic  soda  and 
then  add  a  small  amount  of  bismuth  subnitrate  and  then  boil  (Botger's 
test).  This  on  the  whole  is  a  delicate  and  reliable  test.  It  shows  0.5  per 
mille  of  sugar.  Combined  glycuronic  acid  will  cause  a  reduction  and 
fallacies  may  result  from  the  administration  of  chloral,  salol,  rhubarb, 
antipyrin,  and  turpentine. 

Polariscope  Test. — Glucose  is  dextro-rotatory,  so  that  urine  containing 
it  will  rotate  the  rays  of  polarized  light  to  the  right.  By  measuring  the 
degree  of  rotation,  the  percentage  of  urine  can  be  accurately  determined 
when  above  0.2  per  cent.  For  hospital  and  laboratory  purposes,  it  is  the 
quickest  and  most  satisfactory  quantitative  test.  Half-shadow  and 
circular-shadow  polariscopes  are  made  especially  for  estimating  the 
quantity  of  sugar.  Albumin  should  first  be  removed.  /9-oxybutyric  acid 
is  Ifevo-rotatory,  and  when  present  will  neutralize  some  of  the  dextro- 
rotatory action  of  the  glucose. 

Phcnylhydrazin  Test. — This  can  be  carried  out  by  von  Jaksch's  simple 
method.  To  8  to  10  cc.  of  urine  in  a  test-tube  add  2  knife-points  of 
phenylhydrazin  hydrochloride  and  3  knife-points  of  sodium  acetate, 
and  if  the  salts  do  not  dissolve  on  warming,  add  more  water.  Heat  in  a 
water-bath  for  one  hour.  Then  cool  by  placing  a  test-tube  in  cold  water. 
If  sugar  be  present  a  yellow  deposit  of  phenylglucosazone  occurs  which  on 
microscopic  examination  is  found  to  have  a  yellow  color  and  to  be 
arranged  in  sheaves  and  stars.  Glycuronic  acid  and  other  substances  yield 
similar  crystals  of  an  osazone.  When  any  doubt  arises,  the  crystals 
can  be  differentiated  by  determining  their  melting-points.  Those  yielded 
by  glucose  melt  at  204°  to  205°  C. 


DIABETES  MELLITUS  777 

While  there  tire  other  tests  for  gUicose,  those  above  described  are  the 
ones  which  give  the  best  resuhs.  Bremer  showed  that  diabetic  urine 
readily  dissolved  gentian  violet  powder,  whereas  normal  urine  fails  to. 
He  suggested  this  as  a  test.  Unfortunately  the  urine  in  diabetes  insipidus 
reacts  in  the  same  way. 

Precautions  to  Observe  in  Performing  the  Sugar  Tests. — It  is  a  safe  rule 
never  to  rely  on  one  qualitative  test  alone.  The  most  reliable  single  test  is 
the  fermentation  test.  If  there  is  a  rapid  reduction  of  the  coijper  sulphate 
in  performing  Fehling's  test,  one  can  be  reasonably  certain  that  the  reducing 
agent  is  glucose.  Where  it  is  slow  and  slight,  and,  especially,  if  the  precipi- 
tate be  yellow  rather  than  red,  other  reducing  agents  must  be  considered 
and  eliminated.  The  other  substances  which  reduce  alkaline  copper  sul- 
phate solutions  are  conjugated  glycuronic  acid  sometimes  eliminated  after 
the  taking  of  certain  drugs,  alkapton  (homogentisic  acid),  lactose,  excess 
of  uric  acid,  and  kreatinin.  The  conjugate  glycuronic  acid  also  reduces 
bismuth,  but  is  differentiated  from  glucose  by  being  lievo-rotatory  as 
voided,  becoming  dextro-rotatory  when  the  glycuronic  acid  is  split  off  by 
boiling  with  an  acid.  It  does  not  ferment.  Alkaptonuric  urine  is  recog- 
nized by  being  negative  with  the  bismuth,  fermentation,  and  polariscope 
tests.  Its  special  feature  is  its  darkening  on  exposure  to  the  air  and  on  the 
addition  of  an  alkali.  I^actose,  which  is  very  frequently  eliminated  in  the 
urine  in  the  early  days  of  lactation,  and  when  there  is  retention  of  the  milk 
in  the  breasts  either  from  obstruction  of  the  milk-ducts  or  from  sore  nip- 
ples, reduces  copper  sulphate  and  bismuth,  and  is  dextro-rotatory,  but 
does  not  ferment.  Although  excesses  of  uric  acid  and  kreatinin  may  cause 
slight  reductions  of  copper  sulphate,  there  should  be  no  difficulty  in  differ- 
entiating these  from  glucose  if  one  takes  the  precaution  to  use  one  or 
more  of  the  other  tests,  with  which  they  are  negative. 

It  is  a  safe  precaution  to  use  at  least  both  Fehling's  and  Nylander's 
bismuth  solution  as  qualitative  tests  for  sugar.  The  latter  is  a  little  more 
delicate  and  more  reliable  than  the  former.  If  a  polariscope  be  available 
and  the  urine  be  found  to  be  dextro-rotatory  in  action,  there  is  little  doubt 
about  the  reducing  substance  being  glucose.  When  any  doubt  exists,  the 
fermentation  test,  the  most  reliable  of  all,  should  be  tried. 

Other  Urinary  Ingredients  in  Diabetes. — Mayer  has  shown  that  glycu- 
ronic acid,  like  sugar,  is  present  in  normal  urine  in  minute  traces,  and  that 
it  is  increased  in  diabetes.  It  is  regarded  as  one  of  the  intermedi- 
ary products  of  carbohydrate  metabolism.  It  is  recognized  by  the  orcin 
test.  Rosin  and  Alfthan  demonstrated  that  the  benzoyl  esters  are  also 
increased.  These  normally  do  not  exceed  2  to  3  grams  daily.  Edsall 
has  found  as  high  as  12.5  and  13.8  grams  respectively  in  three  cases  of 
diabetes. 

Mayo  Robson  and  Cammidge,  have  shown  that  in  pancreatic  disease 
glycerine  is  excreted  in  the  urine.  The  glycerine  results  from  the  splitting 
up  of  the  fat  molecule  in  the  areas  of  fat  necrosis.  Cammidge  claims  to 
have  found  it  in  one  case  of  diabetes  due  to  pancreatic  disease.  The  de- 
tails of  the  test  cannot  be  given  here.  Considerable  doubt  has  been  ex- 
pressed as  to  the  value  of  this  test  and  also  as  to  whether  the  authors  have 
properly  interpreted  their  results. 

The  urine  of  diabetics  before  and  during  coma  symptoms  very  frequently, 
if  not  always,  contains  ^-oxybutyric  acid  and  its  derivative  products, 


778  CONSTITUTIONAL  DISEASES 

diacetic  acid  and  acetone.  The  tests  for  these  substances  may  be  briefly 
stated  here. 

It  is  possible,  by  a  process  too  long  to  be  described  here,  to  isolate 
^-oxybuii/ric  acid  (C4II8O3)  from  the  urine  in  crystalline  form.  On  being 
boiled  "with  a  mineral  acid  it  is  decomposed  into  o:-crotonic  acid,  the 
crystals  of  -which  melt  at  71  to  72°  C,  by  which  test  it  can  be  recognized. 
Its  probable  presence  can  be  detected  in  two  ways.  Being  a  hvvo-rotator, 
its  presence  may  be  assumed  if,  after  completely  fermenting  the  urine,  the 
urine  rotates  the  rays  of  polarized  light  to  the  left.  For  the  same  reason 
its  presence  may  be  suspected  if  the  percentage  of  sugar  is  found  to  be  con- 
siderably higher  by  the  Fehling's  than  by  the  polariscope  method.  This 
is  due  to  the  fact  that  dextro-rotatory  power  of  the  glucose  is  partially 
neutralized  by  the  kevo-rotary  power  of  the  acid. 

Diacetic  acid  (C^IIeOg)  is  practically  always  present  when  the  urine 
contains  ^-oxybutyric  acid,  but  the  reverse  is  not  always  the  case.  The 
molecule  of  /9-oxybutyric  acid  by  taking  on  an  atom  of  oxygen  splits  up 
into  diacetic  acid  and  water.  The  former  is  now  universally  accepted  to 
be  the  source  of  the  latter.  The  urine  must  be  fresh  in  testing  for  dia- 
cetic acid,  for  it  readily  breaks  up  into  acetone  and  carbonic  acid.  It  is 
recognized  by  Gerhardt's  ferric  chloride  test.  To  10  cc.  of  urine  add  a 
solution  of  ferric  chloride  until  all  the  phosphates  are  precipitated  as  iron 
phosphate.  Filter  and  continue  to  add  ferric  chloride  to  the  filtrate.  If 
diacetic  acid  be  present,  the  urine  now  takes  on  a  claret  or  Bordeaux-red 
color.  Salicylic  acid  will  give  the  same  reaction.  To  differentiate  them, 
boil  a  second  portion  of  the  urine  for  five  minutes  and  follow  the  same 
procedure.  If  the  Bordeaux-red  color  of  the  first  test  be  due  to  diacetic 
acid,  it  fails  to  appear  in  the  second,  while  it  persists  if  due  to  salicylic 
acid,  because  the  former  is  volatile  and  the  latter  is  not.  A  third  portion 
is  treated  with  sulphuric  acid  and  shaken  with  ether.  The  ether  extract 
is  decanted  off  and  shaken  with  a  very  dilute  watery  solution  of  ferric 
chloride.  If  diacetic  acid  be  present,  the  watery  layer  takes  on  a  Bor- 
deaux-red color  which  disappears  on  heating.  It  is  very  unstable  and 
quickly  becomes  broken  up  into  acetone  and  carbon  dioxide.  This 
instability  renders  it  impossible  to  quantitatively  determine  the  amount  of 
diacetic  acid  in  the  urine.  The  diacetic  acid  and  acetone  are  estimated 
together  and  recorded  in  terms  of  total  acetone. 

Acetone  (CsHgO),  when  present  in  large  quantities,  may  give  the  urine 
a  fruity  odor.  It  may  be  recognized  by  Legal 's  sodiuni-nitroprusside 
test.  To  10  cc.  of  urine  add  a  few  drops  of  a  fresh  solution  of  sodium  nitro- 
prusside.  Then  add  caustic  potash  or  soda  solution,  and,  if  acetone  be 
present,  the  urine  assumes  a  ruby-red  color.  Creatinin  gives  the  same 
color,  but  if  glacial  acetic  acid  be  now  added  the  color  becomes  carmine 
or  purplish-red  in  the  presence  of  acetone,  but  yellow  and  gradually 
green  or  blue  in  the  presence  of  creatinin.  This  test  is  not  so  delicate  as 
Lieben's  iodoform  test.  Distil  the  urine  and  treat  the  distillate  with 
caustic  potash,  and  then  add  Lugol's  solution.  If  acetone  be  present,  the 
distillate  becomes  yellowish-white,  owing  to  the  formation  of  iodoform, 
which  is  recognized  by  its  odor  and  by  hexagonal  or  stellar  crystals  on 
microscopic  examination.  A  very  large  percentage  of  diabetic  urines  will 
give  a  positive  reaction  with  this  test.  For  mere  traces  of  acetone  it  is  the 
most  delicate  of  the  various  tests.     Of  the  three  substances  just  con- 


DIABETES  MELLITUS  779 

sidered  it  is  the  one  most  frequently  found.  There  is  no  relationship 
between  the  quantity  of  these  "acetone  bodies,"  as  the  three  are  often 
called,  and  the  amount  of  sugar  excreted. 

The  nitrogen  output  is  greatly  increased,  chiefly  in  the  form  of  urea. 
This  is  due  largely  to  the  greater  amount  of  proteids  ingested,  but  also 
in  part  to  increased  destruction  of  the  body  proteids  in  the  more  severe 
cases.  Pettenkofer  and  Voit  have  shown  that,  even  when  fasting,  a 
diabetic  patient  excreted  about  8  per  cent,  more  urea  than  a  healthy 
person.  Leo  has  shown  that  the  addition  of  carbohydrates  to  the  diet 
of  a  diabetic  will  occasionally  diminish  nitrogenous  metabolism. 

An  interesting  feature  is  the  extraordinary  increase  in  the  ammonia 
output  in  the  severe  cases,  particularly  when  coma  supervenes.  According 
to  Neubauer,  the  average  amount  of  ammonia  excreted  in  the  urine  by  a 
normal  individual  on  a  mixed  diet  is  about  0.7  grams  daily.  Part  of  the 
ammonia  which  should  go  to  form  urea  is  utilized  in  neutralizing  the 
acids  producing  the  acid  intoxication.  Naunyn  reports  having  found  an 
excretion  of  5.8  grams  of  ammonia  in  a  child  weighing  48  pounds,  and 
states  that  a  daily  excretion  of  6  to  7  grams  is  not  unusual  in  adult  dia- 
betics. Although  this  amount  is  not  often  exceeded,  Stadelmann  records 
a  case  with  an  elimination  of  11  grams.  The  amount  of  ammonia 
excretion  can  be  taken  as  a  safe  measure  of  the  grade  of  acid  intoxication 
in  diabetes. 

The  uric  acid  excretion  is  usually  increased,  as  has  been  shown  by 
Naunyn,  Riess,  and  others.  Gaethgens,  in  a  diabetic  with  fever,  found  the 
uric-acid  excretion  was  2.2  grams  in  the  twenty-four  hours.  The  increase 
is  explained  by  the  excessive  proteids  taken.  It  is  very  common  to  see 
diabetic  urines  with  uric  acid  sediments.  This  precipitation  is  probably 
in  part  due  to  the  diminished  power  of  diabetic  urine  to  retain  uric  acid 
in  solution.  Bischofswerder  has  shown  that  the  total  alloxuric  bodies  are 
also  increased.  Senator  found  the  creatinin  increased  up  to  2  grams 
daily.  This  is  referable  to  the  increased  ingestion  of  meat  and  to  the  in- 
creased destruction  of  the  muscular  tissues  of  the  body. 

Oxaluria  often  occurs,  with  an  actual  increase  in  the  excretion  of  cal- 
cium oxalate.  Teubaum  has  shown  that  the  lime-salts  are  markedly 
increased  in  severe  cases  of  diabetes,  but  not  in  the  mild.  The  sodium  chlor- 
ide is  increased.  The  sulphates  and  phosphates  are  in  excess,  owing  to  the 
increased  destruction  of  ingested  and  body  proteid,  with  oxidation  of  the 
sulphur  and  phosphorus  of  the  proteid  molecule.  A  form  of  "phos- 
phatic  diabetes  "  has  been  described  by  Tessier,  Ralfe,  and  others,  due  to 
an  excessive  excretion  of  calcium  phosphate.  There  is  nervous  irritabil- 
ity, deranged  digestion,  emaciation,  and  pain  in  the  back.  In  severe  cases 
there  may  be  polyuria,  and  the  spnptoms  may  simulate  diabetes.  The 
affection  has  really  nothing  to  do  with  true  diabetes,  although  it  is  said 
that  traces  of  sugar  have  been  found  in  some  cases  or  have  subsequently 
developed. 

Albuminuria  is  absent  in  the  majority  of  cases  of  diabetes  when  they 
are  first  admitted  to  a  general  hospital.  In  private  practice,  w^here  a 
larger  proportion  of  mild  diabetes  in  elderly  persons  is  met  with,  it  is 
more  common.  Five  groups  of  cases  of  albuminuria  may  be  recognized: 
(1)  Cases  of  severe  diabetes  of  considerable  duration,  with  traces  of 
albumin,  but  no  other  evidence  of  actual  nephritis.    (2)  Those  in  dia- 


780  COXSTITUTIOXAL  DISEASES 

betics  of  advanced  age,  with  indications  of  arterial  changes.  (3)  Those 
in  which,  in  addition  to  albuminuria,  there  are  evidences  of  chronic  neph- 
ritis, such  as  oedema,  headaches,  albuminuric  retinitis,  and  cardiovascu- 
lar changes.  (4)  Cases  of  severe  diabetes  complicated  bv  diabetic  coma. 
AVhen  coma  symptoms  have  definitely  manifested  themselves,  albuminuria 
is  practically  always  jnvsent.  (5)  Cases  in  which  the  albuminuria  is  due 
to  a  cystitis,  or  a  balanitis  in  the  male  and  vulvitis  in  the  female.  Naunyn 
and  others  state  that  diabetes  mcllitus  occasionally  passes  over  into  a 
true  nephritis,  with  disappearance  of  the  glycosuria. 

Casts  are  rare  in  diabetic  urine  except  in  those  cases  complicated  by 
actual  nephritis.  There  is  one  striking  exception,  however.  Kiilz  first 
pointed  out  that  diabetic  coma  is  accompanied  by  an  abundant  deposit  of 
casts.  A  urine  previously  free  from  them  and  quite  clear  may  suddenly 
become  turbid,  even  on  voiding,  owing  to  the  enormous  number  of  casts 
present.  In  a  very  short  time  these  settle  to  the  very  bottom  of  the  glass 
as  a  grayish-white  sediment.  When  pipetted  off  and  examined  micro- 
scopically, the  field  is  foimd  to  be  crowded  with  rather  short  hyaline  and 
granular  casts.  The  albuminuria  and  cylindruria  of  diabetic  coma  are 
probably  evidences  of  a  toxic  nephritis.  In  cases  of  cystitis,  balanitis, 
and  vulvitis,  pus-cells  will  be  found  in  the  urinary  sediment. 

Diabetic  urine,  on  standing,  soon  becomes  turbid,  owing  to  the  growth  of 
yeast-cells.  This  fact  is  of  practical  importance,  as  it  indicates  that  sus- 
pected urine  should  be  examined  qualitatively  and  quantitatively  as  soon 
as  possible  after  being  voided,  particularly  in  -v^-arm  weather.  The  yeast 
causes  fermentation  of  the  sugar,  and  where  the  glycosuria  is  slight,  it  may 
cause  a  complete  disappearance  of  the  glucose,  and  in  all  cases  will  cause 
a  reduction  in  the  percentage  of  sugar  on  quantitative  determination. 
The  presence  of  yeast-cells  in  a  urinary  sediment  should  always  arouse  a 
suspicion  of  the  existence  of  glucose.  In  balanitis  in  the  male  and  vulvitis 
in  the  female,  resulting  from  the  constant  irritation  of  the  saccharine  urine, 
there  is  often  a  fungus  growth  in  the  inflamed  mucous  surfaces,  and  fungus 
spores  and  mycelia  may  consequently  be  washed  away  in  the  urine 
dunng  the  act  of  voiding.  These  may  be  recognized  in  the  urine  on 
microscopic  examination. 

Occasionally  yeast-cells  and  fungi  develop  in  the  bladder  and  set  up 
fermentation  processes,  with  the  evolution  of  gas,  producing  fneumaturia. 
This  is  a  rare  condition.  Leube  found  that  diabetic  urine  contains  a  sub- 
stance which  gives  all  the  reactions  of  glycogen.  Lipuria  has  been  de- 
scribed, the  fat  occurring  in  the  form  of  a  fine  emulsion. 

Complications. — 1.  The  Skin. — Boils  and  carbuncles  are  very  com- 
mon, so  much  so  that  when  they  exist  one  immediately  thinks  of  diabetes 
as  a  cause.  Their  frequency  is  due  to  tke  susceptibility  of  the  tissues  of  the 
diabetic  to  infection.  Boils  are  more  common  in  the  milder  forms  of  the 
disease  and  in  stout  diabetics.  Seegen  says  he  has  never  seen  boils  in  an 
advanced  stage  of  the  disease.  The  commonest  seats  are  the  neck,  back, 
and  buttocks.  Cultures  usually  show  staphylococci,  and  the  Staphylococ- 
cus aureus  or  albus  may  occur  in  pure  culture.  Carbuncles  are  less  com- 
mon but  more  serious.  They  are  more  likely  to  occur  in  the  severe  cases. 
The  commonest  situations  are  the  back  of  the  neck  and  between  the 
shoulders.  With  the  surrounding  cellulitis  the  area  involved  may  reach 
20  cm.  (8  in.)  or  more.   They  may  precipitate  an  attack  of  coma. 


DIABETES  MELLITUS  781 

Owing  to  the  irritation  of  the  genitals  hy  the  saeeharine  urine,  and  to  the 
growth  of  fungi  (hyi)homyeetes)  in  the  superficial  layers  of  the  skin,  in- 
flammation of  the  prepuce  and  glans  in  the  male,  and  vulvitis  in  the  female, 
may  occur.  This  may  be  attended  by  intolerable  pruritiis pudendi,  par- 
ticularly in  women,  in  whom  local  boils  or  phlegmons  of  the  genitals  may 
develop.  The  general  pruritus  of  diabetes  is  due  in  all  probability  to 
irritation  of  the  sensory  nerves  by  the  sugar  in  the  blood,  just  as  pruritus 
in  jaundice  and  uraemia  is  due  to  circulating  toxins.  Urticaria,  pur- 
pura simplex,  purpura  hemorrhagica,  dermatitis  herpetiformis,  gan- 
grcena  diabetica  bullosa  serpiginosa  (Koposi)  may  occur.  (Edema  of  the 
feet,  even  without  evident  renal  or  cardiac  affections,  is  not  uncommon  in 
advanced  cachectic  cases.  A  curious  mottled  cyanosis  of  the  extremities 
is  sometimes  observed.  In  rare  instances,  the  skin  may  be  bronzed,  con- 
stituting the  so-called  diabete  bronze  cases.  The  pigmentation  is  a  symp- 
tom of  the  disease  known  as  hsemochromatosis,  in  which  glycosuria 
sometimes  occurs  in  the  late  stages  when  the  interstitial  pancreatitis  be- 
comes marked.  Herpes  zoster  and  perforating  ulcer  of  the  foot  occasionally 
occur,  and  are  expressions  of  a  diabetic  neuritis.  A  paronychia  diabetica 
may  occur.  This  may  result  in  the  loss  of  the  nails.  Williamson  has 
observed  three  cases  with  bulbous  fingers,  due  apparently  to  vasomotor 
changes. 

Spontaneous  diabetic  gangrene  occurs  usually  in  diabetics  after  fifty. 
The  glycosuria  is  usually  of  a  mild  grade.  It  is  commonest  in  the  lower 
extremities,  and  generally  begins  with  a  bluish  discoloration  and  then  a 
blackening  of  the  skin  of  the  big  or  little  toe.  It  is  of  a  moist  type  and 
may  subside,  but  usually  extends  gradually  to  involve  the  whole  foot  or  leg 
until  stopped  by  amputation.  It  may  start  in  the  heel.  William  Hunt 
analyzed  64  cases.  In  50  the  distribution  Avas  as  follows:  feet  and  legs, 
37;  thigh  and  buttock,  2;  nape  of  the  neck,  2;  external  genitals,  1; 
lungs,  3;  fingers,  3;  back,  1;  eyes,  1.  The  artery  supplying  the  affected 
area  shows  arteriosclerosis  in  the  vast  majority  of  cases.  In  many 
instances  it  is  thrombosed,  and  Naunyn  states  that  he  has  never  failed 
to  find  obliteration  of  the  pulse  in  the  early  stages  of  the  complication. 
Phlebitis,  particularly  of  the  veins  of  the  leg,  occasionally  occurs.  It  was 
present  in  1  case  in  the  Johns  Hopkins  Hospital  series. 

Xanthoma  diabeticorum  occurs  as  a  very  rare  complication.  Up  to 
1892,  Morris  could  find  only  21  cases  reported.  The  lesions  consist 
of  small  nodules  about  the  size  of  a  pea,  and  having  a  yellowish  or 
yellowish- red  color  They  are  slightly  sensitive  and  occur  mainly  on  the 
buttocks,  forearms,  and  knees.  The  eyelids  are  much  less  likely  to  be 
involved  than  in  the  xanthoma  multiplex  accompanying  chronic  jaundice. 
The  xanthomata  appear  rapidly  and  disappear  quickly  with  relief  of  the 
glycosuria  by  diabetic  treatment.    They  may  recur  several  times. 

2.  Gastro-Intestinal. — An  aphthous  stomatitis  due  to  the  oidium  albi- 
cans occasionally  occurs.  At  autopsy  the  pharynx  and  oesophagus  often 
show  a  diffuse  growth  of  this  fungus.  Gingivitis  with  pyorrhoea  alveolaris 
frequently  develops.  The  teeth  decay  rapidly  and  tend  to  loosen  and  fall 
out.  The  latter  is  probably  due  to  a  trophoneurosis.  Gastrectasia  occa- 
sionally results  from  the  enormous  quantities  of  food  and  liquids  taken. 
There  may  be  actual  gastric  catarrh.  Although  moderate  constipation  is 
the  rule,  one  occasionally  meets  with  a  case  with  obstinate  diarrhoea.   This 


782  CONSTITUTIONAL  DISEASES 

is  referable  to  an  intestinal  catarrh.  Stcatorrhoca,  or  fatty  stools,  may 
occur  in  pancreatic  diabetes.  Here  fat  digestion  is  interfered  with,  owing 
to  changes  in  the  pancreatic  secretion,  and  the  stools  are  of  a  puli)y  con- 
sistence, of  a  dirty,  dark-gray  color,  and  of  a  greasy  appearance.  In  these 
cases  the  movements  are  often  very  bulky,  and  at  the  end  of  defecation  as 
much  as  a  tablespoonful  of  almost  pure  fat  may  be  passed.  In  a  patient 
seen  with  A.  D.  Atkinson,  of  Baltimore,  the  autopsy  revealed  the  presence 
of  a  large  pancreatic  calculus.  INIicroscopically,  large  oil-globules  and 
abundance  of  fatty  acid  and  soap  crystals  are  seen. 

3.  Pulmonary, — One  of  the  commonest  is  pulmonary  tuhcrndosis. 
Griesinger  analyzed  250  cases  of  diabetes,  and  found  ])ulm()nary  tubercu- 
losis present  in  42  per  cent.,  and  to  be  the  cause  of  deatli  in  39  percent. 
In  50  autopsies,  Frerichs  found  the  lungs  tuberculous  in  25.  In  149 
of  Naunyn's  "pure"  diabetes  cases,  it  was  present  in  25,  or  17  per  cent., 
w'hile  in  113  cases,  due  to  evident  organic  disease,  there  were  8,  or  7  per 
cent.  With  the  progress  of  the  tuberculous  process  the  glycosuria  often 
diminishes,  or  may  entirely  disappear. 

Death  may  result  from  acute  pneumonia,  either  lobar  or  lobular,  A 
chronic  interstitial  pneumonia  may  occur.  The  pneimionia  may  be  com- 
plicated by  abscess  of  the  lung.  In  1  of  the  Johns  Hopkins  series  there 
Avere  multiple  abscesses  in  the  pneumonic  area.  Gangrene  of  the  lung  is 
not  very  uncommon,  Naunyn  saw  12  cases,  all  of  which  terminated 
fatally  with  one  exception.  He  describes  three  forms — an  acute,  a  sub- 
acute or  chronic,  and  a  form  with  numerous  gangrenous  foci  complicating 
a  chronic  pneumonic  process,  with  fibrous  induration. 

4.  Renal, — These  have  been  sufficiently  dealt  with  in  the  accounts  of 
the  pathology  and  of  the  urine, 

5.  Nervous  System, — Here  only  the  nervous  features  directly  refera- 
ble to  the  diabetes  will  be  considered.  It  is  of  interest  that  glucose  has 
been  found  in  the  fluid  obtained  by  lumbar  puncture. 

(a)  Peripheral  Neuritis. — This  is  the  commonest  nerve  complication. 
The  numbness,  tingling,  cramps,  and  neuralgias,  are  probably  expressions 
of  a  mild  neuritis.  Sciatica  is  not  uncommon,  and  other  peripheral  nerves, 
such  as  the  inferior  dental,  may  be  affected.  The  neuritis  may  be  multiple. 
Thus  both  ulnar  nerves  may  be  involved,  causing  muscular  paralysis  and 
anfesthesia  of  the  skin.  As  expressions  of  the  neuritis,  must  be  mentioned 
jailing  out  of  the  nails,  glossy  fingers,  herpes  zoster,  and  perforating  ulcer  of 
the  foot.  The  perforating  ulcer  closely  resembles  that  of  tabes.  Williamson 
met  4  out  of  140  cases.  It  occurs  nearly  always  in  men,  and  in  appar- 
ently mild  cases.  The  sole  of  the  foot,  in  the  region  of  the  metatarso- 
phalangeal joint,  is  the  commonest  seat.  The  bone  may  be  exposed  or 
the  joint  opened.  A  corn  may  precede  the  ulcer.  Attempts  to  remove 
the  corn  lead  to  infection,  and  the  ulcer  proceeds.  On  the  other  hand, 
trophic  changes,  due  to  the  neuritis,  constitute  the  chief  etiological  factor, 
and  the  ulcer  may  commence  with  superficial  death  of  the  skin.  The 
ulceration  is  often  painless.  As  the  knee-jerks  are  often  absent,  the  lesion 
may  be  mistaken  for  the  perforating  ulcer  of  tabes  unless  the  urine  is 
examined, 

A  so-called  diabetic  tabes,  resulting  from  a  polyneuritis,  has  been  de- 
scribed. This  pseudotabes  closely  resembles  true  tabes  dorsalis,  and  was 
first  described  by  Fischer,  in  1886.    It  is  characterized  by  lightning 


DIABETES  MELLITUS  783 

pains  in  the  legs,  loss  of  knee-jerks,  and  loss  of  power  of  the  extensors  of 
the  feet.  There  is  a  characteristic  steppage  gait  similar  to  that  seen  in 
arsenical,  alcoholic,  and  in  other  forms  of  ncuritic  paralysis.  A  typical 
Argyll-Robertson  pupil  is  rarely,  if  ever,  present,  although  Charcot  states 
that  there  may  be  atrophy  of  the  optic  nerve. 

(b)  A  diabetic  paraplegia,  probably  due  to  a  peripheral  neuritis,  with 
paralysis  of  the  arms  and  legs,  has  been  described. 

(c)  Degeneration  of  the  posterior  columns  has  been  described  by  Wil- 
liamson, Sandmeyer,  and  Kalmus.  This  lesion  has  been  considered  in 
the  section  on  pathology. 

(d)  Hemiplegia  occasionally  occurs.  One  would  naturally  expect  to 
find  some  gross  lesion  to  account  for  the  paralysis,  but  cases  have  been 
reported  in  which  careful  search  has  failed  to  find  any  evidences  of 
hemorrhage  or  thrombosis.  The  hemiplegia  in  these  cases  has  been 
attributed  to  toxic  causes,  similar  to  the  cases  of  hemiplegia  in  uraemia 
without  manifest  brain  lesions.  Careful  microscopic  examination  of  the 
brain  is  necessary  in  these  cases  before  stating  that  there  is  no  organic 
lesion,  and  a  thrombosed  vessel  may  explain  the  complication. 

In  this  connection  the  condition  of  the  tendon  re f  exes  may  be  considered. 
The  knee-jerks  are  often  absent,  as  first  pointed  out  by  Bouchard.  Statis- 
tics differ  as  to  the  frequency  with  which  the  knee-jerks  disappear. 
Griibe  found  them  absent  in  only  13.5  per  cent,  of  his  cases,  whereas  Wil- 
liamson found  them  absent  in  50  per  cent  of  his  series.  Their  disappear- 
ance is  probably  dependent  on  a  peripheral  neuritis,  or  changes  in  the 
posterior  columns  of  the  cord.  The  Achilles-reflex  may  disappear  before 
the  patellar,  as  in  locomotor  ataxia.  The  superficial  reflexes — plantar, 
abdominal,  and  epigastric — are  present  in  practically  all  cases.  A  patel- 
lar reflex  may  return  after  being  lost.  The  condition  of  the  reflexes  bears 
no  definite  relationship  to  the  prognosis,  although  the  knee-jerks  are  more 
likely  to  be  found  absent  in  hospital  than  in  private  practice,  the  former 
cases  being  usually  more  severe  than  the  latter. 

(e)  Mental  Complications. — In  addition  to  the  psychical  symptoms  al- 
ready described,  a  group  of  mental  symptoms  is  occasionally  met  with 
closely  resembling  general  paresis.  Laudenheimer  reviewed  the  relation- 
ship between  diabetes  and  general  paresis,  and  concludes  that  diabetes  is 
not  actually  the  cause  of  the  latter.  The  mental  symptom-complex  is 
often  improved  under  anti-diabetic  treatment.  It  has  already  been 
pointed  out  that  actual  general  paresis  is  quite  frequently  the  cause  of 
glycosuria. 

6.  Special  Senses. — Of  the  ocular  complications,  cataract  is  the  com- 
monest. Frerichs  observed  it  in  19  cases  out  of  400  diabetics ;  William- 
son, in  9  out  of  100;  and  Seegen,  in  4  per  cent,  of  his  cases.  It  occurs  in 
the  young  as  well  as  in  the  old.  It  is  usually  bilateral,  and,  in  the  young,  of 
the  soft  variety,  but  in  old  diabetic  patients  it  is  indistinguishable  from 
the  non-diabetic  variety.  There  is  no  satisfactory  explanation  of  its 
cause.  The  view  that  it  is  due  to  abstraction  of  water  is  no  longer  gener- 
ally supported.  Diabetic  retinitis  occurs,  but  is  not  so  common  as  albumi- 
nuric retinitis.  Williamson  found  it  in  7  cases  out  of  a  100  diabetics, 
but  in  some  of  these,  renal  disease  could  not  be  excluded  as  a  cause.  It 
was  first  described  by  Jaeger,  in  1856.  Hirschberg  describes  three  types — • 
a  retinitis  hemorrhagica  diabetica,  a  retinitis  centralis  punctata,  and  a 


784  CONSTITUTIONAL  DISEASES 

combined  form.  Rarely  a  diabetic  iritis  with  hypopyon  occurs.  Diabetic 
amblyopia,  due  to  a  central  scotoma,  and  optic  neuritis,  are  rare  com- 
plications. Dc  Schwcinitz  says  that  premature  preslnjopia,  with  failure 
to  accommodate,  is  a  common  and  often  an  early  symptom.  Sudden 
amaurosis  similar  to  that  in  ura^nia  may  occur.  The  vitreous  may 
contain  masses  of  cholesterin  crystals.  Such  a  case  has  recently  come 
under  the  writer's  observation. 

Ear  complications  are  not  common.  Furuncles  in  the  external  auditory 
meatus,  and  acute  otitis  media  occasionally  occur. 

7.  Sexual  Complications. — ^Most  of  the  sexual  symptoms  have  already 
been  dealt  with,  but  the  relationship  of  diabetes  to  pregnancy  will  be 
considered  here.  INIatthews  Duncan,  Kleinwiichter,  and  Herman,  have 
specially  considered  this  subject.  When  diabetes  develops  during  the 
child-bearing  period,  amenorrhoea  usually  results,  and  it  is  said  that  atro- 
phy of  the  uterus  may  occur.  Conception  is  rare.  According  to  Gaudard, 
33  per  cent,  of  pregnant  diabetic  women  abort.  Herman  states  that  pre- 
mature delivery,  due  to  intra-utcrine  death  of  the  foetus,  has  occurred  in 
about  two-thirds  of  the  published  cases  of  pregnancy  wdth  diabetes.  A 
diabetic  mother  may  bear  a  healthy  child,  however,  and  has  never  been 
known  to  bear  a  diabetic  one.  Usually  the  diabetes  becomes  aggravated 
after  delivery.  Pregnancy  may  go  on  to  full  term  in  certain  instances  with 
marked  amelioration  or  complete  disappearance  of  the  diabetic  features. 
Herman  favors  early  delivery,  for  the  reason  that  the  chances  are  two 
to  one  that  the  child  will  die  in  idero,  and  that  the  earlier  the  pregnancy 
ends  the  more  likely  are  the  diabetic  symptoms  to  ameliorate  in  the 
mother. 

8.  Diabetic  Coma. — This  is  the  most  important  and  most  serious  of 
the  complications  of  diabetes.  It  was  first  described  by  Kussmaul,  in 
1874.    Three  types  of  coma  occur: 

(a)  Typical  dysp7ia;ic  co}na,  or  l\ussTna.u\'s  "air-hunger"  type.  This 
is  the  form  that  Kussmaul  described,  and  is  by  far  the  most  frequent 
of  the  three.  He  observed  three  cases  of  this  type  at  his  Freiburg  clinic 
in  the  year  1874.  As  premonitory  symptoms  there  may  be  lassitude,  head- 
ache, epigastric  pain,  and  occasional  vomiting.  The  patient  becomes 
restless  and  excited,  and  tosses  about  in  bed.  His  speech  becomes  thick 
and  eventually  incoherent.  He  grows  gradually  duller,  and  eventually 
passes  into  deep  coma.  The  pulse  becomes  small  in  volume,  of  low  tension, 
and  frequent,  often  reaching  to  between  120  and  140  per  minute.  A 
characteristic  form  of  dyspnoea  develops.  It  is  inspiratory  at  first,  but  later 
expiration  is  also  involved.  When  fully  developed  the  respirations  are 
full  and  voluminous;  they  are  loud  and  can  be  heard  a  considerable  dis- 
tance, although  they  are  not  stertorous  as  in  apoplexy;  they  are  quite 
regular  and  are  usually  not  increased  in  frequency.  The  volume  of  the 
chest  is  greatly  increased  with  each  inspiration,  and  it  is  this  apparent 
demand  of  the  system  for  air  that  led  Kussmaul  to  designate  the  phe- 
nomenon as  "air-hunger."  The  temperature  is  usually  subnormal. 
There  may  be  some  cyanosis.  The  breath  often  has  a  fruity  odor  (owing  to 
the  exhalation  of  acetone),  which  may  pervade  the  whole  room.  The  urine 
may  also  have  an  acetone  odor.  Traces  of  albumin  and  enormous  num- 
bers of  short  hyaline  and  granular  casts  occur  in  the  urine  just  before 
and  during  the  coma.    Death  almost  invariably  results,  and  occurs  within 


DIABETES  MELLITUS  785 

forty-eight  to  seventy-two  hours  after  the  onset  of  the  coma.  Frerichs  and 
others  recognize  also  the  two  following  forms: 

(6)  The  So-called  Alcoholic  Form. — With  headache  and  symptoms 
suggesting  alcoholic  intoxication;  the  speech  becomes  thick,  the  pulse 
rapid,  and,  without  dyspnoea,  coma  su|)crvenes  and  the  patient  soon  dies. 

(c)  The  Diabetic  Collapfte. — The  patient  suddenly  begins  to  suffer  from 
drowsiness  and  great  weakness.  The  extremites  become  cold;  the  hands, 
feet,  and  face,  become  livid;  the  pulse  is  small,  thread-like,  and  120  to  130 
to  the  minute.  The  respirations  are  slightly  quickened,  b>ut  are  shallow 
and  not  dyspnoeic  in  character.  Drowsiness  develops,  coma  supervenes, 
and  the  patient  dies  in  ten  to  twenty  hours.  There  is  no  acetone  odor  to 
the  breath  nor  acetone  or  diacetic  acid  in  the  urine.  The  collapse  is  be- 
lieved to  be  due  to  cardiac  failure,  probably  induced  by  myocardial 
changes. 

Anomalous  forms  of  coma  occur  due  to  renal  disease,  cerebral  tumor, 
meningitis,  and  apoplexy.  The  coma  in  these  cases  is  due  to  the  accom- 
panying disease,  and  not  to  the  diabetes. 

The  true  diabetic  coma  of  Kussmaul,  or  the  "air-hunger"  type,  is  by  all 
means  the  most  frequent  and  most  important,  and  the  following  considera- 
tions mainly  concern  this  form.  A  large  percentage  of  deaths  in  diabetes 
are  due  to  coma,  and  it  is  almost  invariably  the  cause  in  childern.  An 
idea  of  its  frequency  can  be  gathered  from  the  following  statistics:  Of 
Naunyn  's  44  fatal  cases,  19  died  in  coma,  12  of  which  were  of  the  dyspnoeic 
type.  Frerichs  reported  150  deaths  from  coma  out  of  a  total  of  250  fatal 
cases;  Taylor,  26  out  of  43;  Mackenzie,  19  out  of  87;  and  Williamson, 
28  out  of  40. 

Certain  factors  tend  to  predispose  to  the  development  of  coma.  Among 
these  are  constipation,  excessive  fatigue,  the  onset  of  various  complica- 
tions such  as  carbuncle  and  pneumonia,  subjection  to  an  operation,  and 
sudden  changes  in  diet. 

The  complication  is  universally  recognized  now  to  be  a  manifestation 
of  an  acid  auto-intoxication  due  to  the  abnormal  circulation  of  /?-oxybu- 
ty ric  acid  in  the  blood.  Previous  to  the  establishment  of  this  view,  diabetic 
coma  had  been  attributed  successively  to  the  action  of  acetone  and 
diacetic  acid.  Both  these  substances,  however,  were  shown  to  be  innocu- 
ous when  injected  into  animals.  The  chief  developments  in  our  knowl- 
edge of  the  actual  cause  of  coma  took  place  between  1880  and  1885.  In 
1880,  Hallerworden  found  that  the  urine  of  many  diabetics  showed  a 
remarkable  increase  in  the  ammonia  output.  As  the  urine  in  these  cases 
was  always  markedly  acid  he  thought  there  must  also  be  a  marked  increase 
in  the  excretion  of  certain  inorganic  acids,  eliminated  as  ammonium 
salts.  Stadelmann,  in  1883,  proved  the  correctness  of  this  hj^othesis. 
For  a  series  of  successive  days,  he  estimated  the  total  mineral  acids  and 
mineral  bases,  including  the  ammonia,  in  the  urine  of  a  healthy  man  and 
a  diabetic,  and  compared  them  in  terms  of  sodium.  On  comparison  he 
found  that  in  the  normal  individual  the  sum  of  the  acid  equivalents 
slightly  exceeded  that  of  the  bases.  In  the  diabetic,  on  the  other  hand, 
the  bases  were  far  in  excess  of  the  acids.  He  concluded,  therefore,  that  in 
order  to  satisfy  the  great  excess  in  bases,  an  inorganic  acid  must  be  ex- 
creted in  large  quantities.  He  succeeded  in  isolating  an  acid  which 
proved  to  be  a-crotonic  acid  (C4He03)  but  it  was   shown    later   that 

50 


786  CONSTITUTIOXAL  DISEASES 

this  acid  was  not  excivtcd  as  such  in  the  urine,  but  that  it  was  a  decom- 
position prothict  of  another  acid  which  Minkowski  isohited  in  pure  form  in 
1884,  and  which  he  characterized  as  ,.9-oxybutyric  (C^IIgOa).  Indei)en- 
dently,  and  })racticalh'  sinuiltaneously,  Kiilz  isolated  the  same  acid  from 
the  urine  of  a  diabetic  patient. 

Stadehnann  is  given,  and  deserves,  the  credit  for  first  suggesting  that 
diabetic  coma  is  due  to  an  acid  intoxication.  The  diabetic  patient  who 
was  the  subject  of  his  first  research  died  of  typical  dyspnoeic  coma. 
^Yalter  had  shown  that  when  mineral  acids  were  injected  into  animals, 
marked  dyspntpa,  frequent  pulse,  collapse,  and  death  ensue,  the  symp- 
toms being  very  similar  to  those  in  diabetic  coma.  As  Stadehnann  had 
found  an  excess  of  acid  in  the  blood  of  the  patient,  and  was  familiar 
with  Walter's  experimental  work,  he  conchuled  that  diabetic  coma  resulted 
from  an  acid  intoxication,  and  recommended  that  the  coma  symptoms 
should  be  treated  by  the  administration  of  large  doses  of  alkalis.  His 
theory  and  suggestions  as  to  practical  treatment  have  been  borne  out 
by  subsequent  investigations. 

Without  qualification  we  can,  at  present,  say  that  the  acid  intoxication 
of  diabetic  coma,  or  "acidosis"  as  Naunyn  calls  it,  is  due  to  the  action  of 
/?-oxybutyric  acid.  By  its  action  on  the  respiratory  centre  it  causes  the 
characteristic  dyspnoea;  and  from  its  efl^ect  on  the  brain  in  general,  coma 
supervenes.  The  j(?-oxybutyric  acid  is  eliminated  in  the  urine  not  as 
such,  but  in  combination  with  the  bases,  chiefly  as  sodium  oxybutyrate. 
In  severe  cases  the  output  is  enormous,  reaching  to  between  100  and 
200  grams  daily,  and  in  a  case  reported  by  Kiilz,  to  225  grams.  For  a 
considerable  time  the  available  bases  of  the  tissues  (sodium,  potassium, 
etc.,)  are  sufficient  to  neutralize  the  acid;  but  when  it  is  excreted  for  long 
periods  these  become  used  up,  and  then  ammonia,  derived  from  proteid 
destruction,  is  called  on  for  purposes  of  neutralization.  This  accounts 
for  the  enormous  output  of  ammonia,  reaching  to  seven  or  eight  grams 
in  cases  of  threatened  coma.  We  have  already  shown  that  diacetic  acid 
and  acetone  are  derivative  products  of  /9-oxybutyric  acid,  and  it  is,  there- 
fore, not  surprising  that  we  also  find  these  substances  in  the  urine.  The 
acetone  excretion  in  the  urine  may  reach  10  grams  or  more  daily.  That 
an  acetonaemia  exists  is  indicated  by  the  acetone  odor  of  the  breath  in 
coma  cases.  The  presence  of  diacetic  acid  in  the  urine  in  the  vast  per- 
centage of  cases  means  that  /?-oxybutyric  is  also  present.  Owing  to  the 
difficulty  in  performing  the  tests  for  /?-oxybutyric  acid,  clinically,  we  rely 
mainly  on  the  ferric-chloride  test  for  diacetic  acid  to  indicate  that  an  acid 
auto-intoxication  exists.  Acetone  and  diacetic  acid  are  formed  not 
alone  from  /?-oxybutyric  acid.  This  is  indicated  by  their  sometimes 
being  present  in  the  urine  without  the  latter.  It  is  now  generally  recog- 
nized that  acetone  is  practically  always  formed  from  fat. 

The  presence  of  /?-oxybutyric  acid  or  diacetic  acid  in  the  urine  should 
always  serve  as  a  danger-signal  of  approaching  coma.  There  are  excep- 
tions to  this  rule,  however,  for  one  occasionally  meets  with  cases  in  which 
a  marked  diacetic-acid  reaction  persists  for  months.  Naunyn  refers  to  a 
case  in  which  there  was  an  excretion  of  100  grams  of  /3-oxybutyric  acid 
lasting  for  months,  and  of  another  diabetic  in  whom  it  had  been  detected 
for  years.    These  are  exceptional  cases,  however. 


DIABETES  MELLITUS  787 

The  source  of  the  /?-oxybutyric  acid  in  the  system  has  now  been  defi- 
nitely settled.  Until  recently  it  had  been  attributed  by  nearly  all  investiga- 
tors to  destruction  of  the  body-proteids.  Some  comparatively  recent 
researches  of  Geelmuyden,  Magnus-Levy,  and  others,  have  shown  con- 
clusively that  the  /3-oxybutyric  acid  and  its  two  derivatives  are  produced 
as  a  result  of  the  incomplete  combustion  of  the  fats  of  the  body,  as  well  as 
of  those  of  the  food.  The  latter  suggests  that  it  may  also  result  from 
synthesis  in  the  muscles  or  glands.  It  is  particularly  in  the  cases  with 
this  acid  intoxication  that  we  have  the  best  proof  that  fat  metabolism  is 
also  disturbed  in  this  disease.  Naunyn  formerly  supported  the  view  that 
/?-oxybutyric  acid  is  derived  largely,  if  not  entirely,  from  proteid.  In  the 
second  edition  of  his  work  on  diabetes,  which  appeared  in  1906,  he 
acknowledges  that  fat  is  undoubtedly  a  source  of  the  "acetone  bodies," 
as  /?-oxybutyric  acid  and  its  two  derivatives  are  termed.  One  gets  the 
impression,  however,  that  he  has  not  altogether  abandoned  the  view  that 
proteids  may  also  be  a  source. 

The  relative  amounts  of  acetone,  diacetic  acid  and  /?-oxybutyric  acid 
excreted  may  vary  markedly  in  different  stages  of  the  disease.  The  first 
to  appear  is  acetone,  then  diacetic  acid,  and  lastly  ^5-oxybutyric  acid. 
In  advanced  stages  of  the  disease,  /?-oxybutyric  acid  may  be  excreted  in 
large  amounts,  acetone  having  practically  disappeared  from  the  urine. 
These  changes  are  due  to  the  gradual  diminution  of  the  powers  of  oxida- 
tion in  the  body.  When  it  is  possible  to  improve  the  body  metabolism  the 
acetone  bodies  disappear  in  the  inverse  order  in  which  they  make  their 
appearance. 

As  a  general  rule,  the  addition  of  moderate  amounts  of  carbohydrates 
to  the  diet  causes  a  diminution  in  the  excretion  of  acetone,  as  well  as  of  the 
/?-oxybutyric  acid  when  it  is  present;  their  withdrawal  causes  an  increase. 
While  this  is  the  rule  in  the  mild  cases,  in  the  severest  there  are  often 
exceptions.  It  seems  to  be  quite  certain  that,  when  the  capacity  for  oxi- 
dation in  the  body  is  not  too  much  lowered,  the  presence  of  moderate 
amounts  of  carbohydrates  in  the  food  aids  in  the  oxidation  process  and 
protects  from  destruction  the  fat  which  is  believed  to  be  the  main  source 
of  the  acetone  bodies.  The  feeding  of  fats,  however,  seems  to  be  a  frequent 
cause  for  an  increase  in  these  bodies,  as  has  been  shown  by  Schwartz 
and  others.  Joslin  has  demonstrated  that  the  extent  of  acetone  excretion 
depends  on  the  capability  of  the  fat  for  absorption,  hence  on  the  character 
of  the  fat  employed.  It  can  readily  be  seen  how  important  these  con- 
siderations are  and  how  directly  they  bear  on  the  regulation  of  the  diet 
when  there  are  evidences  of  an  acid  intoxication  in  this  disease. 

W^ith  the  development  of  coma  manifestations  and  the  appearance  of 
^-oxybutyric  acid  in  the  urine,  the  sugar  excretion  often  markedly  dimin- 
ishes, and  the  percentage  of  acid,  which  rarely  reaches  beyond  0.5  to  1  per 
cent.,  may  exceed  that  of  the  sugar. 

Saunders  and  Hamilton  found  the  pulmonary  capillaries  plugged 
with  fat  in  certain  cases  of  diabetes  with  coma.  They  advanced  the  view 
that  diabetic  coma  was  due  to  fat-embolism  of  the  pulmonary  arteries. 
This  view  is  no  longer  held. 

Course  and  Prognosis. — In  children  and  very  young  individuals, 
diabetes  runs  a  very  rapid  course,  and,  almost  invariably,  death  is  caused 
by  coma.     Cases  are  recorded  by  Benson,  Becker,  Bohn,  and  Wallach,  in 


788  CONSTITUTIONAL  DISEASES 

young  individuals  in  which  the  disease  ran  its  entire  course  to  a  fatal 
termination  witliin  five  weeks.  Generally  speaking,  the  later  in  life  the 
symptoms  first  manifest  themselves,  the  better  the  {prognosis  is.  The 
majority  of  cases  after  middle  life  run  a  chronic  course,  and  it  is  not  very 
imcommon  to  see  stout,  elderly  individuals  in  whom  the  disease  has 
lasted  ten  to  fifteen  years.  Cases  without  hereditary  inffuences  are  the 
most  favorable.  Once  the  disease  is  well  established,  it  is  seldom,  if  ever, 
that  a  permanent  cure  is  effected.  Occasionally,  however,  one  sees  a 
glycosin-ia  persisting  for  months  or  years  in  a  very  neurotic  individual 
eventually  entirely  tlisapjiear.  Naunyn  cites  cases  of  acute  or  subacute 
diabetes  resulting  from  head-traunuis  in  which  there  has  been  a  per- 
manent cure.  The  thought  naturally  arises,  are  these  cases  true  diabetes, 
or  are  they  instances  of  traumatic  glycosuria  ?  It  is  always  well  to 
determine  the  power  of  the  individual  to  warehouse  carbohydrates.  If  an 
individual  on  a  non-carbohydrate  diet  excretes  no  sugar,  the  case  may  be 
considered  a  mild  one.  If,  on  the  other  hand,  sugar  is  excreted,  it  means 
that  it  is  being  manufactured  from  the  body-proteids,  and  the  case  is  a 
severe  one.  The  tolerance  of  a  diabetic  to  carbohydrates  is  determined 
by  ascertaining  the  number  of  grams  of  starch  tliat  can  be  added  to  the 
diet  without  sugar  appearing  in  the  urine.  The  presence  of  /?-oxybutyric 
acid  and  diacetic  acid  in  the  urine  is  in  the  majority  of  instances  of  serious 
import,  as  they  indicate  the  possibility  of  approaching  coma.  Once 
coma  is  well  established,  a  fatal  termination  almost  invariably  results 
no  matter  how  active  the  treatment  may  be.' 

Diagnosis. — There  is  usually  no  difficulty  in  arriving  at  a  diagnosis 
if  the  precaution  be  taken  to  use  two  or  three  urinary  tests,  including 
fermentation,  in  any  doubtful  case.  It  is  sometimes  difficult  to  determine 
whether  one  is  dealing  with  a  true  diabetes  or  a  symptomatic  glycosuria. 
Time  is  the  main  factor  in  arriving  at  a  decision  in  these  instances.  The 
presence  of  conjugate  glycuronic-acid  compounds,  homogentisic  acid 
(alkaptonuria),  lactose,  excess  of  uric  acid,  or  creatinin,  may  cause  error 
in  inexperienced  hands.  The  differential  tests  have  been  considered  in 
the  section  on  the  urine.  In  a  few  of  the  cases  of  alkaptonuria  the  con- 
dition has  been  mistaken  at  first  for  diabetes.  This  was  true  in  the  case 
reported  by  the  writer.  The  mistake  is  due  to  the  fact  that  the  homo- 
gentisic acid  which  is  eliminated  in  the  urine  reduced  alkaline  copper 
sulphate  solutions.  The  characteristic  which  the  urine  possesses  of 
darkening  on  standing  or  on  the  addition  of  an  alkali  should  arouse  one's 
suspicions.  Alkaptonuric  urine,  further,  is  negative  with  the  "bismuth, 
phenylhydrazine,  fermentation,  and  polariscope  tests.  Bremer's  blood- 
test  may  be  of  some  value  when  a  patient  is  seen  for  the  first  time  with 
suspected  coma  symptoms  and  no  urine  is  available. 

Deception  may  be  practiced  by  the  patient.  Osier  cites  a  case  under 
his  care  of  a  young  girl  who  had  a  urine  with  a  specific  gravity  of  1065, 
and  in  which  the  sugar-reactions  proved  to  be  those  of  cane-sugar.  The 
literature  records  one  case  in  which  a  woman,  after  detection,  bought 
cane-sugar  and  introduced  it  into  her  bladder! 

Pentosuria,  although  only  nineteen  cases  have  been  recorded,  is  pro- 
bably more  common  than  is  generally  supposed.  Some  of  the  cases  have 
been  mistaken  for  diabetes.  Salkowski  and  Jastrowitz  reported  the  first 
case  Id  1892.   The  urine  contained  a  copper  reducing  substance  which  was 


DIABETES  MELLITUS  789 

optically  Inactive,  did  not  ferment,  and  which  from  its  osazone  they 
identified  as  pentose.  C.  Janeway  has  recently  reported  two  cases  in 
brothers  and  states  that  there  is  a  family  predisposition  to  the  disease. 
He  describes  three  forms:  (1)  the  alimentary  pentosuria,  due  to  the 
ingestion  of  large  amounts  of  vegetables  or  fruits  containing  pentosanes; 
(2)  rare  cases  occurring  in  severe  diabetes  in  which  the  inability  to  burn 
carbohydrates  extends  to  the  pentoses;  (3)  chronic  pentosuria  occurring 
without  reference  to  the  pentoses  of  the  food.  The  sugar  excreted  in 
this  form  is  the  optically  inactive  r-arabinose.  Pentosuria  is  recognized 
as  follows:  Fehling's  solution  is  reduced  in  an  atypical  way,  the  color 
remaining  unchanged  for  a  minute  or  so  after  boiling  and  then  turning 
suddenly  a  green  yellow  or  muddy  orange  color  throughout.  It  gives  the 
phenylhydrazine  test,  but  is  optically  inactive  and  does  not  ferment. 
If  doubt  still  remains  the  oricin  test  must  be  performed,  in  which  the 
characteristic  absorption  bands  of  pentose  are  examined  for  with  the 
spectroscope. 

Treatment. — Prophylactic  measures  should  be  taken  in  families  in 
which  there  is  a  predisposition  toward  diabetes.  Often  there  is  also  a 
tendency  to  obesity  in  these  families.  It  is  advisable  to  determine  the 
ability  of  its  individual  members  to  warehouse  carbohydrates.  If  glyco- 
suria results  from  administering  100  grams  of  glucose  on  an  empty  stom- 
ach, it  maybe  concluded  that  the  assimilation  for  carbohydrates  is  lowered, 
for  a  normal  person  can  take  from  180  to  250  grams  of  glucose  without 
sugar  appearing  in  the  urine.  By  restricting  the  carbohydrates  in  the 
members  whose  assimilation  limit  is  shown  to  be  lowered,  von  Noorden 
thinks  that  the  possible  development  of  diabetes  in  these  individuals  may 
be  warded  off. 

It  may  be  well  to  emphasize  at  this  point  that,  although  certain  general 
principles  govern  the  treatment  of  diabetes  as  a  disease,  yet  it  is  the  duty 
of  the  practitioner  to  study  each  individual  case  separately,  with  special 
reference  to  his  dietetic  needs.  It  is  only  in  this  way  that  the  disease  can  be 
intelligently  treated.  The  patient  should  be  weighed  periodically,  say 
every  two  weeks  in  private  practice  and  twice  weekly  in  hospital  work, 
and  a  careful  record  kept.  The  patient's  weight  is  the  best  single  criterion 
we  possess  of  the  success  of  any  line  of  treatment.  This  has  especial  refer- 
ence to  the  dietetic  treatment.  No  matter  what  the  condition  of  the 
urine  may  be  with  reference  to  the  presence  or  absence  of  sugar,  the 
patient  on  any  line  of  treatment  must  be  regarded  as  doing  badly  if  his 
weight  is  progressively  diminishing.  It  is  much  better  for  the  mdividual 
to  excrete  moderate  amounts  of  sugar  and  hold  or  increase  his  weight, 
than  to  be  aglycosuric  and  steadily  lose  weight.  It  is  important  to  keep 
this  axiom  always  in  mind,  particularly  in  regulating  the  diet.  It  is  not 
infrequent  to  find  that  a  diabetic  will  lose  weight  when  on  a  non-carbohy- 
drate diet  and  excreting  no  sugar  or  only  small  amounts,  whereas  he  will 
begin  to  increase  in  weight  if  moderate  amounts  of  carbohydrates  be 
added,  even  though  he  excretes  more  sugar.  This  is  probably  explained 
by  Leo's  research,  in  Avhich  he  showed  that  the  administration  of  a 
certain  amount  of  carbohydrates  to  a  diabetic  spared  proteid  metab- 
olism. 

The  treatment  of  diabetes  may  be  considered  under  four  headings — 
hygienic,  dietetic,  medicinal,  and  treatment  of  the  complications. 


790  CONSTITUTIONAL  DISEASES 

Hygienic. — It  is  very  important  to  look  after  the  personal  hygiene  of 
the  patient.  Daily  baths  assist  materially  in  kee])ing  the  skin  functions 
active,  and  diminish  the  liability  to  furunculosis.  By  i)ersonal  cleanliness 
the  distressing  pruritus  pudcndi  can  be  partially  alleviated.  To  the  thin 
diabetic,  with  a  dry,  harsh  skin,  the  lukewarm  bath  is  often  soothing.  The 
more  robust  patients  can  stand  a  cold  bath.  An  occasional  Turkish  bath 
is  useful  in  the  obese  cases,  as  it  is  a  [)artial  substitute  for  massage.  Light 
woolen  underwear  should  be  worn.  Moderate  exercise  should  be  taken, 
as  a  certain  amount  of  nuiscular  activity  favors  sugar  combustion.  Vio- 
lent physical  exertion  should  be  avoided  in  the  severe  cases,  as  it  tends  to 
induce  coma.  Massage  is  useful,  as  it  tones  up  the  muscular  system  and 
thus  probably  aids  carbohydrate  metabolism.  All  sources  of  worry  and 
anxiety  should  be  eliminated  as  much  as  possible.  More  or  less  obstinate 
constipation  is  the  rule  in  diabetes,  and  it  is  of  the  utmost  importance  that 
this  should  be  corrected,  as  persistent  constipation  in  severe  cases  is  held 
by  many  to  favor  the  development  of  coma. 

Dietetic. — We  have  seen  that  the  sjanptoms  of  diabetes  are  directly  or 
indirectly  dependent  upon  the  hyperglycnemia,  the  grade  of  which  is 
pretty  accurately  indicated  by  the  amount  of  glucose  excreted.  Our 
object,  therefore,  should  be  to  eliminate  the  hyperglycsemia  if  possible. 
This  will  be  most  quickly  effected  by  cutting  out  of  the  dietary  those 
constituents  that  are  most  readily  converted  by  the  digestive  processes 
into  grape-sugar — namely,  the  carbohydrates. 

When  a  diabetic  patient  comes  under  observation,  it  should  be  the 
physician's  first  duty  to  ascertain  the  patient's  capacity  to  ware- 
house carbohydrates,  or,  in  other  words,  to  determine  his  tolerance  for 
carbohydrates.  This  is  done  by  placing  the  individual  for  at  least  five 
days  on  a  diet  absolutely  free  from  starches  and  sugar;  that  is,  on  a  pro- 
teid-fat  diet.  In  so  doing  his  weight  must  be  taken  into  consideration 
and  the  diet  so  arranged  that  it  Avill  provide  approximately  forty  calories 
for  each  kilo  body-weight.  This  can,  as  a  rule,  be  fairly  readily  done — 
and  in  hospital  work  should  always  be  done — as  the  proteid  and  fat  per- 
centage of  the  various  foods  is  given  in  some  of  the  standard  works  on 
dietetics.  Knowing  that  1  gram  each  of  proteid  and  carbohydrates  yields 
4.1,  and  1  gram  of  fat,  9.3  heat  units,  the  caloric  equivalent  of  the  diet 
can  be  readily  calculated.  As  the  carbohydrates,  which  ordinarily 
provide  the  largest  number  of  calories  in  our  diet,  are  cut  off,  it  will  be 
seen  that-the  proteids  and  fats  must  be  largely  increased  to  make  up  for 
this  deficit.  Before  arranging  the  non-carbohydrate  diet,  the  individual 
likes  and  dislikes  of  the  patient  should  be  ascertained,  so  as  to  secure  one 
that  will  be  most  palatable  and  one  that  will  likely  be  entirely  eaten  each 
day  during  the  test.  The  following  may  be  used  as  a  "standard"  diet 
for  the  tolerance  test,  subject,  to  be  sure,  to  variations  according  to  the 
patient's  age,  weight,  and  likes  or  dislikes  for  certain  forms  of  meats: 

Breakfast.— 7. SO  A.  M.  120  grams  (5iv)  of  beefsteak  or  mutton-chops 
without  bone;  two  boiled  or  poached  eggs;  200  cc.  (ovj)  of  tea  or  coffee. 

Lu7ich.— 12.30  P.  M.  SOO  grams  (ovj)  cold  roast-beef,  mutton,  or 
chicken;  60  grams  (5ij)  celery,  fresh  cucimibers,  or  tomatoes,  with  5  cc. 
(3j)  vinegar,  10  cc.  (5ij)  oil,  pepper  and  salt  to  taste;  20  cc.  (3v)  whisky 
(if  desired);  400  cc.  (§xiij)  of  water  or  ApoHinaris  water;  60.  cc.  (5ij) 
coffee. 


DIABETES  MELLITUS  791 

Dinner. — 6  p.  m.  200  cc.  (5vj)  clear  bouillon;  200  grams  (5vj)  roast 
beef;  60  grams  (Sij)  lettuce  with  10  cc.  (3ij) 'vinegar;  20  cc.  (5iv)  olive 
oil,  or  three  tablespoonsful  of  some  well-cooked  green  vegetable,  as  spin- 
ach; three  sardines  a  I'huile;  20  cc.  (3iv)  cognac  or  whisky  (if  desired), 
with  400  cc.  Apollinaris  water. 

Slipper. — 9  p.  M.  2  eggs,  raw  or  cooked;  400  cc.  Apollinaris  or  Seltzer 
water. 

With  the  four  meals  at  least  fifteen  grams  (about  5iv)  of  butter  should 
be  used  in  making  the  gravies  and  with  the  eggs.  No  milk  or  sugar  m 
permitted  with  the  tea  or  cofPee.  Saccharin  may  be  used  to  sweeten 
them.  The  time  of  taking  lunch  and  dinner,  of  course,  may  be  reversed. 
This  daily  diet  should  provide  a  person  of  60  kilos  (132  pounds)  with  a 
little  over  the  requisite  2,400  calories  for  an  individual  of  that  weight. 
One  precaution  must  be  emphasized  here.  If  the  patient  has  been 
eating  freely  of  starches  these  must  be  cut  down  slowly  for  two  or  three 
days  before  he  is  placed  on  the  standard  diet.  Any  sudden  and  radical 
change  from  one  diet  to  another  is  liable  to  induce  coma.  As  it  has  been 
found  that  a  dog  must  fast  five  days  before  the  glycogen  of  his  liver 
has  been  all  used  up,  it  is  well  to  keep  the  diabetic,  on  the  above  diet 
for  at  least  five  days;  by  so  doing  it  practically  eliminates  the  possibility 
that  any  sugar  excretion  at  the  end  of  that  time  is  derived  from  the 
stored-up  glycogen  of  the  liver. 

While  on  this  diet,  the  total  amount  of  urine  should  be  collected  for 
each  twenty-four  hours,  mixed,  measured,  and  the  sugar  determinations 
made  from  a  specimen  of  the  twenty-four  hour  amount.  The  reduction  in 
the  sugar  excretion  is  often  very  striking  in  the  first  twenty-four  hours.  If 
the  patient  becomes  aglycosuric  within  the  first  five  days  the  case  may 
then  be  considered  a  mild  form  of  the  disease,  and  it  is  then  desirable  to 
ascertain  how  much  starch  can  be  added  to  his  diet  without  sugar  appear- 
ing in  the  urine;  in  other  words,  to  determine  his  tolerance  for  carbo- 
hydrates. This  is  probably  best  done  by  allowing  the  patient  a  weighed 
quantity  of  plain  white  bread,  which  contains  approximately  about  55 
per  cent,  of  starch.  For  the  first  day  25  grams  of  bread  may  be  allowed. 
If  sugar  fails  to  appear  in  the  urine  another  25  grams  (a  little  less  than 
Sj)  may  be  added  the  next  day  and  so  on  until  glycosuria  does  develop. 
The  formula  for  the  tolerance  is  as  follows:  Tolerance  =  Standard 
diet+^  grams  starch,  x  representing  the  number  of  grams  of  starch  the 
patient  can  take  without  sugar  appearing  in  the  urine. 

If  the  patient  continues  to  excrete  sugar  after  being  on  the  standard 
diet  for  five  days,  it  indicates  that  he  is  suffering  from  a  severe  form  of  the 
disease.  It  further  means  that  the  tolerance  for  carbohydrates  is  entirely 
destroyed,  and  that  the  sugar  eliminated  in  the  urine  is  manufactured  from 
his  tissue-albumins.  In  the  cases  in  which  glycosuria  persists  after  the 
patient  has  been  on  the  non-carbohydrate  diet  for  five  days,  Naunyn 
recommends  that  a  "Hunger  Tag,"  or  hunger-day  be  instituted,  during 
which  time  no  food  whatever  is  taken  for  twenty-four  hours.  In  a  certain 
percentage  of  these  cases  the  patients  will  become  aglycosuric  as  a  result 
of  the  starvation-day.  Naunyn's  reason  for  establishing  a  hunger-day  is  to 
remove  the  hyperglycaemia  even  though  it  be  for  only  twenty-four  hours. 
By  so  doing  he  claims  that  the  tolerance  for  starches  is  increased,  and  that 
it  is  then  possible  to  give  small  quantities  of  starch  without  glycosuria 


792  CONSTITUTIOXAL  DISEASES 

occurring,  and,  which,  without  the  hunger-day,  would  not  be  warehoused. 
This  increased  tolerance  is  believed  to  be  due  to  the  tissues  securing  a 
temporary  rest  from  sugar  formation.  The  writer's  experience  with  the 
hunger-day  is  that  it  is  useless  to  advise  it  if  the  percentage  of  sugar  is 
0.5  or  over  as  when  it  is  that  high  the  sugar  rarely  entirely  disappears. 
In  the  treatment  of  diabetes  it  is  most  advisable  to  put  them  on  such  a 
standartl  diet  at  least  every  three  months  in  order  that  their  tolerance  for 
carbohydrates  may  be  increased. 

The  foods  the  diabetic  should  be  warned  against  taking,  excepting 
with  the  permission  of  the  j)hysician,  are  as  follows:  Bread  of  all  sorts, 
wheaten,  rye,  and  brown ;  all  farinaceous  preparations  such  as  rice,  sago, 
tapioca,  hominy,  semolina,  arrow-root,  and  vermicelli. 

Thick  soups  are  to  be  avoided.  Among  meats,  liver  is  about  the  only 
form  to  be  prohibited,  owing  to  the  glycogen  it  contains.  For  the  same 
reason,  oysters  are  sometimes  prohibited. 

All  starchy  vegetables:  Potatoes,  turnips,  parsnips,  squashes,  vege- 
table marrow,  beets,  corn,  peas,  and  artichokes. 

Beverages:  Beer;  the  sweet  wines  and  sweet  aerated  drinks.  These 
are  excluded  owing  to  the  sugar,  and  not  to  the  alcohol,  they  contain. 

Fruits:  Grapes,  dates,  figs,  currants,  raisins,  dried  prunes  and  plums, 
and  other  dried  fruits  rich  in  sugar,  should  be  forbi(iden.  Certain  fruits 
such  as  peaches,  apricots,  stewed  green  gooseberries,  may  be  permitted  in 
mild  cases.  Some  authorities  on  this  disease  are  inclined  to  be  rather 
more  lenient  in  regard  to  fruits.  It  is  well  to  remember  that  Isevulose 
(fruit-sugar)  has  been  shown  to  be  tolerated  better  by  the  diabetic  patient 
than  any  other  form  of  sugar. 

Sugar  for  sweetening  purposes  must  be  omitted.  Without  the  physi- 
cian's permission,  milk  must  not  be  taken. 

The  following  foods  the  diabetic  may  take  unconditionally:  Soups: 
Bouillon,  ox-tail,  and  turde;  broths;  soups  with  marrow  and  eggs  per- 
mitted. Fresh  meats:  All  the  muscular  parts  of  the  ox,  calf,  sheep,  pig, 
deer,  wild  and  domestic  birds — roast  or  boiled — warm  or  cold,  in  their 
own  gravy  or  in  a  mayonnaise  sauce. 

Internal  parts  of  animals:  Tongue,  heart,  brain,  sweetbreads,  kidneys, 
marrow-bones,  served  with  non-farinaceous  sauces. 

Preserved  meats :  Dried  or  smoked  meat,  smoked  or  salt  tongue,  corned 
beef,  American  canned  meats. 

Fresh  fish:  All  kinds  of  fresh  fish,  boiled  or  broiled,  prepared  without 
breadcrusts  or  cracker-meal  and  served  with  any  kind  of  non-farinaceous 
sauce,  preferably  melted  butter. 

Preserved  fisli:  Dried  fish,  salt  or  smoked  fish  such  as  codfish,  had- 
dock, herring,  mackerel,  flounders,  salmon,  sprats,  eels,  etc.;  tinned  fish, 
such  as  sardines  in  oil,  anchovies,  etc.;  caviar. 

Eggs :  Raw  or  cooked  in  any  way,  but  without  any  admixture  of  flour. 
Fresh  vegetables:  Green  lettuce,  cress,  spinach,  cucumbers,  onions, 
asparagus,  cauliflower,  red  and  white  cabbage,  French  beans.  The  vege- 
tables, as  far  as  they  are  suited  to  this  method  of  preparation,  are  best 
cooked  with  meat  or  a  solution  of  Liebig's  Extract  and  salt,  and  cooked 
plentifully  with  butter.    The  addition  of  flour  is  not  permissible. 

Preserved  vegetables:  Tinned  asparagus,  French  beans,  pickled  cucum- 
bers, mixed  pickles,  sauerkraut,  and  olives. 


DIABETES  MELLITUS  793 

Spices:  Salt,  white  and  black  pepper,  Cayenne  pepper,  curry,  cinna- 
mon, cloves,  nutmeg,  English  mustard,  and  capers. 

Cheese-  Neufchatel,  Edam,  Stracchino,  old  Camembert,  Gorgonzola, 
and  other  fat  and  so-called  crean  cheeses. 

Beverages:  All  kinds  of  natural  and  carbonated  waters,  either  clear  or 
with  lemon  juice,  or  with  rum,  whisky,  cognac,  and  cherry  brandy.  Light 
Moselle  or  Rhine  wines,  claret,  dry  sherry,  or  Burgundy,  in  amounts  pre- 
scribed by  the  physician.  Coffee,  black  or  with  cream,  without  sugar 
but  sweetened  with  saccharin  if  desired.    Tea,  clear  or  with  cream  or  rum. 

From  this  list  it  will  be  seen  that  the  number  of  articles  not  containing 
starch  the  diabetic  may  choose  from,  is  quite  extensive,  and  permits  him  to 
vary  his  dietary  from  time  to  time.  In  making  up  the  "standard  diet" 
certain  of  the  articles  in  the  above  list  may  be  substituted  for  some  of 
those  in  the  diet  outlined. 

Bread  is  the  article  of  diet  the  cutting  off  of  which  the  diebetic  tolerates 
least  well.  Sooner  or  later  a  craving  for  it  is  inevitable.  Various  substi- 
tutes have  from  time  to  time  been  put  on  the  market.  The  oldest  of  these 
and  the  one  in  most  extensive  use  is  gluten  bread  or  biscuits  made  from 
gluten  flour,  first  introduced  by  Bouchardat,  in  1841.  It  is  prepared  by 
washing  away  the  starch  from  wheat  flour.  The  text-books  on  cooking 
give  recipes  for  making  bread  and  biscuits  from  this  flour.  Many  firms 
claim  to  make  pure  gluten  flour.  Others  are  more  conscientious,  and 
state  the  percentage  of  starch  their  various  preparations  contain.  It  is 
easy  to  demonstrate  that  these  gluten  flours  almost  without  exception 
contain  starch,  by  adding  a  few  drops  of  Lugol's  solution.  A  blue,  or 
even  black,  reaction  is  obtained,  according  to  the  amount  of  starch 
present. 

Another  substitute  is  bread  or  biscuits  made  from  aleuronat  flour,  advo- 
cated by  Ebstein  and  prepared  by  Dr.  Hundhausen  of  Hamm,  West- 
phalia, Germany.  It  is  a  vegetable  albumin  prepared  by  a  special  process 
from  wheat.  It  contains  from  80  to  90  per  cent,  of  albumin  in  the.  dry 
substance  and  only  7  per  cent,  of  carbohydrates.  In  making  bread  from 
it,  a  considerable  percentage  of  starch  has  to  be  added. 

Flours  prepared  from  the  soya  bean,  almonds,  cocoanuts,  and  Iceland 
moss,  have  had  their  advocates  as  substitutes  for  wheat  flour.  The 
writer's  experience  has  been  limited  to  the  use  of  gluten  and  aleuronat 
bread,  and  it  has  taught  him  that  patients  eventually  tire  of  them  and 
they  still  crave  white  wheat  bread.  Owing  to  the  expense  and  the  un- 
reliability of  most  gluten  flours,  the  writer  has  given  up  their  use.  It 
is  much  better  to  allow  a  diabetic  to  have  daily  a  definite  weighed  quantity 
of  white  bread,  the  starch  percentage  of  which  we  know  to  be  about  55 
per  cent.  It  is  well  to  have  the  bread  thoroughly  toasted.  Well  toasted 
graham  bread  may  be  used  as  a  substitute  with  advantage. 

Starch,  in  the  form  of  potato,  is  thought  to  be  more  easily  assimilated 
than  wheat  starch,  and  the  comparatively  recent  work  of  ^losse  seems 
to  bear  this  out.  The  observations  at  the  Johns  Hopkins  Hospital  tend 
to  confirm  this  view.  Mosse  allowed  his  cases  1  to  1.5  kilos  (2  to  3 
pounds)  of  potatoes  daily.  He  says  that  there  is  a  marked  amelioration 
of  all  the  distressing  symptoms  under  the  potato  treatment.  It  is  best  to 
bake  the  potatoes.  Naunyn  does  not  speak  very  enthusiastically  of  this 
special  cure  in  his  last  edition.    He  thinks  that  when  benefits  result,  it  is 


794  CONSTITUTIONAL  DISEASES 

due  mainly  to  the  fact  that  the  diet  in  the  case  heretofore  has  not  been 
properly  arranged  so  far  as  the  allowance  of  carbohydrates  is  concerned. 
Von  Noorden  recently  has  atlvocated  very  strongly  a  specially  prepared 
oatmeal,  and  has  claimed  remarkable  results  in  eliminating  the  glycosuria. 

In  the  mild  cases  of  diabetes  (those  that  have  become  aglycosuric  on  the 
standard  diet),  the  best  course  to  pursue  is  to  add  to  this  standard  diet 
weighed  quantities  "of  woll-toasted  white  bread,  the  amount  to  vary  with 
the  tolerance  of  the  individual.  Occasionally,  a  roast  potato  may  be  sub- 
stituted for  the  bread.  In  these  cases  milk  is.especially  useful  as  it  con- 
tains only  between  4  and  5  per  cent,  of  lactose  which  is  very  well  assimi- 
lated by  diabetics.  A  jiint  or  a  pint  and  a  half,  accordingly,  may  be 
permitted  daily.  The  monotony  of  the  standard  diet  may  be  from  time 
to  time  relieved  by  making  substitutes  from  the  list  of  unconditionally 
allowable  foods  given  above. 

In  the  severe  cases  (those  who  fail  to  become  aglycosuric  on  the  standard 
diet)  it,  at  first  thought,  would  appear  that  the  addition  of  carbohydrates 
would  be  contra-indicated  as  they  would  tend  to  increase  the  glycosuria, 
considering  that  the  tolerance  is  ?^^7.  Experience,  however,  shows  that 
these  do  better,  and  are  more  likely  to  hold  their  weight  if  given  very 
moderate  cjuantities  of  starchy  food.  The  danger  of  coma  is  increased  by 
any  long  continuation  of  an  exclusive  proteid-fat  diet. 

In  both  forms,  a  return  to  the  strict  diet,  in  order  to  increase  the  toler- 
ance, should  be  made  at  least  every  three  months  for  a  period  of  ten  days. 
It  is  desirable  at  shorter  intervals  in  the  severe  forms. 

No  attempt  should  be  made  to  restrict  the  water  taken  by  the  diabetic. 
No  good  will  follow  by  doing  so,  as  the  thirst  and  polyuria  are  dependent 
on  the  hj^erglycjemia.  Harm,  on  the  other  hand,  is  likely  to  ensue,  as  the 
increased  thirst  causes  increased  mental  and  physical  distress.  Apollin- 
aris  and  Seltzer  water  may  be  allowed,  and  the  thirst  may  be  quenched 
by  drinking  lemonade  sweetened  with  saccharin  instead  of  sugar.  A 
drink  made  by  dissolving  a  dram  of  cream  of  tartar  in  a  pint  of  boiling 
water  and  flavoring  with  lemon  peel  and  saccharin  and  then  cooling,  may 
be  given  freely  for  the  same  purpose. 

Alcohol,  in  the  form  of  whisky,  cognac,  or  rum,  is  to  be  recommended 
as  it  aids  fat  digestion,  and  tends  to  make  up  for  the  loss  in  heat-units 
resulting  from  the  cutting  off  of  carbohydrates.  One  gram  of  alcohol  by 
its  combustion  yields  7.0  calories. 

Sawyer,  of  Cleveland,  claims  to  have  obtained  marked  benefit  in 
diabetes  by  systematic  gastric  lavage. 

Medicinal. — Few  diseases  have  had  a  greater  number  of  drugs  advoca- 
ted for  their  treatment;  all  of  which  goes  to  show  that  most  of  them  are 
useless.  In  connection  with  no  disease  is  quackery  in  and  out  of  the 
profession  more  rampant.  It  is  the  duty  of  the  practitioner,  as  much  as 
possible,  to  discourage  the  patient  from  using  the  proprietary  remedies 
so  blatantly  advertised  in  the  daily  press.  These  are  all  expensive  and 
for  the  most  part  absolutely  useless. 

Only  a  few  drugs  have  proven  of  any  service  whatever.  The  most 
useful  is  opium  and  some  of  its  alkaloids.  Its  use  in  diabetes  dates  from 
the  latter  part  of  the  eighteenth  and  beginning  of  the  nineteenth  century 
and  particularly  since  its  strong  recommendation  by  Pelham  Warren, 
in  1812.    It  is  claimed  that  it  diminishes  the  thirst,  appetite,  amount  of 


DIABETES  MELLITUS  795 

urine,  excretion  of  sugar,  and  nervous  irritability.  As  a  consequence 
the  weight  increases  and  the  general  condition  of  the  patient  improves. 
Diabetic  patients  are  unusually  tolerant  to  opium  and  its  alkaloids,  and 
can  take  large  doses  without  narcotism.  By  some,  the  crude  opium,  or 
the  dried  extract,  are  thought  to  give  the  best  results.  The  patient  may 
be  started  on  half  a  grain  of  either,  three  times  a  day,  and  this  may  be 
increased  until  a  total  of  from  4  to  6  grains  daily  are  taken.  Morphia, 
in  increasing  doses,  has  its  advocates  but  the  alkaloid  now  most  extensively 
used  in  codeia.  Half-grain  doses  of  codeia  sulphate  after  each  meal  may 
be  administered  at  first,  and  increased  until  a  total  of  6  to  8  grains  daily 
is  reached.  It  is  less  constipating  than  the  crude  drug  or  morphia.  There 
should  be  a  gradual  withdrawal  of  the  opiates  when  the  sugar  is  reduced 
to  a  minimum. 

Arsenic  stands  next  to  opium  in  its  apparent  efficacy.  It  may  be  given 
as  Fowler's  Solution,  commencing  with  3  minims  and  gradually  in- 
creasing up  to  10,  three  times  daily.  Leube  gives  one-third  of  a  grain  of 
arsenious  acid  three  times  daily.  In  diabetes  with  marked  functional 
nervous  manifestations,  bromide  of  potassium  or  soda  is  often  useful. 
It  tends  to  allay  the  nervous  irritability  and  to  diminish  the  glyco- 
suria. The  coal-tar  products  have  been  strongly  advocated,  and  in  neu- 
rotic cases  antipyrine  in  5  or  10  grain  doses  three  times  a  day  may  prove 
useful.  Potassium  iodide  should  be  given  a  thorough  trial  where  strong 
suspicions  of  a  luetic  basis  for  the  disease  exist.  Salicylates  may  be  given 
where  there  are  evidences  of  rheumatic  arthritis.  Uranium  nitrate  in 
recent  years  has  been  strongly  advocated  in  certain  quarters,  but  is  un- 
certain in  its  effects.  No  attempt  will  be  made  to  enumerate  the  multitude 
of  other  medicinal  remedies  that  from  time  to  time  have  been  recommen- 
ded. Drugs  play  a  very  minor  part  in  the  treatment  of  diabetes.  The 
writer  rarely  resorts  to  them,  excepting  for  the  relief  of  special  symptoms 
or  complications. 

Throughout  the  treatment,  the  urine  should  be  regularly  tested  for 
the  iron-chloride  reaction  for  diacetic  acid.  If  this  be  present,  sodium 
bicarbonate  in  2  to  3  gram  (30  to  40  grain)  doses,  three  times  daily,  should 
be  administered.    In  this  way  the  danger  of  coma  may  be  averted. 

Here  also,  brief  reference  to  treatment  at  mineral  spas,  and  by  alkahne 
mineral  waters,  may  be  made.  Of  the  spas  abroad,  those  of  Carlsbad, 
Neuenahr,  Vichy,  Marienbad,  and  Contrexeville,  are  probably  the  best 
for  mild  diabetics,  and,  particularly,  for  those  in  whom  there  are  gouty 
manifestations.  No  severe  case  should  be  recommended  to  run  the 
risks  of  a  long,  fatiguing  journey  to  reach  these  places.  Only  too  often 
a  fatal  termination  is  hastened.  Undoubtedly,  many  mild  cases  are 
benefited.  How  much  benefit  is  actually  attributable  to  the  waters 
themselves  is  diflficult  to  determine.  Undoubtedly,  those  that  are  mildly 
laxative,  and  those  containing  considerable  quantities  of  carbonates  and 
bicarbonates,  thus  tending  to  neutralize  the  abnormal  acids  of  the  blood, 
are  helpful.  There  is  no  question,  however,  that  the  chief  benefit  is 
derived  from  the  greater  willingness  of  the  patient  to  submit  to  a  dietetic 
regimen,  from  the  diversion  and  the  freedom  from  business  cares  and 
worries.  A  bottle  of  Vichy  or  a  couple  of  glasses  of  Carlsbad  water  daily 
may  be  taken  with  benefit  in  any  part  of  the  world.  In  the  United  States, 
mild  cases  may  be  benefited  by  a  course  at  Saratoga  Springs  where  the 


796  CONSTITUTIOXAL  DISEASES 

Hathorn  water  is  probably  the  best,  at  Bedford  Springs,  Pennsylvania, 
and,  possibly,  at  Poland  Springs. 

Pancreatic  preparations  have  been  given  a  fair  trial,  but  the  results 
have  been  disa]ipointing.  This  must  necessarily  be  the  case  until  we 
possess  some  clinical  test  by  which  we  can  recognize  the  cases  due  to 
pancreatic  disease.  Cammidge  thinks  this  may  be  possible  by  his  recently 
devised  test.  Paftcrcatic  juice  and  extract  have  failed  to  produce  any 
material  benefit.  Williams,  of  Bristol,  transplanted  the  pancreatic  gland 
of  a  shee]>  under  the  skin  of  the  breast  and  abdomen  of  a  diabetic.  The 
patient  tlied  in  three  days  of  coma.  Lepine  advocated  the  use  of  pilo- 
carpine, hypodermically,  to  stimulate  the  secretion  of  the  pancreas,  but 
without  any  satisfactory  results.  The  same  investigator,  believing  that 
diabetes  is  due  to  the  failure  of  the  pancreas  to  produce  a  necessary 
glycolytic  ferment,  produced  such  a  ferment  from  malt  diastase  and 
administered  it  to  several  diabetic  patients  with  apparent  satisfactory 
results.  Pancreatic  thei'apy,  up  to  the  present,  may  be  said  to  have  yielded 
no  beneficial  effects.  The  recent  investigations  of  Otto  Cohnheim 
suggest  that  a  combination  of  pancreas  and  muscle-juice  may  offer  better 
prospects  of  success  in  the  future. 

Treatment  of  Complications. — (1)  Diabetic  Coma. — Certain  factors 
predisposing  to  coma  must  be  carefully  guarded  against.  Obstinate  con- 
stipation must  be  counteracted;  prolonged  restriction  of  a  severe  case  to 
a  diet  entirely  free  from  carbohydrates  may  tend  to  induce  the  complica- 
tion. Sudden  and  radical  changes  from  a  mixed  diet  containing  con- 
siderable starch,  to  a  rigid  diet,  or  vice  versa,  may  precipitate  it.  We  have 
seen  that  the  coma  is  due  to  an  acid-intoxication,  the  toxic  agent  being 
/?-oxybutyric  acid,  derivative  products  of  which  are  acetone  and  diacetie 
acid.  Stadelmann,  who  first  advanced  the  acid-intoxication  theory,  was 
also  the  first  to  recommend  and  use  the  alkaline  treatment — the  only  one 
that  has  proved  of  any  benefit.  The  existence  of  an  "acidosis,"  indicated 
by  the  elimination  of  either  /3-oxybutyric  acid  in  the  urine,  or  its  product 
(diacetie  acid),  or  an  excess  of  ammonia,  should  at  once  be  followed  by  the 
administration  of  sodium  carbonate  or  sodium  bicarbonate  by  mouth. 
The  most  serviceable  clinical  test  for  the  "acidosis"  is  the  ferric-chloride 
reaction  for  diacetie  acid.  If  this  be  present,  sodium  bicarbonate,  in  2 
to  3  gram  (30  to  45  grain)  doses,  three  times  a  day,  should  be  at  once 
started.  By  so  doing  the  acid-intoxication  can  be  stopped,  and  the  ferric- 
chloride  reaction  ceases  to  be  obtained.  The  alkali  neutralizes  the  acid 
in  the  circulating  blood,  and  the  tissue-bases  (sodium,  potassium,  etc.), 
and  the  ammonia  which  is  derived  from  the  breaking  down  of  the  body- 
proteids  are  spared.  In  mild  cases  of  acidosis,  it  is  important  to  remember 
that  the  latter  may  be  relieved  by  making  moderate  additions  of  carbo- 
hydrates to  the  diet  if  the  latter  has  previously  been  very  restricted. 
Although  the  presence  of  /3-oxybutyric  acid,  or  diacetie  acid,  in  the  urine 
must  always  be  considered  a  danger  signal  of  possible  impending  coma, 
occasional  cases  are  met  with  in  which  they  are  present  for  months  with- 
out apparent  harm.  Naunyn  states  that  when  the  ammonia  excretion 
reaches  4  grams  daily,  he  has  never  seen  a  case  in  which  it  was  possible 
to  ward  off  an  eventful  attack  of  fatal  coma. 

W^hen  actual  symptoms  of  coma  have  set  in,  treatment  is  almost  hope- 
less, and  the  rule  that  prevention  is  better  than  cure  is  nowhere  better 


DIABETES  MELLITUS  797 

illustrated  than  in  this  dreaded  complication.  When  coma  symptoms  do 
intervene,  the  most  active  treatment  should  be  instituted,  however. 
Carbohydrates  should  be  added  to  the  food  if  th(;  j)atient  is  still  able  to 
swallow.  We  have  already  seen  that  acetone,  diacetic  acid,  and  [j-oxy- 
butyric  acid  are  largely,  if  not  entirely,  derived  from  fat  owing  to  the 
diminished  power  the  tissues  of  the  diabetic  possess  of  properly  oxidizing 
the  fats  of  the  food  and  tissues.  The  mildest  grade  of  this  defective  power 
of  oxidation  manifests  itself  in  the  appearance  alone  of  acetone  in  the 
urine;  the  medium  grade  with  the  appearance  of  acetone  and  diacetic 
acid;  and  the  severest  grade  with  the  occurrence  of  both  these,  and  an 
addition  of  /9-oxybutyric  acid.  As  coma  supervenes  the  amount  of  acetone 
diminishes  and  the  quantity  of  /5-oxybutyric  acid  increases.  The  knowl- 
edge that  the  adniinistration  of  carbohydrates  will  diminish  or  clear  up 
the  acidosis  when  it  has  not  reached  too  severe  a  grade  is  one  of  the 
important  recent  advances  in  the  therapy  of  diabetes.  The  administered 
carbohydrate  in  some  peculiar  manner  favors  the  more  complete  oxidation 
of  the  fats.  In  the  severest  cases  of  diabetes,  even  those  with  coma  mani- 
festations, the  organism  never  entirely  loses  its  capacity  to  burn  up 
carbohydrates.  Milk  is  most  valuable  in  these  cases.  From  500  to  1,000 
cc.  maybe  given  in  the  twenty-four  hours.  Of  all  carbohydrates  Isevulose  is 
most  easily  burnt  up  by  the  diabetic.  Recently  von  Noorden  has  advocated 
the  subcutaneous  injections  of  5  to  10  per  cent,  solutions  of  Isevulose  in 
cases  wdth  threatened  coma.  Naunyn  prefers  its  administration  either  by 
mouth  or  by  enema.  Realizing  the  origin  of  the  acetone  bodies,  the 
importance  of  cutting  down  the  fats  in  threatened  coma  becomes  at  once 
apparent.  Those  containing  the  lower  fatty  acids  are  most  injurious. 
The  fats  permitted  should  be  chiefly  those  of  vegetables  and  meats,  as 
these  contain  comparatively  little  of  the  lower  fatty  acids.  Butter,  if 
used,  must  be  given  in  limited  quantities  and  only  after  having  been 
thoroughly  washed  with  water  to  remove  the  above  acids.  It  is  probably 
better  to  entirely  exclude  butter  in  the  threatened  coma  cases,  as  it  has 
been  shown  to  very  materially  increase  the  output  of  the  /3-oxybutyric 
acid.  Soduim  carbonate,  or  bicarbonate,  should  be  given  by  mouth, 
rectum,  and  intravenously,  in  enormous  quantities.  As  much  as  4  to 
8  grams  (1  to  2  drams)  of  sodium  bicarbonate,  every  hour,  by  mouth, 
if  deglutition  is  still  possible,  and  double  this  quantity  per  rectum 
every  two  hours,  should  be  administered.  More  effectual  results  will 
follow  an  intravenous  alkaline  injection.  Enormous  quantities  of  sodium 
carbonate  have  been  introduced  at  one  injection.  Thus  Minkowski  gave 
84,  Lepine  44,  Wolfe  30,  and  Rosenstein  20  grams  at  one  operation.  The 
temporary  results  are  often  striking.  The  respirations  becomes  quieter, 
and  when  the  coma  is  not  deep  there  may  be  temporary  return  to  con- 
sciousness. As  strong  a  solution  of  sodium  carbonate  as  3  to  5  per  cent, 
has  been  used.  In  practically  all  these  cases  there  is  a  recurrence  of  the 
coma  in  a  few  hours  and  death  within  twenty-four  or  forty-six.  The 
custom  at  the  Johns  Hopkins  Hospital  has  been  to  introduce  a  liter  of  a 
2  per  cent,  solution  of  sodium  bicarbonate  in  normal  salt  solution  slowly 
into  one  of  the  median  basilic  veins,  and  to  repeat  the  procedure  on  the 
opposite  side  in  four  or  six  hours.  From  200  to  400  cc.  of  blood  should  be 
first  removed.  In  a  young  girl  of  twelve,  definite  symptoms  of  com- 
mencing coma  were,  in  this  way,  temporarily  warded  off,  death  resulting 


798  CONSTITUTIOXAL  DISEASES 

a  week  later  from  typical  coma.  Intravenous  injections  of  Ringer's 
solution  have  been  reeomnKMuled.  Naunyn  states  that,  once  coma  is 
well  established,  he  does  not  think  it  possible  permanently  to  relieve  it. 
The  grade  of  the  acid-intoxication  in  these  severe  cases  is  indicated  by  the 
fact  that,  no  matter  how  vigorously  the  alkalis  are  pushed,  it  is  not 
possible  to  render  the  urine  alkaline.  Griihberger,  in  1905,  performed 
lumbar  puncture  in  a  coma  case  and  found  acetone  and  diacetic  acid  in 
the  cerebrospinal  fluid,  although  the  urine  was  free  from  diacetic  acid. 
Naunyn  suggests  that  in  these  cases  there  may  be  a  direct  toxic  action 
on  the  central  nervous  system  and  that  the  matter  needs  further  inves- 
tigation. 

2.  Prvritus. — Frequent  bathing  of  the  genitalia,  to  prevent  them  from 
becoming  saturated  with  the  saccharine  urine,  is  the  best  preventive. 
Bathing  with  soda  solution,  or  100  to  200  solution  of  carbolic  acid, 
may  give  some  relief.  The  best  remedy  is  a  solution  of  boric  acid  or  of 
hyposul})hite  of  soda  (30  grams  or  1  ounce  to  the  liter  or  quart  of  water), 
applied  as  a  lotion.  Ichthyol  and  lanolin  ointment  may  give  relief  in 
some  cases.  Menthol  ointment  (grs.  x  to  vaseline  oj)  sometimes  gives 
relief.  These  are  purely  local  measures  and  the  symptom  will  yield  when 
the  glycosuria  is  relieved  by  the  usual  measures. 

3.  Gangrene  and  Carbuncle. — As  temporary  measures,  the  affected 
parts  should  be  dressed  with  bichloride  compresses.  Early  amputation 
and  excision,  respectively,  are  indicated.  There  is  a  certain  risk  of 
either  the  anresthetic  or  the  operation  itself  precipitating  coma,  but  this 
is  much  less  than  the  danger  from  the  complications,  as  both  are  liable 
in  themselves  to  cause  death  by  inducing  coma. 


CHAPTER  XXX. 

DIABETES  INSIPIDUS. 
By  THOMAS  B.  FUTCHER,  M.  B. 

Definition. — A  chronic  affection,  characterized  by  the  passage  of  large 
quantities  of  pale  urine  of  low  specific  gravity,  free  from  sugar,  albumin, 
and  casts,  and  usually  accompanied  by  an  insatiable  thirst. 

Although  Thomas  Willis,  in  1674,  first  recognized  a  difi'erence  between 
a  saccharine  and  a  non-saccharine  polyuria,  it  was  Johann  Peter  Frank 
who,  in  1794,  first  gave  us  a  definition  for  diabetes  insipidus  when  he 
described  it  as  a  long-continued,  abnormally  increased  secretion  of  non- 
saccharine  urine  which  is  not  caused  by  a  diseased  condition  of  the  kid- 
neys. He  distinguished  two  forms  of  diabetes,  a  diabetes  insipidus,  or 
spurious,  and  a  diabetes  mellitus,  or  verus.  In  1838,  Robert  Willis  proposed 
the  following  classification  of  the  diabetes  insipidus  cases  according  to 
the  urea  secretion:  Hydruria  included  those  cases  where  there  was  poly- 
uria and  a  normal  urea  output;  azoturia,  those  with  polyuria  and  increased 
urea  excretion;  anazoturia,  those  with  polyuria  and  diminished  urea 
elimination.  It  is  now  well  recognized  that  these  do  not  represent  distinct 
types  of  the  affection. 

Incidence. — Diabetes  insipidus  is  a  rare  disease.  In  the  seventeen 
years  ending  May  15,  1906,  since  the  opening  of  the  Johns  Hopkins  Hos- 
pital, there  were  8  cases  out  of  106,000  ward  and  dispensary  medical 
patients,  or  0 .  007  per  cent.  Six  of  these  were  in-patients  among  19,685 
medical  admissions,  or  0.03  per  cent.  Among  113,600  patients  treated 
at  the  Charite,  Berlin,  from  1877  to  1896,  there  were  55  cases,  or  0 .  048 
percent.  Eichorst  observed  7  cases,  or  0.02  per  cent.,  among  a  total 
of  35,942  patients  at  the  Zurich  Hospital. 

Etiology. — The  majority  of  cases  occur  in  comparatively  young  per- 
sons. Of  85  cases  collected  by  Strauss,  9  were  under  five  years;  12, 
between  five  and  ten  years;  36,  between  ten  and  twenty-five  years.  In 
van  der  Heijden's  series  of  87  collected  cases,  there  were  7  in  the  first, 
19  in  the  second,  23  in  the  third,  and  19  in  the  fourth,  decade.  A 
hereditary  tendency  has  been  noted  in  certain  cases.  The  most  remark- 
able instance  of  the  influence  of  heredity  is  in  the  family  reported  by 
A.  Weil.  Of  91  members  of  four  generations,  23  had  persistent  polyuria 
without  any  deterioration  of  health,  namely,  the  great  grandfather,  his 
three  children,  seven  grandchildren,  and  twelve  great  grandchildren.  Of 
the  22  affected  descendants  of  the  original  case,  there  were  1 1  males  and 
11  females.  The  cases  were  congenital  and  persisted  throughout  life. 
Lacombe,  Pain,  and  Gee,  have  reported  similar  instances  of  heredity  in  this 
disease.  Males  are  more  liable  to  the  affection  than  females.  Cases  have 
been  reported  to  be  due  to  the  effects  of  exposure,  drinking  copiously  of  cold 

799 


800  CONSTITUTIOXAL  DISEASES 

fluids,  and  a  drinkin<T-boiit.  Trousseau  noted  that  it  was  not  unusual 
to  find  that  the  parents  of  patients  suffering  from  diabetes  insipidus  were 
either  albuminuric  or  glycosuria.  Ralfe  emphasized  the  frequency  with 
which  a  history  of  tuberculosisj  syphilis,  and  gout,  were  obtained  in 
one  or  both  parents. 

Before  proceeding  with  an  account  of  the  organic  lesions  that  have  been 
found  in  many  of  the  cases  of  diabetes  insipidus,  it  may  be  of  some  assist- 
ance, in  showing  their  bearing  on  this  affection,  brieffy  to  outline  the 
results  of  the  work  done  on  experimental  poli/uria.  In  1S49,  Claude 
Bernard  demonstrated  that  there  was  a  point  m  the  floor  of  the  fourth 
ventricle  of  animals,  just  in  front  of  the  "glycosuric"  centre,  injury  of 
which  frequently  j)roduced  a  sim])le  polyuria,  but  occasionally  also  an 
accompanying  albuminuria.  Eckhard,  from  1869  to  1872,  jniblished  the 
results  of  his  experiments,  which  were  more  elaborate  than  those  of 
Bernard.  He  found  that  the  vagus  had  no  influence  on  the  secretion  of 
urine  in  dogs  or  rabbits.  Cutting  of  the  greater  splanchnic  nerve  in  dogs 
produces  an  immediate  increase  in  the  urinary  secretion,  the  amount 
being  about  four  times  that  normally  eliminated.  Stimulation  of  the 
penj:)heral  end  of  the  cut  splanchnic  stoj^ped  the  increased  elimination. 
He  concluded  that  the  greater  splanchnic  is  the  vasomotor  and  special 
secretorv  nerve  of  the  kidney  in  dogs.  Section  "of  the  spinal  cord  at  the 
level  of  the  sixth  or  seventh  vertebra,  as  well  as  at  higher  levels,  produced, 
without  exception,  an  immediate  and  persistent  suppression  of  the  urine. 
He  therefore  inferred  that  the  centre  regulating  the  urinary  secretion  is 
above  this  level.  The  nerve  fibers  supplying  the  kidneys  were  found  to 
pass  from  the  medulla  in  the  cord  to  the  level  of  the  sixth  or  seventh  cervical 
vertebra,  where  the}^  leave  by  the  upper  thoracic  nerves,  whence  they  pass 
along  the  walls  of  the  aorta  and  renal  arteries  to  the  kidneys.  In  rabbits, 
Eckhard  found  that  stimulation  of  points  in  the  floor  of  the  fourth  ventricle 
— other  than  Bernard's  "polyuric"  centre — occasionally  produced  an  ex- 
cessive flow  of  urine.  In  these  animals,  also,  he  found  that  injury  of  the 
vermiform  process  of  the  middle  lobe  of  the  cerebellum  occasioned  polyuria. 
This  was  most  readily  produced  by  injury  of  the  most  posterior  of  the 
convolutions  of  the  middle  lobe  of  the  cerebellum  seen  from  above.  To 
this  convolution  Eckhard  gave  the  name  "lobus  hydruricus  et  diabeticus" 
— "diabeticus"  because  the  polyuria  was  frequently  accompanied  by 
glycosuria.  Deep  injuries  of  the  posterior  lobe  of  the  rabbit's  brain  (that 
occupying  the  concavity  of  the  temporal  bone)  were  occasionally  followed 
by  polyuria.  Kahler  made  further  valuable  contributions  to  the  subject 
in  1886.  By  injecting  minute  quantities  of  a  concentrated  silver-nitrate 
solution  into  various  regions  of  the  brain,  he  was  able  to  cause  lesions 
which  produced  either  a  temporary  or  permanent  polyuria.  He  found 
that,  whereas  lesions  of  the  middle  lobe  of  the  cerebellum  produce  a  more 
or  less  temporary  polyuria,  wounds  of  the  medulla  oblongata,  on  the  other 
hand,  are  followed  by  a  permanent  polyuria.  The  corpus  trapezoides  of 
the  pons,  and  the  lateral  part  of  the  exposed  portion  of  the  medulla  oblon- 
gata, were  the  areas,  injury  of  which  was  most  likely  to  produce  f>  per- 
manent polyuria.  The  portion  of  the  rabbit's  brain  just  designated 
corresponds  in  the  human  brain  with  the  area  of  the  pons  where  the  sixth 
and  seventh  cranial  nerves  make  their  exit  from  the  brain.  This  throws 
some  light  on  the  cause  for  the  existence  of  paralysis  of  the  sixth  nerve. 


DIABETES  INSIPIDUS  801 

occasionally  seen  in  diabetes  insijiidus.  Kahlcr  also  found  that  destruc- 
tion of  the  inner  part  of  the  cerebellum  with  Dieter's  nucleus  and  its 
caudal  processes,  causes,  practically  always,  a  permanent  polyuria. 

From  this  experimental  work  it  would  appear  that  in  dogs  or  rabbits 
a  simple  polyuria  is  most  likely  to  result  from  the  following  lesions: 
(a)  By  injury  of  a  point  in  the  floor  of  the  fourth  ventricle  a  little  anterior 
to  Claude  Bernard  s  "glycosuric"  centre;  (b)  injuries  to  various  portions 
of  the  middle  lobe  of  the  cerebellum,  particularly  the  "lobus  hydruricus 
et  diabeticus"  of  Eckhard;  (c)  by  lesions  of  the  corpus  trapezoides  of 
the  pons  and  the  lateral  part  of  the  exposed  portions  of  the  medulla 
oblongata;    (d)  by  cutting  the  greater  splanchnic  nerve  in  dogs. 

By  analogy,  we  would  expect  that  lesions  in  these  situations  in  man 
would  produce  a  simple  polyuria,  although  positive  conclusions  must  not 
be  drawn.  We  can  see  how  tumors  occupying  the  medulla  or  the  base  of 
the  brain,  or  a  basilar  meningitis  of  syphilitic  or  other  origin,  could  be 
capable  of  producing  symptoms  of  diabetes  insipidus  in  the  human  subject. 

The  immediate  cause  for  the  polyuria  in  the  above  experiments  is  not 
definitely  settled.  Although  Eckhard  claimed  he  had  demonstrated 
special  secretory  nerves  for  the  kidney,  all  the  leading  modern  physiolo- 
gists deny  the  existence  of  such  nerves,  as  they  have  never  been  demon- 
strated to  enter  the  renal  cells,  and  they  believe  the  polyuria  results  from 
increased  blood  pressure.  The  possible  effect  on  the  urinary  secretion  of 
remote  lesions  of  the  nervous  system  was  clearly  stated  by  Ralfe  in  the 
following  terms  "  It  is  interesting  to  trace  the  course  of  the  nerves  form- 
ing the  renal  plexus,  as  irritation  from  eccentric  or  distant  sources  may 
play  a  part  in  inhibiting  the  renal  nerves.  Thus  the  nerves  forming  the 
renal  plexus  are  derived  chiefly  from  the  solar  plexus;  as  the  right  vagus 
and  greater  and  lesser  splanchnics  join  the  solar  plexus,  it  is  probable  that 
branches  of  these  nerves  enter  the  kidney  by  way  of  the  renal  plexus. 
The  splanchnics,  also,  send  branches  direct  to  the  renal  plexus,  and  the 
left  vagus  sends  some  fibers  to  the  left  kidney.  They  contain  medullated 
and  non-medullated  fibers;  and  Krause  has  traced  the  latter  as  far  as  the 
apices  of  the  papillae.  Their  mode  of  termination  is  unknown.  Physiolog- 
ically, vasoconstrictor,  vasodilator,  and  sensory  nerves,  have  been 
ascertained.  The  connection  through  the  vagus  brings  us  into  range 
with  the  medulla  oblongata,  and  with  many  organs  susceptible  of  tuber- 
cular or  syphilitic  growths,  or  of  sudden  shock,  such  as  a  chill.  The  solar 
plexus  may  propagate  the  effect  of  abdominal  new-growths  or  aneurisms." 

We  are  now  in  a  better  position  to  understand  the  effect  of  the  various 
lesions  found  in  diabetes  insipidus.  According  to  Stoermer,  traumatism  to 
the  brain  is  the  cause  in  30  per  cent  of  the  cases.  Trauma  of  the  soft  parts 
has  not  the  same  effect.  The  only  authentic  exception  is  a  case  reported 
by  Nothnagel  in  which  the  affection  followed  a  kick  on  the  abdomen.  In 
traumatic  injuries  of  the  brain  it  does  not  seem  essential  that  any  special 
part  of  the  brain  be  involved.  The  polyuria  seems  to  result  from  the 
effects  of  the  concussion  the  brain  sustains.  In  1865,  Leyden  reported 
a  case  following  cerebral  hemorrhage,  and  Ollivier  subsequently  drew 
attention  to  the  comparative  frequency  of  hemorrhage  as  a  cause.  Van 
der  Heijden  saw  a  case  in  chronic  hydrocephalus.  It  has  been  observed 
in  general  paresis,  and  has  followed  the  effects  of  otitis  media.  Cerebral 
tumors  rank  at  the  head  of  the  list  of  gross  brain  lesions  in  the  frequency 

51 


802  CONSTITUTIONAL  DISEASES 

with  which  they  are  followed  by  diabetes  insipidus.  The  nature  of  the 
tumor  is  a  minor  factor.  It  may  be  a  gumma,  a  malignant  growth,  or 
a  tuberculous  focus.  Diabetes  insipidus  is  more  likely  to  follow  where 
the  tumor  involves  the  floor  of  the  fourth  ventricle,  or  the  immediate 
vicinity. 

The  writer  has  been  impressed  recently  with  the  importance  of  cerebral 
syphilis  as  a  cause  of  the  affection,  having  recently  reported  9  cases  of 
diabetes  insipidus,  in  4  of  which,  from  the  history,  symptoms,  and  the 
improvement  under  potassium  iodide,  it  seemed  without  doubt  that 
cerebral  syphilis  was  the  cause.  In  1  of  these  the  lesion  was  a  gumma,  and 
in  the  other  3,  the  symj)toms  pointed  toward  there  being  a  basilar  syphilitic 
meningitis  as  a  part  of  the  syphilitic  lesion.  Polyuria  and  polydipsia  have 
long  been  described  as  symptoms  of  cerebral  syphilis.  Fournier  reported 
6  cases  in  which  these  symptoms  were  present  in  association  with  various 
cerebral  manifestations  of  the  disease.  Lancereaux,  Oppenheim,  and 
others,  have  noted  the  association.  The  lesion  usually  producing  the 
polyuria  is  a  basilar  syphilitic  meningitis.  This  was  the  form  of  lues  in 
Buttersack's  case,  in  which  the  disease  was  localized  mainly  in  the  inter- 
peduncular space.  Polyuria  was  the  initial  symptom  in  his  patient. 
Nonne  states  that  it  is  not  necessary,  as  was  formerly  held,  that  the  lesion 
should  involve  the  medulla  oblongata  or  its  vicinity.  He  asserts  that  all 
we  can  say  is  that  polyuria  and  polydipsia  are  most  liable  to  occur  in 
syphilitic  brain  lesions  which  manifest  themselves  in  the  form  of  a  diffuse 
basilar  meningitis.  One  can  appreciate  how  a  basilar  meningitis  might 
cause  a  polyuria,  when  one  recalls  that,  in  experimental  polyuria,  it  was 
shown  that  injuries  to  the  middle  lobe  of  the  cerebellum,  and  to  the  super- 
ficial areas  of  the  pons  and  medulla,  caused  a  profuse  flow  of  urine. 

Many  of  the  cases  of  diabetes  insipidus  due  to  basilar  syphilitic  menin- 
gitis have  been  associated  with  a  peculiar  form  of  bilateral  hemianopsia. 
Oppenheim  considers  an  "oscillatory"  form  of  hemianopsia  or  "hemian- 
opsia bitemporalis  fugax"  as  being  practically  pathognomonic  of  this 
particular  lesion.  He  has  reported  3  such  cases,  in  1  of  which  polyuria 
and  polydipsia  were  associated.  Spanbock  and  Steinhaus  state  that  in  50 
collected  cases  of  temporal  hemianopsia,  there  was  polyuria  in  11.  The 
hemianopsia  comes  and  goes  several  times  in  the  twenty-four  hours,  and 
such  a  history  was  obtained  in  2  of  the  4  cases  of  diabetes  insipidus  with 
cerebral  lues  reported  by  the  writer. 

Hadra  and  Ralfe  have  reported  cases  accompanying  aneurism  of  the 
carotid  and  of  the  abdominal  aorta  respectively.  The  affection  has  not 
infrequently  been  noted  in  affections  of  the  abdominal  viscera.  In  1794, 
Frank  observed  a  fatal  case  in  a  patient  with  chronic  disease  of  the  intes- 
tine. Schapiro  reported  5  similar  cases  from  Eichwald's  clinic.  Dick- 
inson recorded  an  instance  in  a  patient  with  carcinoma  of  the  liver  with 
secondary  metastases  in  the  retroperitoneal  lymph  glands,  which  had 
involved  branches  of  the  solar  plexus. 

Affections  of  the  spinal  cord  have,  in  rare  instances,  been  regarded  as 
the  cause  of  the  disease.  Schlesinger  saw  a  case  in  a  patient  with  tabes. 
In  a  case  of  Westphal's,  it  occurred  in  association  with  spastic  spinal 
paralysis.  F.  Schultze  saw  a  case  in  a  patient  with  a  dift'use  tumor  of  the 
cord.  Instances  of  persistent  polyuria  have  been  observed  by  Krauss  in 
syringomyelia,  and  by  Friedreich  in  hereditary  ataxia. 


DIABETES  INSIPIDUS  803 

Diabetes  insipidus  has  been  known  to  follow  the  infectious  fevers. 
Thus,  it  has  been  observed  after  typhoid,  typhus,  diphtheria,  measles, 
and  scarlet  fever. 

In  very  rare  instances,  a  diabetes  mellitus  may  pass  over  into  a  diabe- 
tes insipidus.  This  is  most  likely  to  occur  after  traumatism  to  the  brain, 
in  which,  at  first,  sugar  accompanies  the  polyuria,  but  later  disappears, 
leaving  the  characteristic  urinary  features  of  diabetes  insipidus.  Occa- 
sionally, however,  diabetes  insipidus  may  pass  over  into  diabetes  mellitus. 
In  1897,  Senator  reported  such  a  case  in  a  woman,  aged  forty-three  years, 
who,  since  childhood,  had  voided  daily  from  12  to  15  liters  of  urine  of 
a  specific  gravity  of  from  1,001  to  1,003,  and  who  developed  a  mild  glycos- 
uria. Three  years  before  her  death  0.3  per  cent,  of  sugar  was  found  in 
her  urine.    No  organic  lesions  were  detected  at  autopsy. 

Clinical  Classification. — The  disease  may  be  divided  clinically  into 
two  groups:  (1)  The  primary  or  idiopathic  cases.  This  group  includes 
the  cases  in  which  there  is  no  evident  organic  basis  for  the  disease,  and 
comprises  a  considerable  percentage  of  the  total.  (2)  The  secondary  or 
symptomatic  cases.  These  include  the  cases  in  which  there  is  evidence  of 
organic  disease  of  the  nervous  system  or  elsewhere,  the  lesion  being  con- 
sidered the  cause  of  the  polyuria. 

Symptoms. — The  disease  may  begin  abruptly,  as  after  a  severe  fright. 
More  commonly  it  develops  slowly.  Polyuria  is  the  most  constant  and 
characteristic  feature.  The  quantity  of  urine  passed  daily  may  be  enor- 
mous. Trousseau  had  a  patient,  aged  twenty-four  years,  who  passed 
43  liters  in  a  day.  The  weight  of  the  urine  voided  daily  may  almost 
equal  that  of  the  patient.  Thus,  Vierordt  cites  an  instance  of  a  child 
weighing  13.2  kilograms,  voiding  12.3  kilograms  of  urine  daily.  The 
largest  daily  elimination  in  any  of  the  writer's  9  cases  was  16.5  liters. 
One  passed  1,700  cc  at  a  single  voiding.  The  urine  is  usually  almost 
colorless.  It  may  have  a  bluish  tint.  The  specific  gravity  generally 
ranges  between  1,001  and  1,005.  It  may  be  much  higher,  if  there  is  a 
marked  excretion  of  urea.  Thus  Laparguois  observed  a  case  in  which 
6  liters  of  urine  was  passed  daily  with  a  specific  gravity  of  1,017.  The 
urine  is  usually  free  from  albumin,  sugar,  or  casts.  Occasionally,  traces 
of  albumin  may  appear  in  the  late  stages.  In  the  early  stages  the  output 
of  urine  may  far  exceed  the  intake  of  fluids.  This  is  due  to  withdrawal 
of  fluids  from  the  tissues.  The  writer  has  noted  this  inequality  in  cases 
of  long  standing.  Dickinson  conducted  experiments  suggesting  that  this 
was  in  part  due  to  absorption  of  the  moisture  of  the  air  through  the 
skin.  The  balance  of  opinion  favors  the  view  that  a  condition  of  "brady- 
uria"  rather  than  "tachyuria"  exists  in  this  disease.  In  other  words, 
when  a  copious  draft  of  fluid  is  taken,  an  increase  in  the  flow  of  urine 
is  slower  m  making  its  appearance,  and  the  total  elimination  is  slower 
m  a  patient  with  diabetes  insipidus  than  in  a  healthy  individual.  There 
is  a  slight  increase  in  the  urinary  solids  in  the  majority  of  cases.  The 
urea  may  be  markedly  increased,  but  this  is  due  to  the  food  ingested, 
rather  than  to  any  increased  tissue  metabolism.  The  chlorides  are  some- 
times increased.  Muscle-sugar,  or  inosite,  has  been  frequently  demon- 
strated in  the  urine.  This  is  believed  to  result  from  the  flushing  out  of 
the  muscles  by  the  enormous  quantity  of  fluids  ta^ken. 


804  CONSTITUTIONAL  DISEASES 

Thirst  is  practically  a  constant  and  often  a  distressing  symptom.  In 
many  cases  it  is  the  first  one  complained  of,  as  it  first  attracts  the  patient's 
attention.  One  patient  of  the  writer  said  he  "simply  lived  to  drink," 
and  described  the  infinite  satisfaction  it  gave  him  to  be  able  to  take  a 
whole  pitcher  of  water  at  one  draught.  Trousseau's  patient  drank  50 
liters  in  twenty-four  hours.  In  experiments  in  which  the  fluids  have  been 
cut  off,  the  patient,  as  in  Strubell's  case,  has  been  known  to  drink  his  own 
urine.  It  is  very  difficult  in  many  cases  to  determine,  from  the  history  or 
otherwise,  whctiier  one  is  dealing  with  a  primary  polyuria  or  a  primary 
polydi}xsia.  These  can  scarcely  be  considered  independent  diseases,  how- 
ever. Nothnagel's  case  is  usually  cited  as  a  typical  instance  of  a  primary 
polydipsia.  A  man,  aged  thirty-five,  was  kicked  in  the  abdomen  and  fell, 
striking  his  head  in  the  region  of  the  right  ear,  against  a  stick  of  wood,  but 
was  not  rendered  imconscious.  Half  an  hour  later  he  began  to  have  in- 
tense thirst  and  drank  three  liters  of  water,  but  it  was  not  until  about 
three  hours  afterward  that  the  first  urine  was  voided.  Buttersack  gives 
the  following  conditions  as  indicating  a  primary  polydipsia  in  any  partic- 
ular case:  (1)  There  is  normal  sweat  secretion.  (2)  The  urine  is  less  than 
the  amount  of  fluids  taken.  (3)  The  polyuria  ceases  on  cutting  off  the 
fluids.  (4)  The  urine  elimination  and  liquids  taken  run  parallel.  Stoermer 
states  that  in  primary  pohdipsia  the  blood  is  of  normal  concentration, 
while  in  primary  polyuria  it  is  increased. 

The  appetite  varies  considerably  in  different  cases.  Often  it  is  not 
increased,  and  may  be  diminished.  On  the  other  hand,  it  may  be  raven- 
ous, as  in  Trousseau's  patient,  who  ate  in  the  Paris  restaurants,  where 
the  meals  were  a  fixed  price  and  the  bread  was  not  charged  for.  He  de- 
voured so  much  of  the  latter  that  it  was  more  profitable  for  the  restaurant 
keepers  to  pay  him  to  remain  away.  These  bulimia  cases  are  the  ones  in 
which  there  is  such  a  marked  increase  in  the  urea  output.  Absence  of 
sweating  is  the  rule.  The  insensible  perspiration  is  also  diminished. 
Constipation  is  common.  Cataract  has  been  described.  One  of  the 
writer's  patients  had  bilateral  plaques  of  xanthoma  palpebrarum.  As 
already  stated,  there  may  be  recurring  attacks  of  transitory  bitemporal 
hsemianopsia  in  cases  due  to  basilar  syphilitic  meningitis.  Choked  disk 
may  be  present.  Paralysis  of  the  sixth  nerve  is  sometimes  seen.  Many  of 
the  cases  due  to  cerebral  disease  have  intense  headaches.  Some  suffer 
early  arid  throughout  the  disease,  with  racking  pains  in  the  back  and 
legs.  In  one  of  the  waiter's  cases  there  were  several  attacks  of  transitory 
left-sided  hemiplegia,  followed  by  an  attack  of  longer  duration,  from 
wdiich  it  took  Aveeks  to  recover.  Impotence  not  infrequently  occurs. 
Marked  emaciation  may  develop  in  the  secondary  symptomatic  cases. 
In  the  idiopathic  cases,  on  the  other  hand,  there  may  be  no  loss  in  weight. 
CEdema  of  the  feet  may  occur  in  the  last  stages  of  the  asthenic  cases.  In 
contrast  to  diabetes  mellitus,  the  knee-jerks  are  likely  to  be  exaggerated. 
Of  9  cases,  they  were  exaggerated  in  5,  normal  in  1 ,  diminished  in  2,  and 
not  noted  in  1.  The  results  of  researches  show  that  metabolism  is  but 
little  disturbed,  notwithstanding  the  abnormal  fluid  exchanges.  In  some 
of  the  cases  the  blood  is  concentrated  and  the  red  cells  may  be  between  six 
and  seven  millions  per  cmm.  The  temperature  is  always  subnormal, 
unless  some  complication  intervenes.  During  febrile  attacks  the  amount 
of  urine  may  diminish  considerably.   The  pulse  is  usually  of  small  volume, 


DIABETES  INSIPIDUS  805 

and  there  Is  said  to  be  no  increase  in  the  blood  pressure.  Toward  the  end 
the  exhaustion  may  be  extreme.  Death  is  sometimes  preceded  by  an 
uncontrollable  diarrhoea.  Drowsiness  eventually  ensues,  and  death 
occurs  with  the  patient  in  coma.  The  immediate  cause  in  many  cases  is  a 
low  form  of  congestive  pneumonia. 

Morbid  Anatomy.  — There  are  no  lesions  peculiar  to  the  disease.  The 
various  morbid  processes  found  at  autopsy,  and  already  given  in  the  sec- 
tion on  etiology,  are  primary  rather  than  secondary.  The  kidneys  are 
usually  enlarged  and  hypersemic.  The  bladder  is  dilated,  and  its  walls 
hypertrophied.  Dilatation  of  the  ureter  and  pelves  of  the  kidneys  is 
occasionally  found. 

Theories  as  to  Cause. — The  essential  cause  for  the  polyuria  has  been 
the  subject  of  much  research,  and  is  still  far  from  being  satisfactorily  ex- 
plained. However  it  may  be  brought  about,  the  determining  factor  seems 
to  be  a  disturbance  of  the  secretory  function  of  the  kidneys.  Osier  says 
that  "it  results  from  a  vasomotor  disturbance  of  the  renal  vessels,  due 
either  to  local  irritation,  as  in  the  case  of  an  abdominal  tumor,  to  cerebral 
disturbance  in  cases  of  brain  lesion,  or  to  functional  irritation  of  the  cen- 
tre in  the  medulla,  giving  rise  to  continuous  renal  congestion."  Dietrich 
Gerhardt  states  that  in  the  idiopathic  forms  "the  disease  is  due  to  a 
disturbance  of  the  secretory  function  of  the  kidneys  and  not  to  an  increase 
in  the  thirst  or  to  blood  changes."  Meyer,  in  a  research  published  from 
Mliller's  clinic  in  May,  1905,  comes  to  the  conclusion  that  in  diabetes 
insipidus  one  has  to  do  with  a  primary  polyuria,  which  results  from  an 
incapacity  of  the  kidneys  to  secrete  a  urine  of  normal  concentration.  In 
consequence  of  this  functional  incapacity  of  the  kidneys,  the  diabetes  in- 
sipidus patient,  in  order  to  eliminate  the  end-products  of  tissue  metab- 
olism circulating  in  the  blood,  has  to  imbibe  larger  quantities  of  water 
than  does  the  normal  individual.  Thus,  the  administration  of  sodium 
chloride  to  a  patient  with  primary  polyuria  is  not  followed  by  the 
elimination  of  a  urine  of  increased  specific  gravity,  the  quantity  of  urine 
being  actually  increased.  In  primary  polydipsia  on  the  other  hand,  ac- 
cording to  Meyer,  the  power  of  the  kidneys  to  secrete  a  more  concen- 
trated urine  is  not  destroyed.  Thus,  the  administration  of  sodium 
chloride  to  such  a  patient  is  followed  by  an  increase  in  the  specific  gravity, 
without  any  increase  in  the  volume  of  the  urine. 

Diagnosis. — There  is  no  arbitrary  line  separating  the  physiological  from 
the  pathological  polyurias,  so  far  as  the  amount  of  urine  is  concerned. 
The  chief  distinguishing  features  of  the  polyuria  of  diabetes  insipidus  is 
its  permanence,  a  physiological  polyuria  usually  being  transitory  The 
greatest  difficulty  will  arise  in  distinguishing  the  cases  from  those  of 
chronic  interstitial  nephritis,  where  an  abundant,  pale  urine  is  common. 
In  the  latter,  the  existence  of  albumin  and  a  few  casts,  with  certain  cardio- 
vascular features,  should  not  cause  much  difficulty.  The  hysterical  poly- 
uria will  usually  be  recognized  by  the  existence  of  certain  nervous  and 
psychical  symptoms.  The  polyuria,  further,  is  likely  to  be  intermittent 
in  character.  Some  have  included  hysterical  polyuria  as  a  form  of  diabe- 
tes insipidus,  but  this  hardly  seems  justifiable.  The  absence  of  sugar  and 
the  low  specific  gravity  differentiate  the  affection  from  diabetes  mellitus. 
Whether  or  not  "primary  polyuria"  and  "primary  polydipsia"  should  be 
considered  as  two  distinct  affections  is  doubtful.    The  writer's  feeling  is 


806  CONSTITUTIONAL  DISEASES 

that  they  should  not,  as  the  clinical  features  in  the  two  are  practically 
identical.  As  stated,  INIeyer  holds  that,  in  the  former,  the  kidneys  are 
incapable  of  secreting  a  more  concentrated  urine  on  the  addition  of 
sodium  chloride,  etc.,  to  the  diet,  whereas  this  capacity  is  not  destroyed 
in  the  latter. 

Prognosis. — Idiopathic  diabetes  insipidus  is  much  the  more  benign  of 
the  two  forms.  There  is  usually  no  marked  emaciation,  and  the  cases 
have  been  known  to  last  for  fifty  years.  The  prognosis  is  less  favorable  in 
the  secondary  or  symptomatic  cases.  Emaciation  is  often  rapid  and  an 
early  fatal  termination  may  ensue.  The  length  of  life  depends  largely  on 
the  seat  and  nature  of  the  organic  lesion  causing  the  polyuria. 

Treatment. — This  is  on  the  whole  most  unsatisfactory.  Once  the 
polyuria  is  established,  it  is  practically  impossible  permanently  to  relieve 
it.  The  long  list  of  drugs  recommended  is  ample  evidence  of  their  general 
inefficiency.  Preparations  of  opium  have  been  used  with  some  benefit. 
The  crude  opium  or  extract,  in  half-grain  doses,  three  times  daily,  and 
gradually  increasing  until  a  total  of  4  to  G  grains  daily  are  taken,  may  be 
tried.  Codeia  may  be  administered  in  the  same  way.  The  relief,  pallia- 
tive rather  than  curative,  is  probably  due  to  the  lessening  of  the  sense  of 
thirst.  The  commonest  drug  administered  is  valerian.  Either  the 
powdered  root,  given  at  first  in  5  grain  doses,  three  times  daily,  and 
increased  until  the  patient  takes  a  total  of  2  drams,  or  the  valerianate 
of  zinc  in  15  grain  doses,  increased  to  30  grains  three  times  daily,  may 
be  tried.  Preparations  of  ergot  have  a  good  reputation,  and  to  a  certain 
extent,  justifiably  so.  Ten  minims  of  the  tincture  or  fluid  extract,  three 
times  daily,  may  be  tried,  and  it  is  not  infrequently  followed  by  an 
appreciable  reduction  in  the  amount  of  urine.  The  benefit  is  temporary 
and  symptoms  of  ergotism  must  be  guarded  against.  According  to  Erich 
Meyer,  theocin  seems  to  increase  the  functional  activity  of  the  kidneys. 
After  its  administration,  the  specific  gravity  is  increased,  and  there  is  no 
increase  in  the  amount  of  urine.  It  may  be  given  in  0 . 3  gram  (5  grain) 
doses,  three  times  daily. 

As  it  is  probable  that  a  larger  percentage  of  cases  are  due  to  cerebral 
lues  than  is  generally  supposed  by  the  profession,  a  luetic  history  should 
be  carefully  inquired  for,  and  late  syphilitic  manifestations  searched  after. 
Where  there  are  marked  cerebral  symptoms,  potassium  iodide  and 
mercurial  inunctions  should  be  given  a  thorough  trial.  In  the  4  of  9 
cases  in  which  syphilis  was  believed  to  be  the  cause  of  the  disease,  there 
was  marked  improvement  in  the  cerebral  manifestations,  in  the  general 
health,  and  a  striking  increase  in  the  weight,  in  all  instances  after  a 
thorough  course  of  luetic  treatment.  There  was,  however,  no  material 
diminution  in  the  amount  of  the  urine. 

These  are  the  drugs  which  experience  has  shown  to  give  the  best  results. 
The  long  list  of  other  remedies  that  have  been  tried  will  not  be  enumer- 
ated. 

It  is  not  advisable  to  greatly  restrict  the  liquids.  When  a  patient  first 
comes  under  observation,  it  is  wxU  to  reduce  the  fluids  a  pint  a  day,  so 
long  as  there  is  a  corresponding  reduction  in  the  amount  of  urine.  When 
the  reduction  of  urine  ceases  to  follow  the  reduction  in  fluids,  no  further 
limitation  of  the  latter  should  be  made,  as  it  means  that  the  patient  is 
abstracting  fluids  from  his  own  tissues.    For  the  thirst,  the  usual  acidu- 


DIABETES  INSIPIDUS  807 

lated  drinks  may  be  tried.  If  the  digestive  powers  are  good,  there  is  no 
occasion  for  any  special  Hmitation  of  the  food.  Strongly  salted  meats 
should  be  avoided,  as  they  will  tend  to  increase  the  thirst  and,  conse- 
quently, the  polyuria.  Meyer  holds  that  meats  in  general  should  be 
restricted.  They  yield  more  products  which  are  ordinarily  excreted  by 
the  kidneys  than  do  the  other  foodstuffs,  and  a  diet  liberal  in  meats  would 
tend  to  aggravate  the  symptoms,  since  the  patient  would  have  to  drink 
more  freely  of  water  in  order  to  produce  a  solution  of  these  products 
sufficiently  dilute  for  the  kidneys  to  be  able  to  excrete  them 

The  tendency  to  constipation  should  be  counteracted,  and  it  is  advisable 
to  place  the  patient  on  a  good  general  tonic. 


CHAPTER  XXXI. 

GOUT. 
By  THOMAS  B.  FUTCHER,  M.  B. 

Definition. — A  nutritional  disorder,  characterized  by  disturbances  in 
nitrogen  metabolism,  with  an  excess  of  uric  acid  in  the  circulating  blood, 
and,  usually,  by  an  arthritis,  the  distinguishing  feature  of  which  is  the 
deposition  of  sodium  biurate  in  the  peri-articular  cartilages  and  tissues. 

Historical.— The  writings  of  Hippocrates,  who  lived  about  350  B.C., 
show  that  he  was  familiar  with  the  symptoms  of  gout.  Celsus  and  Galen 
also,  had  some  knowledge  of  the  affection.  Aretseus,  who  wrote  about  the 
middle  of  the  second  century  of  the  Christian  era,  classified  the  disease 
according  to  the  part  affected,  and  called  it  Podagra,  Gonagra,  and 
Chiragra,  when  the  attack  seized  the  foot,  knee,  and  hand,  respectively. 
He  also  mentions  that  a  gouty  patient  has,  during  the  interval  between 
the  acute  attacks,  even  won  in  the  Olympic  games.  These  early  writers 
were  also  familiar  with  the  hereditary  nature  of  the  affection.  The  name 
gout  (gutta,  a  drop)  was  introduced  by  Radulfe  at  the  end  of  the  thirteenth 
century.  It  owes  its  origin  to  the  prevailing  belief  that  the  disease  was 
due  to  the  presence  in  the  blood,  of  some  peculiar  humour  which  is  thrown 
out,  or,  as  it  were,  distilled  into  the  joints,  drop  by  drop.  Thomas  Syden- 
ham (1624-1689),  Avho  was  himself  a  martyr  to  the  affection,  gave  us  an 
account  of  its  clinical  symptoms  that  has  never  been  surpassed.  In  1776, 
Scheele  and  Bergmann  first  discovered  uric  acid  in  vesical  calculi  and  in 
human  urine.  The  association  between  uric  acid  and  gout  dates  from 
1797,  the  year  in  which  Wollaston  demonstrated  that  the  gouty  deposits 
about  the  joints  contained  uric  acid.  Garrod,  in  1848,  by  his  well-known 
thread-test,  demonstrated  uric  acid  in  the  circulating  blood  of  gouty  indi- 
viduals. 

Incidence. — Gout  is  not  so  rare  a  disease  in  this  country  as  the  text- 
books would  lead  us  to  suppose.  If  physicians  will  recognize  the  fact 
that  there  is,  probably,  no  such  affection  as  chronic  rheumatism,  and  that 
the  vast  majority  of  cases  of  chronic  arthritis  are  either  gout  or  arthritis 
deformans,  it  will  be  found  that,  with  due  regard  to  the  points  in  the 
differential  diagnosis,  a  great  many  more  cases  will  be  justly  attributed  to 
gout  than  has  been  the  case  in  the  past.  In  the  first  seventeen  years  since 
the  opening  of  the  Johns  Hopkins  Hospital,  ending  May  15,  1906,  there 
have  been  63  cases  of  gout  among  a  total  of  19,685  medical  admissions, 
or  0. 32  per  cent.  A  comparison  between  the  number  of  gout  admissions 
to  the  Johns  Hopkins  Hospital  and  those  admitted  to  St.  Bartholomew's 
Hospital,  London,  for  fourteen  years  showed  that  the  ratio  was  just  2  to  3. 
Considering  that  gout  is  more  prevalent  in  Southern  England  than 
anywhere  else  in  the  world,  it  indicates  that  in  the  vicinity  of  Baltimore, 

808 


GOVT  809 

at  least,  the  disease  is  only  one-third  less  frequent  among  hospital  patients 
than  in  London.  It  must  be  remembered  that  the  better  classes,  in  which 
it  is  more  common,  do  not  usually  seek  hospital  treatment. 

Etiology. — 1.  Predisposing  Causes. — (a)  Heredity. — Hereditary  pre- 
disposition is,  undoubtedly,  one  of  the  most  important  factors  and 
plays  a  part  in  from  50  to  75  per  cent,  of  the  cases.  This  is  particularly 
true  with  the  well-to-do  class.  Scudamore  states  that  out  of  523  gouty 
patients,  309,  or  59  per  cent.,  gave  a  history  of  the  disease  in  the  parents 
or  grandparents.  Garrod  found  that  the  predisposition  was  inherited  in 
50  per  cent,  of  his  hospital  patients.  In  his  private  cases,  however, 
he  believed  that  the  tendency  was  inherited  in  75  per  cent.  In  the 
Johns  Hopkins  Hospital  series  of  63  cases,  there  was  a  history  of  gout 
or  "rheumatism"  in  20,  or  31  per  cent.  It  would  appear,  therefore,  that 
gout  in  the  United  States  is  acquired  or  "free-hold,"  rather  than  inherited 
or  "copy-hold, "  to  use  the  classification  of  old  Sir  William  Browne.  It  is 
an  interesting  feature  that,  althtDugh  the  women  of  gouty  families  may 
escape  gouty  manifestations,  they  are  more  likely  to  transmit  the  disease  to 
their  offspring  than  are  the  men.  A  grandson  may  inherit  gout  from  a 
gouty  grandfather  through  a  mother  who  has  never  shown  any  manifest 
symptoms  of  the  disease.  Gout  acquired  from  extrinsic  causes  may  be 
transmitted  to  the  offspring. 

(6)  Age,  Sex,  and  Race. — Although,  in  inherited  gout,  infants  at  the 
breast  have  shown  manifestations  of  the  disease,  it  is  a  rare  affection  in 
infancy  and  childhood.  This  is  illustrated  by  Scudamore's  statistics  of  515 
cases,  in  which  only  4  occurred  before  the  age  of  seventeen,  the  young- 
est being  eight  years  old.  There  were  but  13  in  the  first  two  decades. 
When  gout  appears  in  a  very  young  person  it  is  nearly  always  inherited. 
In  our  series  of  63  cases,  the  ages  on  admission  to  the  hospital,  accord- 
ing to  decades  were  as  follows:  One  to  ten,  none;  eleven  to  twenty,  2; 
twenty-one  to  thirty,  4;  thirty-one  to  forty,  13;  forty-one  to  fifty,  17; 
fifty-one  to  sixty,  18;  sixty-one  to  seventy,  7;  seventy-one  to  eighty,  2. 
Although  this  analysis  shows  the  largest  number  of  cases  in  the  sixth 
decade,  that  is,  between  fifty-one  and  sixty  years  inclusive,  general  sta- 
tistics indicate  that  the  initial  attack  makes  its  appearance  most  fre- 
quently in  the  fourth  decade,  namely,  between  the  ages  of  thirty-one  and 
forty. 

Males  are  much  more  liable  to  the  disease  than  females.  In  fact  it  is 
rare  in  women  until  after  the  child-bearing  period  is  over.  Since  the 
time  of  Hippocrates,  the  relative  immunity  in  women  has  been  attributed 
to  the  influence  of  the  catamenia.  Of  80  cases  collected  by  a  spe- 
cial commission  of  the  French  Academy,  only  2  were  in  females.  Of  124 
cases  admitted  to  St.  Bartholomew's  Hospital,  in  fourteen  years,  24  were 
in  women.  In  our  series  of  63  cases,  there  were  only  2  in  females.  Gout 
in  women  is  usually  inherited.  Their  relative  immunity  is  undoubtedly 
due,  in  large  part,  to  their  not  being  exposed  to  the  exciting  factors  to  the 
same  extent  that  men  are. 

The  colored  race  does  not  escape.  In  the  Johns  Hopkins  Hospital 
series  there  were  3  male  negroes.  Two  came  to  autopsy  and  the  biurate 
deposits  were  found  in  the  joint  cartilages,  and  in  the  third  there  were 
numerous  tophi  in  the  ears  in  which  the  sodium  biurate  crystals  were 
demonstrated. 


810  CONSTITUTIONAL  DISEASES 

(c)  Alcohol  — It  is  probable  that  alcohol  heads  the  list  in  importance 
among  the  predisposing  causes.  It  is  a  curious  fact  that  the  fermented 
beverages,  such  as  wines,  particularly  port  and  sherry,  beer,  ale,  and  por- 
ter, are  much  more  injurious  than  the  distilled  liquors — whisky,  brandy, 
rum,  and  gin.  The  quality  of  the  alcohol  seems  to  be,  therefore,  as  im- 
portant as  the  quantity.  In  Scotland,  where  whisky  is  the  prevailing 
drink,  gout  is  much  less  prevalent  than  in  Southern  England,  where  beer 
is  the  ciiief  beverage.  Investigation  has  failed  to  explain  this  difference 
in  the  action  of  the  alcohol.  It  is  apparently  not  due  to  the  greater  acidity 
of  the  fermented  beverages,  nor  to  the  greater  percentage  of  sugar  or 
salines  containetl  in  them.  Although  the  lighter  beers  of  this  country  are 
considered  less  potent  as  an  etiological  factor  than  the  heavier  beers  of 
England  and  Germany,  the  analysis  of  our  series  seems  to  show  that  beer 
is  the  chief  etiological  factor  in  the  United  States. 

A  very  important  contribution  to  our  knowledge  as  to  how  alcohol  acts 
injuriously  in  disturbing  uric  acid  metabolism,  has  recently  been  made  by 
Beebee,  in  Chittenden's  laboratory.  It  was  found  that  if  a  patient  be 
put  on  a  diet  containing  a  definite  quantity  of  purin  or  nuclein  containing 
food  and  while  on  this  diet  he  is  given  alcohol,  there  is  an  immediate 
increase  in  the  output  of  uric  acid  in  the  urine.  The  alcohol,  however, 
did  not  produce  this  result  when  taken  with  a  light  diet,  or  with  one  free 
from  purin  compounds.  In  other  w'ords,  the  alcohol  only  influences  that 
portion  of  the  uric  acid  which  is  derived  from  the  ingested  food,  that  is, 
the  "  exogenous "  uric  acid.  Alcohol  is  well  known  to  interfere  with  oxi- 
dative processes  in  the  liver.  Schittenhelm  has  shown  that  the  liver 
and  other  organs  contain  an  enzyme  "oxidase,"  which  has  the  power 
of  oxidizing  uric  acid  into  urea  and  other  products.  It  is  quite  probable 
that  the  increase  of  the  uric  acid  in  the  blood  and  urine,  after  the  ingestion 
of  alcohol  and  purin-containing  food,  is  due  to  the  inhibitory  action  of  the 
alcohol  on  this  oxidase  which  normally  oxidizes  the  uric  acid  into  urea. 
The  failure  of  the  enzyme  to  effect  this  transformation,  results  in  an  ex- 
cess of  uric  acid  in  the  blood  and  consequently  also  in  the  urine.  This 
important  work  explains  how  a  rich  proteid  diet,  together  with  the  con- 
sumption of  alcoholic  fluids,  predisposes  to  the  development  of  gout. 

(d)  Food  mid  Exercise. — Gout  undoubtedly  is  a  penalty  of  high  living. 
Rich,  nitrogenous  foods,  particularly  the  red  meats  and  game,  have  al- 
w^ays  been  held  to  be  specially  injurious.  There  is  a  growing  tendency, 
however,  to  place  less  importance  on  the  quality  of  the  food  and  more  on 
the  quantity,  and  habits  as  regards  to  exercise.  Overeating  and  the 
leading  of  a  sedentary  life  are  probably  most  important  factors.  Syden- 
ham stated  the  case  clearly  when  he  wrote:  "Great  eaters  are  liable  to 
gout,  and  of  these  the  costive  more  especially.  Eating  as  they  used  to 
eat,  when  in  full  exercise,  their  digestion  is  naturally  impaired.  Even  in 
these  cases,  simple  gluttony  and  free  use  of  food,  although  common  in- 
centives, by  no  means  so  frequently  pave  the  way  for  gout  as  reckless  and 
inordinate  drinking."  Neither  the  quality  of  the  food  nor  its  quantity 
does  so  much  harm  as  the  fact  that  it  is  "unearned  by  muscular  exertion, " 
as  Ewart  puts  it.  We  must  remember  that  gout  is  not  confined  to  the  rich, 
however.  Osier  says:  "In  England  the  combination  of  poor  food,  defect- 
ive hygiene,  and  the  consumption  of  excessive  malt  liquors,  makes  'the 
poor  man's  gout'  a  common  affection."    These  were  the  conditions  that 


GOUT  811 

largely  prevailed  in  our  series,  as  55  of  the  CO  patients  were  treated  in 
the  public  wards,  and  belonged  to  the  poorer  classes. 

(e)  E^ect  of  Lead. — Musgrave,  Iluxham,  and  Falconer  (1772),  had 
called  attention  to  the  association  between  lead  poisoning  and  gout,  but  it 
remained  for  Garrod  to  show  the  importance  of  lead  as  an  etiological  fac- 
tor. He  found  that  33  per  cent,  of  the  gout  patients  that  came  under  his 
care  in  hospital  practice,  had  at  some  period  of  their  lives  suffered  from 
lead  poisoning,  and  had  for  the  most  part  been  plumbers  or  painters. 
Only  3  in  our  series  showed  positive  evidences  of  lead  poisoning.  One 
had  lead  colic,  and  2  had  a  blue  line  on  the  gums.  Seven  others, 
however,  had  occupations  exposing  them  to  possible  lead  infection.  Of 
the  9  patients,  6  were  painters,  and  3  were  tinners.  Thus  in  9  of  the  GO 
cases,  or  15  per  cent.,  lead  was  probably  a  contributory  etiological  factor. 

We  do  not  know  in  just  what  way  lead  infection  predisposes  to  gout. 
Garrod  found  that  the  blood  of  patients  suffering  from  lead  poisoning 
contained  an  excess  of  uric  acid.  He  pointed  out  also  that  these  patients 
were  liable  to  develop  chronic  nephritis,  and  drew  the  conclusion  that  the 
increased  amount  of  uric  acid  in  the  circulating  blood  resulted  from  a 
renal  insufficiency.  The  majority  of  subsequent  investigators  have  sup- 
ported this  view.  Sir  Dyce  Duckworth  holds  that  the  lead  acts  injuriously 
through  its  effects  produced  on  the  nervous  centres.  As  will  be  seen 
later,  Duckworth  supports  the  nervous  theory  of  the  origin  of  gout. 

(/)  Occupation  and  Physique. — As  stated,  those  whose  occupations 
bring  them  into  constant  contact  with  lead,  such  as  painters,  plumbers, 
and  enamelers,  and  to  a  less  extent,  tinners,  are  specially  liable  to  be 
attacked.  Bartenders  and  employees  in  breweries,  owing  to  the  oppor- 
tunity for  free  indulgence  in  the  use  of  malt  liquors,  are  also  very  prone 
to  the  disease. 

It  is  a  conspicuous  fact  that  one  rarely  sees  gout  in  a  weakly,  under- 
sized, and  poorly  nourished  individual.  Persons  of  large  frame,  good 
physique,  and  with  a  tendency  to  obesity,  are  the  ones  who  usually 
manifest  the  disease,  and  seem  particularly  susceptible  to  the  baneful 
influence  of  the  predisposing  factors  already  considered. 

(g)  Traumatism  is  thought  by  many  to  be  a  contributory  factor.  The 
prevalence  of  the  attacks  in  the  big  toe  joints  has  been  in  part  explained 
by  the  liability  of  this  articulation  to  injury  while  walking  or  from  pres- 
sure by  an  ill-fitting  shoe. 

II.  Metabolic  Causes. — From  the  chemical  standpoint,  the  etiology  of 
gout  is  closely  connected  with  nitrogen  metabolism,  and  with  the  forma- 
tion and  excretion  of  certain  compounds  of  which  nitrogen  is  a  component. 
Since  1797,  the  year  in  which  Wollaston  demonstrated  that  the  gouty  de- 
posits about  the  joints  contained  uric  acid,  the  vast  majority  of  those  who 
nave  studied  the  disease  have  concluded  that  it  is  connected  in  some  way 
with  the  formation  and  elimination  of  uric  acid.  There  is  a  steadily 
growing  conviction  among  the  best  students  of  this  disease  at  the  present 
day  that  uric  acid  plays  little  or  no  part  in  the  actual  etiology  of  gout. 
Although  an  excess  of  uric  acid  in  the  blood  and  of  its  salts  in  the  tissues 
dominates  the  picture  in  well-marked  cases,  this  excess  of  uric  acid  is 
held  to  play  a  secondary  part  and  to  be  a  mere  weapon  of  the  disease. 
There  is  no  experimental  proof  showing  that  an  excess  of  uric  acid 
causes  any  special  toxic  symptoms.    The  growing  belief  is  that  gout  is 


812  CONSTITUTIONAL  DISEASES 

really  a  disease  of  intermediary  purin  metabolism.  This  view  receives 
added  support  from  the  very  important  recent  discovery  that  certain 
tissue  ferments  play  a  most  important  role  in  the  metabolism  of  the  purin 
bodies.  While  it  will  seem  hard  for  us  to  divorce  our  minds  from  the  long 
prevailing  uric  acid  theory  of  gout,  the  following  considerations  of  purin 
metabolism  indicate  strongly  that  we  shall  probably  have  to  do  so. 

(a)  Uric-Acid  Metabolism  under  Normal  Condiiions. — To  better  appre- 
ciate the  metabolic  disturbances  in  gout,  it  is  important  to  understand,  as 
fully  as  our  present  knowledge  permits,  the  chemistry  of  uric  acid  and  its 
closely  allied  compounds  under  physiological  conditions. 

Uric   acid   has  the   empirical  formula,  C5H4N4O3  and   the   rational 

HN— CO 

II 
formula,  OC      C — NH  The  generally  accepted  view,  at  the 

I       II      UTi^-CO. 
HN-C-NH 

present  time,  is  that  it  is  derived  partly  from  nuclein  resulting  from  the 
disintegration  of  cell  nuclei,  and  partly  from  the  hypoxanthin,  which  is 
produced  as  a  product  of  muscle  metabolism.  At  least  4  other  nitrog- 
enous compounds  are  known  to  be  derived  from  nuclein.  These  are 
xanthin  (C5H4N4O2),  hypoxanthin  (C5H4N4O),  guanin  (C5H5N5O)  and 
adenin  (C5H5N5).  In  addition  to  these,  there  are  5  other  compounds 
closely  allied  to  them  in  general  structure.  They  are  as  follows :  Hetero- 
xanthin  (CeHgN^Os),  paraxanthin  (C7H8N4O2),  episarkin  (CiHeNgO), 
carnin  (CyHgN^Og),  and  epiguanin  (CeHyNgO). 

These  10  nitrogenous  compounds  were  given  the  name  alloxuric  bodies, 
{alloxur  korper)  by  Kossel  and  Kriiger,  whereas  the  last  9  constitute 
the  alloxuric,  xanthin  or  nuclein  bases.  The  term  "alloxuric"  was  ap- 
plied to  them  because  each  was  made  up  of  a  combination  of  an  alloxan 
and  urea  nucleus.  Emil  Fischer  has  shown  that  there  is  a  very  intimate 
relationship  between  the  various  members  of  this  group,  and  has  demon- 
strated the  remarkable  fact  that  a  number  of  them  can  be  prepared 
synthetically.  He  found  that  they  are  all  derived  from  a  compound 
C5H4N4,  which  he  termed  "purin,"  having  a  carbon-nitrogen  nucleus, 
the  "purin  nucleus,"  as  a  basis.      Purin,  according  to  Fischer,  has  the 

N=C 

II 
formula  HC     C — NH  and  the  different  purin  bodies  are  derived 

II  II  ~:^CH 

N— C— N-^ 

therefrom  by  the  substitution  of  the  various  hydrogen  atoms  by  hydroxyl, 
amide,  or  alkyl  groups.  In  order  to  designate  the  different  positions  of 
substitution,  Fischer  has  proposed  to  number  the  9  atoms  of  the  purin 

IN— C6 

I      I 
nucleus  in  the  following  way:  2C     C5 — N7s^^ 

I      I  >C8 

3N— C4— N9^ 


GOUT  813 

In  studying  the  structural  formula  of  uric  acid  given  above,  it  will  there- 
fore be  seen  that  it  is  2.6.8  trioxypurin.  Xanthin,  accordingly,  is  2.6 
dioxypurin;  hypoxanthin  is  6.  oxypurin;  adcnin  is  6.  amino  purin;  and 
guanin  is  2.  amino-6.  oxypurin,  etc.  To  summarize,  thcrcifore,  the  allox- 
uric  or  purin  bodies  include  uric  acid,  together  with  the  alloxuric,  purin, 
nuclein,  or  xanthin  bases.  The  purin  substances  are  supposed  to  be  con- 
tained in  the  nucleic  acid  of  the  cell  nuclei  in  the  form  of  a  loosely  com- 
bined phosphorus-containing  body — the  nucleotin-phosphoric  acid,  as 
Schmiedeberg  has  termed  it. 

The  close  relationship  between  uric  acid  and  the  xanthin  or  purin  bases, 
and  their  common  origin  from  nuclein,  is  shown  by  the  following  scheme: 

Nuclein . 

Albumin     Nucleic  acid 

Phosphoric  acid    Mother  substance 

Uric  acid     alloxuric,  purin,  nuclein,  or  xanthin  bases. 

Experimentally,  this  was  clearly  shown  by  Horbaczewski.  He  found  that 
by  adding  some  oxidizing  substance,  such  as  fresh  blood,  to  macerated 
spleen  pulp  and  then  keeping  the  whole  at  a  constant  temperature  of 
45°  C.  for  several  hours,  he  obtained  a  certain  amount  of  uric  acid.  If,  on 
the  other  hand,  no  oxidizing  agent  was  added,  and  only  heat  applied,  he 
was  unable  to  obtain  any  uric  acid,  but  secured  an  identical  amount  of 
nuclein  or  xanthin  bases,  as  indicated  by  the  nitrogen  content  of  each.  In 
other  words,  it  depended  upon  the  facilities  afforded  for  oxidation  as  to 
whether  the  product  obtained  would  be  uric  acid  or  the  nuclein  or  xanthin 
bases. 

The  feeding  of  nuclein  to  man  and  dogs  is  followed  by  a  marked 
increase  in  the  uric-acid  output.  Horbaczewski,  who  advanced  the  erro- 
neous view  that  uric  acid  was  derived  mainly  from  nuclein  of  the  disin- 
tegrated leukocytes,  thinks  that  the  increase  in  the  uric  acid  after  nuclein 
ingestion  is  not  due  to  the  ingested  nuclein,  but  to  the  nuclein  derived 
from  the  increased  number  of  leukocytes  occasioned  by  the  nuclein 
administered.  An  amount  of  proteid  not  containing  any  purin  or  nuclein 
bases,  but  containing  an  identical  quantity  of  nitrogen  in  some  other  form, 
does  not  produce  a  similar  rise  in  the  uric-acid  excretion,  as  has  been 
demonstrated  by  Schmoll  and  Kaufmann. 

The  purin  bodies  from  which  uric  acid  is  mainly,  if  not  entirely,  de- 
rived, come  from  two  sources.  Burian  and  Schur  have  designated  them 
the  "exogenous"  and  "endogenous"  purins.  The  exogenous  purins 
are  those  introduced  with  the  ingested  food,  whereas  the  endogenous 
purins  are  those  derived  from  the  nucleins  of  the  body  and,  according  to 
recent  investigations,  chiefly  from  muscle  metabolism.  In  the  same 
manner,  we  speak  of  "exogenous"  and  "endogenous"  uric  acid,  when 
it  is  derived  from  these  respective  sources.  By  the  use  of  a  purin-free  diet 
(such  as  milk,  eggs,  butter,  cheese,  white  bread,  rice,  sago,  and  fruits)  it 
has  been  possible  to  estimate  the  quantity  of  nuclein  derivatives  or  purin 
bodies  which  arise  solely  as  a  result  of  cellular  processes.    During  the 


814  CONSTITUTIONAL  DISEASES 

year  1905,  Burian  demonstrated  that  the  muscle  purins,  particularly  hypo- 
xanthin,  are  the  chief  source  of  the  endogenous  uric  acid.  He  finds  that 
muscular  exertion  is  always  accompanied  by  a  decided  rise  in  the  output  of 
uric  acid.  The  investigations  of  Burian  and  Schur  show  that  the  endog- 
enous purins  excreted  in  the  urine  in  twenty-four  hours  vary  from  0.10 
to  0.20  grams,  expressed  in  terms  of  nitrogen,  of  which  one-fiftieth  to  one- 
tenth  is  in  the  form  of  xanthin  or  purin  bases  and  the  rest  as  uric  acid.  On 
such  a  diet,  Rockwood,  working  in  Chittenden's  laboratory,  found  that 
the  daily  output  of  uric  acid  in  a  normal  individual  ranges  between  0.3  and 
0.4  grams.  He  also  confirmed  the  observations  of  Burian  and  Schur,  that 
a  given  individual  shows  a  certain  degree  of  constancy  in  the  daily  excre- 
tion of  uric  acid.  In  other  words,  the  elimination  of  endogenous  uric  acid 
is  constant  for  each  individual;  that  is,  it  is  an  individual  factor  dependent, 
probably  in  part,  upon  the  weight  of  the  individual  or  of  the  contained 
organs  and  tissues.  The  figures  of  Burian  and  Schur  given  above  do  not 
represent  the  entire  amount  of  nuclein  decomposed  in  the  body.  The 
remainder  is  transformed  by  specific  enzymes  of  the  liver  and  other  organs 
(to  be  referred  to  later)  and  excreted  as  urea,  or  as  bodies  intermediate 
between  the  purin  bodies  on  the  one  hand  and  uric  acid  and  urea  on  the 
other.  Allantoin  is  one  of  these  intermediate  bodies.  Wiener  holds  that 
glycocoll  is  the  only  decomposition  product  of  uric  acid.  Of  the  total 
purin  bodies  of  the  urine,  nine-tenths  is  excreted  as  uric  acid  and  one- 
tenth  as  the  xanthin  or  purin  bases. 

Seat  of  Formation  of  Uric  Acid. — Until  a  very  recent  date,  we  have  pos- 
sessed no  definite  knowledge  as  to  the  seat  of  formation  of  uric  acid,  nor 
in  what  organs  the  various  purin  bases  were  contained  or  oxidized  into 
higher  oxidation  products.  Garrod,  Latham,  and  Luff,  hold  that  the  uric 
acid  is  formed  in  the  kidneys.  Zaleski,  after  extirpating  the  kidneys  of 
snakes,  and  von  Schroder,  after  removal  of  these  organs  in  birds,  have 
shown  that  there  is  an  accumulation  of  uric  acid  in  the  blood  and  tissues 
of  these  animals.  This  goes  to  show  that  the  kidneys  of  birds  and  snakes,  at 
least,  are  not  the  only  organs  that  produce  uric  acid.  Hammarsten  claims 
that  we  have,  up  to  the  present  time,  no  direct  jDroof  that  uric  acid  is 
formed  in  the  kidneys  and  the  general  opinion  is  against  the  view  that 
uric  acid  is  formed  in  these  organs. 

It  is  probable  that  uric  acid  originates  in  the  system  only  as  a  result 
of  oxidative  processes.  Experimentally,  the  synthetic  formation  of  uric 
acid  has  been  demonstrated.  By  passing  ammonium  lactate  through  the 
livers  of  geese,  Kowaleski  and  Salaskin,  in  1901,  showed  that  it  was  syn- 
thetized  into  uric  acid,  as  indicated  by  the  great  increase  of  the  latter  in 
the  blood  leaving  the  liver.  There  is  no  conclusive  evidence,  however, 
that  a  similar  synthetic  formation  of  uric  acid  occurs  in  the  human  sub- 
ject, although  it  is  possible  that  it  may  occur. 

Physiologists  and  physiological  chemists  have  demonstrated  that  many 
of  the  chemical  transformations  in  the  body,  previously  not  understood, 
are  really  due  to  the  action  of  specific  ferments  or  enzymes.  The  very 
recent  investigations  of  Jones,  and  his  coworkers,  Partridge  and  Winter- 
nitz,  and  of  Schittenhelm,  have  clearly  shown  us  that  the  various  glands 
and  tissues  of  the  body  contain  specific  ferments  which  are  essential  for 
the  conversion  of  one  xanthin  base  into  another,  and  for  the  conversion 
of  the  xanthin  bases  into  uric  acid.    It  has  also  been  ascertained  that 


GOUT  815 

certain  glands  contain  only  certain  ones  aniong  the  xanthin  bases.  Jones 
has  found  that  when  such  glands  as  the  thymus,  suprarenal,  spleen,  etc., 
are  subjected  to  autodigestion  for  several  hours  at  body-temperature  in 
the  presence  of  an  antiseptic,  definite  chemical  changes  occur.  In  the 
case  of  the  thymus,  large  amounts  of  xanthin,  and  a  small  amount  of 
hypoxanthin,  together  with  uracil,  are  found  in  the  fluid.  With  the  supra- 
renal gland,  large  quantities  of  xanthin  and  a  small  quantity  of  hypo- 
xanthin, are  found.  In  both  of  these  glands,  however,  guanin  and  adenin 
are  entirely  lacking.  By  autodigesion  of  the  spleen,  on  the  other  hand, 
guanin  and  hypoxanthin  are  formed  abundantly,  while  adenin  and  xanthin 
are  wanting.  It  will  be  seen  that  xanthin  and  hypoxanthin  are  the  chief 
products  of  self-digestion  of  these  glands.  Quite  different  results  are 
reached  when  the  glands  or  their  respective  nucleoproteids  are  boiled 
with  acids.  When  mineral  acids  are  used  as  the  hydrolyzing  agent,  then 
the  above  glandular  tissues  yield  chiefly  guanin  and  adenin.  This  differ- 
ence in  the  result  by  autolysis  and  by  hydrolysis,  with  acids,  is  due  to  the 
fact  that,  in  autolysis,  the  changes  are  induced  by  the  presence  of 
specific  intracellular  ferments  which  possess  the  power  of  acting  upon 
certain  parts  of  the  purin  bodies,  transforming  them  into  other  related 
substances. 

Jones  and  Partridge  have  shown  that,  in  self-digestion  of  the  pancreas 
in  an  alkaline  medium,  large  amounts  of  xanthin  and  hypoxanthin  are 
found  as  end  products  of  the  autolysis.  Guanin  and  adenin  are  also 
formed  in  all  probability,  but  they  are  gradually  converted  into  xanthin 
and  hypoxanthin  by  intracellular  enzymes.  They  found  that  if  pure 
guanin  is  placed  in  a  mixture  containing  finely  divided  pancreas,  with 
chloroform  to  prevent  putrefaction,  and  the  mixture  kept  at  40°  C.for 
some  time,  the  guanin  is  slowly  but  completely  converted  into  xanthin. 
The  ferment  that  effects  this  transformation  they  have  called  guanase,  and 
it  is  likewise  present  in  the  thymus  and  adrenals,  but  is  absent  from  the 
spleen.  Jones  and  Winternitz  have  found  a  similar  intracellular  enzyme 
which  they  term  adenase,  owing  to  the  property  it  possesses  of  transforming 
adenin  into  hypoxanthin.  It  is  found  in  the  thymus,  adrenals,  pancreas, 
and  liver.  The  two  ferments  are  true  hydrolyzing  agents,  the  chemical 
reactions  occurring  being  quite  simple  and  as  follows : 

Cs  Hs  Ns  O+H2  0=C5  U,  N,  O2+NH3 

Guanin  Xanthin 

C5  H5  N5+H2  0=C5  H,  N,  O+NH3 

Adenin  Hypoxanthin 

It  will  be  noted  that  there  is  not  only  a  taking-on  of  water  with  the  re- 
tention of  the  oxygen,  under  the  influence  of  the  enzyme,  but  there  is  also 
a  giving-off  of  ammonia,  bv  which  the  change  is  made  possible.  As 
Chittenden  has  recently  stated,  these  two  enzymes  are  typical  deamidiz- 
ing  ferments,  destroying  the  NHg  group  of  the  adenin  and  guanin. 

Schittenhelm  has  made  the  important  discovery  that  it  is  possible  to 
obtain  from  simple  extracts  of  the  spleen,  liver,  lungs,  and  muscles,  an 
oxidizing  ferment  which  is  termed  oxidase,  and  which  possesses  the  power 
of  transforming  the  purin  bases  quantitatively  into  uric  acid.  Thus  xan- 
thin is  converted  into  uric  acid  by  the  mere  addition  of  an  atom  of  oxygen, 


816  CONSTITUTIONAL  DISEASES 

and  Burian  has  given  to  the  ferment  that  brings  this  about  the  name  of 
"xanthin  oxidase."  Schittenhchn  failed  to  find  it  in  the  thymus,  intes- 
tine, kidneys,  or  blood. 

It  has  for  some  considerable  time  been  known  that  the  nucleoproteids, 
nucleins,  and  nucleic  acid,  when  fed,  caused  an  increased  excretion  of  uric 
acid,  but  it  has  not  been  heretofore  understood  how  this  is  brought  about. 
Recent  investigations,  however,  have  made  this  clear.  It  has  been  found 
that  certain  body  cells  contain  an  intracellular  enzyme  termed  nuclease, 
which  has  the  power  of  liberating  the  purin  bases  from  their  combination 
as  a  component  part  of  tissue  nucleoproteids.  These  liberated  nuclein 
bases,  such  as  guanin  and  adenin,  are  converted  by  the  deamidizing 
enzymes,  guanase  and  adenase,  into  xanthin  and  hyj)oxanthin  respectively. 
Then,  by  the  action  of  the  oxidase  just  referred  to,  hypoxanthin  is  oxi- 
dized to  xanthin,  and  xanthin  to  uric  acid.  It  jnust  be  emphasized  that 
these  enzymes  are  not  distributed  indiscriminately  throughout  the  body, 
but  are  confined  to  definite  organs  or  tissues,  as  has  been  pointed  out.  It 
will  thus  be  seen  that  we  have  four  distinct  enzymes — iiucleasc,  gua?iase, 
adenase,  and  xanthin  oxidase,  or  xanthase,  which  are  responsible  for  the 
production  of  uric  acid  in  the  body.  A  further  observation  of  great  im- 
portance is  that  of  Schittenhelm,  in  which  he  found  that  there  is  another 
tissue  oxidase — contained,  so  far  as  is  known  at  present,  in  the  kidneys, 
liver,  muscles,  and  perhaps,  the  bone-marrow — which  has  the  power  of 
oxidizing  and  destroying  the  uric  acid,  and  converting  it  into  urea  and 
other  bodies.  This  discovery  has  a  direct  relationship  to  the  excess  of 
uric  acid  in  the  blood  in  gout;  for  it  is  possible  to  conceive  that  this  excess 
may  be  due  as  well  to  an  inhibition  of  the  action  of  this  uric  acid  destroy- 
ing ferment  as  to  an  excessive  activity  of  the  ferments  which  lead  to  the 
production  of  uric  acid.  As  pointed  out  in  the  section  on  the  predis- 
posing causes  for  gout,  it  is  possible  that  alcohol  may  act  injuriously  by 
inhibiting  the  activity  of  the  uric  acid  destroying  enzyme. 

For  the  above  enzymes  to  perform  their  functions  properly,  there  must 
be  a  proper  relationship  between  the  quantity  of  the  purin  bodies  to  be 
acted  on,  and  the  various  ferments.  Mendel  has  shown  that,  if  the  purin 
bodies  be  in  excess,  their  thorough  oxidation  does  not  take  place,  and 
instead  of  their  being  largely  oxidized  to  urea,  an  intermediate  oxidation 
product — allantoin,  is  produced,  and  excreted  in  the  urine  in  excess. 

The  exogenous  purins  we  take  in  our  food  are  either  in  the  form  of  the 
free  bases  adenin,  guanin,  hypoxanthin,  and  xanthin,or  as  combined  purins 
and  nucleoproteids.  Of  the  free  purin  bases  in  the  ordinary  food  stuffs 
it  is  the  oxypurins,  hypoxanthin,  and  xanthin,  that  the  body  has  mainly  to 
deal  with,  as  they  are  contained  in  large  amounts  in  meat  broths  and  ex- 
tracts. They  are,  hoAvever,  easily  oxidized  into  uric  acid,  and  excreted  as 
such,  or  further  oxidized  into  urea  or  other  products  by  the  special  oxi- 
dase. When  combined  purins  are  introduced  in  the  form  of  nucleins  and 
nucleoproteids,  adenin  and  guanin  are  liberated  by  the  action  of  nuclease. 
The  continuance,  unchanged,  of  these  two  bodies,  depends  upon  the  pres- 
ence and  action  of  the  two  enzymes,  adenase  and  guanase.  If  these  are 
present  and  active  in  normal  degree,  we  can  conceive  of  a  rapid  conversion 
into  hypoxanthin  and  xanthin  and  then  into  uric  acid.  If  the  enzymes 
be  deficient,  then  the  adenin  and  guanin  will  circulate  unaltered  in  the 
blood,  for  a  time  at  least.    Chittenden  offers  the  suggestion  that  the  pro- 


GOUT  817 

longed  circulation  of  these  aminopurins  may  account  for  the  renal  changes 
in  certain  diseased  conditions,  presumably  gout;  for  it  has  been  shown 
that  when  adenin  is  administered  to  dogs  and  rabbits,  it  causes  anatomical 
changes  in  the  tubules  of  the  kidneys,  with  deposits  of  spheroliths  of 
uric  acid  and  ammonium  urate  in  the  kidney  substance. 

Since  the  division  of  uric  acid  into  the  exogenous  and  endogenous 
forms,  it  has  been  held,  until  a  very  recent  date,  that  the  endogenous  uric 
acid  resulted  entirely,  or  almost  entirely,  from  the  nuclein  derivatives 
derived  from  the  destruction  of  the  nuclein  of  the  glandular  and  tissue 
cells.  In  1905,  Burian  showed  that  this  view  is  erroneous.  He  finds  that 
only  a  very  small  amount  of  the  endogenous  uric  acid  has  its  origin  in  the 
nucleoproteids  of  disintegrating  tissue  cells  or  leukocytes,  the  larger  part 
being  derived  from  the  purin-base  hypoxanthin,  which  is  continually 
being  formed  as  a  metabolic  product  of  living  muscle  tissue.  It  is  not 
possible  to  go  fully  into  this  important  observation  here.  It  is  sufficient 
to  say  that  Burian's  work  opens  up  a  new  chapter  in  purin  metabolism, 
bearing  on  the  production  of  endogenous  uric  acid.  In  the  resting 
state,  muscle  is  continually  giving  up  to  the  blood  a  certain  amount 
of  uric  acid  formed  at  the  expense  of  the  hypoxanthin  which  originates 
within  its  own  tissue.  The  oxidation  of  the  hypoxanthin  to  uric  acid  is 
accomplished  by  the  specific  oxidase  which  the  muscle  itself  contains. 
Burian  points  out,  however,  that  this  oxidase  must  be  so  located  that  the 
hypoxanthin  is  converted  into  uric  acid  just  as  it  is  passing  from  the  mus- 
cle fibre  into  the  blood  or  lymph,  since  muscle  itself  never  contains  any 
uric  acid,  only  purin  bases.  He  also  believes  that  a  certain  amount  of 
the  uric  acid  is  at  once  decomposed  by  the  other  oxidizing  ferment  which 
destroys  this  acid. 

The  portion  of  the  endogenous  uric  acid  that  results  from  the  disin- 
tegration of  the  nuclei  of  body  cells  and  leukocytes  is  also  fully  believed 
to  be  the  result  of  the  action  of  the  specific  ferments  already  described.  It 
will  thus  be  seen  that  these  investigations  have  given  an  entirely  new 
conception  of  the  seat  and  method  of  formation  of  uric  acid  in  the  system. 
It  seems  justifiable  to  hope  that  this  additional  knowledge  may  soon  lead 
to  a  better  understanding  of  the  disturbances  of  nitrogenous  metabolism 
which  appear  to  lie  at  the  foundation  of  gout. 

Forvi  in  Which  Uric  Acid  Circulates  in  the  Blood. — This  question  re- 
quires elucidation.  Uric  acid  is  a  dibasic  acid,  and  as  such  may  be 
represented  by  the  formula  H2(C5H2N403).  It  thus  has  two  atoms  of 
replacable  hydrogen.  It  forms  two  groups  of  salts,  and  according  to 
Bence- Jones  and  Sir  William  Roberts,  three  different  salts.  For  purposes 
of  illustration,  sodium  may  be  used  as  the  replacing  metal.  The  salts  are 
as  follows:  (1)  Neutral  sodium  urate,  Na2C5H2N403.  (2)  Biurates, 
or  acid  sodium  urate,  or  sodium  biurate,  NaHCgHaN^Og.  (3)  The 
quadriurates  of  Roberts,  in  which  the  sodium  takes  the  place  of  one-fourth 
of  the  displaceable  hydrogen  of  two  molecules  of  uric  acid  loosely 
combined  together,  such  as  NaHC5H2N403,H2C5H2N403,  the  sodium 
quadriurate. 

The  neutral  urates  are  purely  laboratory  compounds,  and  under  no 
circumstances  occur  in  the  human  economy.  The  biurates  are  not 
believed  to  occur  physiologically.  They  constitute  the  form  in  which 
uric  acid  is  deposited  about  the  joints,  and  in  the  tophi  of  gout  patients. 

52 


818  COXSTITUTIOXAL  DISEASES 

Free  uric  acid  never  occurs  in  the  blootl  or  tissues,  either  under  physio- 
logical or  pathological  conditions.  Sir  ^Yilliam  Roberts  holds  that  the  uric 
acid  circulates  in  the  blood  as  the  loosely  combined,  readily  soluble, 
quadriurate.  While  accepted  by  a  number  of  investigators,  this  view 
has  met  with  considerable  opposition.  INIost  of  the  present  day  physio- 
logical chemists  claim  that  there  is  no  such  uric  acid  compound,  and 
that  it  is  impossible  for  it  to  exist  in  a  medium  such  as  that  of  the  circula- 
ting blood.  Opinions  differ  as  to  whether  it  is  possible  to  demonstrate 
the  presence  of  uric  acid  or  its  combinations  in  the  blood  of  normal 
individuals.  Garrod,  Abeles,  and  Magnus-Levy,  claim  to  have  found 
it  in  minute  traces;  INIinkowski  and  Klemperer  were  unable  to  demon- 
strate uric  acid  in  the  blood  of  healthy  persons.  This  diversity  in  results 
is  thought  to  be  due  to  the  fact  that,  normally,  the  uric  acid  is  in  loose 
combination  with  some  other  purin  product  which  consequently  prevents 
its  precipitation  by  the  usual  reagents.  Minkowski  holds  that  it  is  com- 
bined with  the  purin-base,  nucleotin-phosphoric  acid,  and  that  it  is  in 
this  form  that  uric  acid  circulates  in  the  blood.  Others  think  that  it 
circulates  in  combination  with  one  of  the  other  pyrimidin  derivatives  of 
nuclein,  namely,  thymic  acid. 

Daily  Excretion  of  Uric  Acid. — The  amount  of  uric  acid  eliminated 
daily  in  the  urine  by  the  healthy  adult  of  average  weight,  when  on  a  mixed 
diet,  ranges  between  0.4  and  1 .0  grams.  Hammarsten  gives  0.7  grams  as 
the  average.  Of  the  total  purin  or  alloxuric  bodies  in  the  urine,  nine- 
tenths  exist  as  uric  acid  and  one-tenth  as  the  purin,  alloxuric,  xanthin,  or 
nuclein  bases.  The  ratio  of  uric  acid  to  urea  ranges  in  health  between 
1  to  50  and  1  to  70,  and  of  uric  acid  nitrogen  to  total  nitrogen,  according  to 
Minkowski,  between  1  to  20  and  1  to  120.  The  form  in  which  uric  acid  is 
eliminated  in  the  urine  has  not  been  definitely  ascertained,  but  Bunge  and, 
later,  Riidel  suggested  that  it  is  here  also  excreted  in  loose  combination 
with  some  other  organic  substance.  They  hold  that  this  combination  is 
easily  broken  up,  and  the  uric  acid  is  then  set  free.  It  may  then  either 
remain  free  or  enter  into  combination  with  the  sodium,  potassium,  or 
ammonium  contained  in  the  urine. 

(6)  Uric  Acid  Metabolism  in  Gout. — There  is  undoubtedly  marked  dis- 
turbance of  nitrogenous  metabolism  in  gout.  The  total-nitrogen  equilib- 
rium is  disturbed.  It  has  been  definitely  shown  by  the  investigations  of 
Vogel,  Schmoll,  and  others,  that  a  nitrogen  retention  occurs;  that  is,  that 
the  total  nitrogen  output  is  less  than  the  nitrogen  intake.  Since  the 
adoption  of  the  classification  of  purins  into  the  "endogenous"  and  "exogen- 
ous" varieties,  too  little  time  has  elapsed  and  too  few  investigations  have 
been  published,  to  draw  absolute  conclusions  as  to  how  the  metabolism  of 
each  is  affected.  The  studies  of  Reach,  Kaufmann,  Vogt,  and  Chalmers 
Watson,  show  that  in  gout,  the  exogenous  purins  are  more  slowly  excreted 
than  in  health,  and  that  in  some  cases  there  is  a  distinct  retention.  Vogt 
gave  rich  purin-holding  food  to  a  gouty  patient  and  to  a  healthy  individual, 
and  found  that  in  the  former  there  was  a  delayed  excretion,  and  definite 
retention  of  the  purin  bodies.  It  can  safely  be  concluded  that  exogenous 
purins,  in  part  at  least,  lead  to  an  excess  of  the  nuclein  derivatives  in 
the  blood-stream.  There  is  no  question  but  that  the  metabolism  of  the 
endogenous  purins  is  also  markedly  disturbed  in  gout.  This  will  probably 
be  best  shown  by  a  consideration  of  the  amount  of  uric  acid  excreted  in 


GOUT  819 

the  urine  as  well  as  of  that  present  in  the  circulating  blood  in  this  dis- 
ease. 

The  Excretion  of  Uric  Acid  in  Gout. — Garrod  was  the  first  to  claim 
that  there  is  a  diminished  excretion  of  uric  acid  in  gout.  He  believed  that 
this  was  true  both  of  the  acute  attack  as  well  as  of  chronic  gout.  Since 
the  adoption  of  more  reliable  methods  of  quantitative  analysis  in  recent 
years,  Garrod 's  results  have  not  been  confirmed  in  toto.  P'rom  the  analysis 
of  Ebstein,  Pfeiffer,  Luff,  Camerer,  Weintrand,  Kaufmann  and  Mohr, 
Magnus-Levy,  His,  and  others,  Minkowski  states  that  the  following  con- 
clusions may  be  drawn:  (1)  The  daily  excretion  of  uric  acid,  in  the  inter- 
vals between  acute  attacks,  ranges  within  the  same  limits  as  does  the 
excretion  in  healthy  individuals.  (2)  Jn  chronic  gout,  even  in  those  cases 
in  which  there  is  niarked  deposition  of  biurates  in  the  tissues,  a  constant 
diminution  in  excretion  of  the  uric  acid  has  not  been  definitely  proved. 
(3)  Immediately  preceding  an  attack  there  is  regularly  a  diminution 
in  the  amount  of  uric  acid  eliminated  in  the  urine,  whereas,  during  and 
after  the  attack,  the  uric  acid  output  is  increased. 

The  writer's  analyses,  made  with  Folin's  modification  of  the  Hopkins 
method  for  estimating  uric  acid,  fully  accords  with  the  results  stated 
in  Section  3.  They,  however,  differ  materially  from  those  given  in  Section 
2  as  the  uric  acid  elimination  has  almost  always  been  below  the  lower 
limit  for  normal,  viz.,  0.4  grams,  in  the  intervals  between  the  acute  at- 
tacks in  chronic  tophaceous  gout. 

To  what  are  these  variations  in  the  uric  acid  excretion  due  ?  Various 
possibilities  present  themselves.  The  diminution  in  the  excretion  of  uric 
acid  before  the  onset  of  an  acute  attack  may  be  interpreted  as  meaning 
either  a  diminished  uric  acid  production,  or  a  temporary  diminished 
capacity  on  the  part  of  the  kidneys  to  excrete  uric  acid  The  sudden 
deposition  of  uric  acid  salts  about  the  joints  and  in  the  tissues  affords  a 
third  possible  explanation  The  increased  uric  acid  output  during  an 
attack  may  be  due  to  an  increased  uric  acid  production,  or  to  the  possi- 
bility that  the  previously  retained  uric  acid  is  temporarily  excreted  in 
increased  quantity.  The  variations  in  the  excretion  may  further  be 
explained  on  the  supposition  that  at  times  a  smaller,  and  at  other  times, 
a  larger,  part  of  the  uric  acid  in  the  organism  is  metabolized  into  other 
waste  products,  such  as  urea.  It  may  be  possible  to  draw  more  definite 
conclusions  as  to  the  cause  or  causes  of  these  variations  in  the  uric  acid 
elimination  in  gout  after  we  consider  the  uric  acid  content  and  alkalinity 
of  the  blood  in  this  disease. 

The  Uric  Acid  in  the  Blood  in  Gout. — Practically  all  observers  agree 
that  there  is  a  marked  increase  of  the  uric  acid  in  the  circulating  blood. 
Garrod  first  demonstrated  this  excess  by  quantitative  analysis  and,  also,  by 
his  well-known  "thread- test."  Klemperer,  who  was  unable  to  demon- 
strate uric  acid  in  normal  blood,  found  in  three  cases  of  gout  0.067,  0.088, 
and  0 .  0915  grams  of  uric  acid  in  1000  cc.  of  blood,  during  an  acute  attack. 
Magnus-Levy  made  34  analyses  in  17  cases  of  g^ut,  and  found  the  uric 
acid  to  range  between  0.021  and  0. 10  grams  in  1,000  cc.  of  blood.  The 
same  observer  also  sought  to  ascertain  whether  there  was  any  regular 
difference  in  the  amount  of  uric  acid  in  the  blood  during  an  acute  attack 
and  in  the  intervals.  Of  10  cases  studied,  the  uric  acid  was  the  same 
during  the  acute  attack  as  in  the  intervals  in  5;  greater  in  2;  and  less  in  3. 


820  CONSTITUTIONAL  DISEASES 

It  cannot  be  said  then  that  there  is  by  any  means  a  constant  increase  in  the 
amount  of  uric  acid  in  the  blood  during  an  acute  attack  over  that  present 
in  the  intervals. 

J' he  Alkalinity  of  the  Blood  in  Gout. — The  methods  of  determining  the 
degree  of  alkalinity  of  the  blood  are  notoriously  unreliable.  Fokker  and 
others,  on  the  basis  of  recent  work,  deny  that  the  blood  of  the  normal 
individual  is  alkaline,  claiuiing  that  it  is  neutral.  However  true  this  may 
be,  (larrod  based  his  theory  of  the  production  of  gout  largely  on  the  belief 
that  the  alkalinity  of  the  blood  is  diminished.  He  simply  makes  the  state- 
ment that  the  alkalinity  of  the  blood  in  gout  is  markedly  diminished, 
and  no  reference  is  found  in  his  writings  to  any  quantitative  determina- 
tions nor  any  intimation  as  to  how  he  arrived  at  this  conclusion.  Recent 
investigations  along  this  line,  and  by  methods  believed  to  be  reliable,  are 
conflicting  in  their  results.  Pfeiffer,  Jeffries,  and  Drouin,  claim  to  have 
found  an  increased  alkalinity.  Klempcrer,  in  3  cases  of  acute  febrile 
gout  in  which  the  alkalinity  was  determined  by  estimating  the  carbonic 
acid  in  the  blood — the  most  reliable  method — found  a  very  slight  diminu- 
tion, but  not  enough  to  account  for  the  precipitation  of  the  uric  acid.  In 
16  cases  in  which  Lowy's  titration  method  was  used,  Magnus-Levy 
found  no  appreciable  diminution  in  the  alkalinity.  In  11  cases  he  com- 
pared the  degree  of  alkalinity  during  and  between  attacks.  In  3  there 
was  a  diminution  during  the  attack;  in  2,  an  increase;  and  in  6,  there 
was  no  difference.  These  results  in  general  show  that  there  is  no  constant 
diminution  in  the  alkalinity  of  the  blood  in  gout,  nor  is  the  alkalinity 
apparently  diminished  to  a  greater  extent  during  the  acute  attack  than  in 
the  intervals. 

Klemperer  conducted  a  series  of  experiments  which  have  a  very  impor- 
tant bearing  on  the  alkalinity  of  the  blood  in  healthy  and  in  gouty 
individuals,  as  well  as  on  the  effect  that  a  possible  change  in  the  alka- 
linity may  have  on  the  power  of  the  plasma  to  hold  uric  acid  in  solution. 
He  found  that  the  blood  of  the  gouty  person  is  not  a  saturated  solution 
of  uric  acid  and  that  it  is  still  capable  of  dissolving  more  of  the  acid. 
Whereas,  100  cc.  of  blood  serum  from  3  healthy  persons  was  capable 
of  dissolving  0.166,  0. 171  and  0. 174  grams  of  uric  acid,  the  same  amount 
of  serum  from  3  gouty  patients  was  still  capable  of  dissolving  0.126, 
0.14,  and  0.18  grams  of  the  acid.  The  conclusion  to  be  drawn  from  this 
observation  is,  that  an  over-loading  of  the  blood  with  uric  acid  is  not 
alone  to  be  regarded  as  the  cause  for  the  deposition  of  the  sodium  biurate 
in  the  tissues.  This  is  substantiated  by  the  fact  that  in  other  diseases, 
such  as  leukaemia,  there  is  a  marked  increase  in  the  uric  acid  in  the  blood, 
yet  biurate  depositions  in  the  tissues  do  not  usually  occur.  There  are 
apparently  only  5  cases  reported  in  the  literature  in  which  definite  gouty 
manifestations  have  been  found  in  association  with  leukaemia.  This 
number  is  so  small  that  the  co-existence  may  well  be  considered  acci- 
dental. 

Origin  of  the  Excess  of  Uric  Acid  in  the  Blood. — Three  possibilities 
present  themselves.  One  can  conceive  of  the  increase  being  due  to:  (1) 
Diminished  destruction  or  oxidation;  (2)  increased  formation;  (3)  di- 
minished excretion  by  the  kidneys. 

The  evidence  on  this  point  has  recently  been  analyzed  by  Wiener  in  his 
excellent  review  of  uric  acid  in  its  relationship  to  gout.    He  claims  that 


GOVT  821 

there  is  no  special  evidence  to  point  toward  the  excess  being  due  to  de- 
ficient oxidation.  Klemperer  has  shown  that  the  blood  of  the  gouty 
individual  still  possesses  the  power  in  vitro  of  destroying  uric  acid,  pre- 
sumably by  oxidation.  Wiener's  analysis  was  published  just  previous  to 
the  appearance  of  the  recent  studies  showing  the  important  part  that 
specific  ferments  play  in  the  formation  and  destruction  of  uric  acid.  As 
already  pointed  out,  the  excess  of  uric  acid  in  the  blood  in  gout  may 
eventually  be  shown  to  be  due  to  a  deficiency  in  the  oxidase  which  nor- 
mally converts  it  into  urea  and  other  products.  The  knowledge  that 
there  is  a  special  oxidase  in  the  liver,  kidneys,  muscles  and  bone-marrow 
whose  function  is  to  further  oxidize  uric  acid  to  urea  and  other  products, 
renders  it  quite  possible  that  the  excess  of  uric  acid  in  the  blood  may 
be  due  to  influences  which  interfere  with  the  oxidizing  power  of  this 
particular  oxidase.  The  diminished  oxidation  theory  is  the  one  receiving 
the  best  support  at  the  present  time,  and  is  the  one  for  which  the  writer 
thinks  there  is  the  most  evidence. 

Although  the  increase  in  the  uric  acid  in  the  blood  and  urine  in  leukse- 
mia  and  pneumonia  is  undoubtedly  due  to  increased  formation,  resulting 
from  increased  nuclein  destruction,  the  evidence  is  not  nearly  so  con- 
vincing in  the  case  of  gout.  We  know  that  uric  acid  is  formed  partly  by 
oxidative  processes  from  the  nucleins  and  partly  by  synthetic  formation 
in  the  liver.  There  is  no  definite  evidence  of  any  increased  nuclein  de- 
struction in  gout.  There  is  no  leukocytosis,  excepting  a  slight  temporary 
one  during  the  acute  febrile  attacks;  so  an  increase  in  the  leukocytes  with 
their  increased  disintegration  cannot  explain  the  increase  of  uric  acid  in 
the  blood.  We  have  no  definite  evidence  to  point  toward  an  increased 
synthetic  formation  of  uric  acid  in  the  liver. 

There  are  some  points  favoring  the  view  that  the  excess  of  uric  acid  in 
the  blood  is  due  to  diminished  excretion  by  the  kidneys.  In  support  of  it, 
is  the  prevalence  of,  and,  according  to  Levison,  the  constant  association 
of  an  interstitial  nephritis  in  gout.  Most  authorities  are  inclined  to  con- 
sider the  nephritis  as  a  result  of  the  gout.  The  influence  of  nephritis  on 
uric  acid  excretion  and  its  deposition  about  the  joints  is  shown  by  Ord 
and  Greenfield's  statistics.  Out  of  96  cases  of  renal  disease  there  were 
biurate  deposits  in  the  joints  in  18.  Levison  claimed  that  it  was  always 
with  contracted  kidneys  that  this  deposition  occurred.  This  was  sup- 
ported by  the  investigations  of  Luff,  who  found  biurate  deposits  in  the 
joints  in  20  out  of  26  cases  of  chronic  interstitial  nephritis.  These  obser- 
vations tend  to  show  that  in  interstitial  nephritis  there  is  some  condition 
produced,  presumably  a  retention  of  uric  acid,  which  favors  the  latter 's 
deposition  in  the  joints.  In  support  of  the  retention  theory  may  be 
mentioned  the  researches  of  Hans  Vogt  and  Reach,  who  found  that  the 
excretion  of  uric  acid  after  the  ingestion  of  nuclein  or  nuclein-containing 
food  is  much  less  marked  in  the  gouty,  than  in  the  healthy,  individual. 
Schreiber  claims,  contrary  to  Levison 's  view,  that  interstitial  nephritis  is 
not  always  present  in  gout.  In  these  cases  without  organic  renal  disease, 
Minkowski  is  inclined  to  support  the  older  view  of  Garrod  that  it  is 
possible  that  a  functional  disturbance  of  the  kidney  may  occur  which 
lessens  its  ability  to  excrete  uric  acid.  He  favors  the  retention  theory 
as  the  cause  of  the  excess  of  uric  acid  in  the  blood.  He  and  His  have 
advanced  the  view  that  the  uric  acid,  in  gouty  individuals,  circulates  in 


822  CONSTITUTIONAL  DISEASES 

the  blood  in  a  (liffcrcnt  organic  combination  from  that  in  which  it  exists 
in  the  blood  of  healthy  persons,  and  that  consequently  the  kidneys  are 
functionally  incapable  of  eliminating  it  as  in  health,  A  very  strong 
artrument  against  this  retention  theory  is  the  fact  that,  even  in  cases  with 
Avell-marketl  nephritis,  it  is  well  known  that  the  kidneys  are  capable  of 
excreting  uric  acid  in  quantities  considerably  above  the  upper  limit  for 
normal  for  two  or  three  days  after  the  onset  of  an  acute  attack. 

Taking  everything  into  consideration,  the  weight  of  evidence,  in  the 
writer's  opinion,  seems  to  favor  the  retention  theory  as  the  most  plausible 
view  to  ex])lain  the  excess  of  uric  acid  in  the  circulating  blood  in  this  dis- 
ease. Subsequent  investigations,  however,  may  show  that  the  excess  is 
due  to  failure  in  the  action  of  the  special  oxidase  in  the  liver  and  other 
tissues  whose  function  is  to  further  oxidize  uric  acid. 

Theories  of  Gout. — Considering  the  number  of  these,  only  the  more 
important  ones  can  be  considered  and  these  merely  briefly. 

Garrod  held  that  in  acute  gout  the  alkalinity  of  the  blood  is  lessened 
and  the  uric  acid  of  the  blood  is  increased  owing  to  deficient  power  of 
elimination  on  the  part  of  the  kidney.  The  latter  is  due,  usually,  to  organic 
disease  but  may  result  from  a  purely  functional  disturbance.  He  attrib- 
utes the  deposition  of  sodium  biurate  in  the  tissue  to  the  diminished 
alkalinity  of  the  plasma,  which  is  unable  to  hold  the  uric  acid  combination 
in  solution.  During  an  acute  paroxysm  there  is  an  accumulation  of  the 
urates  in  the  blood  and  the  local  inflammation  is  caused  by  their  sudden 
deposition  in  crystalline  form  about  the  joints. 

This  theory  has  had  many  supporters  and  in  large  part  can  be  accepted, 
but,  as  we  have  already  seen,  any  explanation  based  on  the  degree  of 
alkalinity  of  the  blood  must  be  received  with  some  skepticism. 

Sir  William  Roberts  believed  that  uric  acid  normally  circulates  in  the 
Blood  in  the  form  of  a  soluble  quadriurate,  which  may  be  represented 
by  the  formula  NaHCgHaN^Og,  H2C5H2N4O3,  which  is  sodium  quadri- 
urate. The  sodium  atom  may  have  its  place  taken  by  an  atom  of  any 
of  the  univalent  metals.  In  the  gouty  state,  according  to  Roberts,  either 
from  deficient  action  of  the  kidneys,  or  from  overproduction  of  urates, 
the  quadriurate  accumulates  in  the  blood.  The  detained  quadriurate, 
being  very  unstable  and  circulating  in  a  medium  rich  in  sodium  carbonate, 
takes  up  an  additional  atom  of  the  base,  and  is  converted  into  the  biurate 
as  follows:  2  (NaHCsH^N.Og,  H2C5H2N403)+Na2Co4=4NaHC5H2N4 
O3+CO2+H2O.  The  biurate  is  very  insoluble  and  less  easily  excreted 
by  the  kidneys.  It  consequently  accumulates  in  the  blood,  and  exists 
first  in  a  gelatinous,  and  later  in  the  almost  insoluble,  crystalline  form. 
It  is  then  that  precipitation  is  imminent  or  actually  takes  place.  This 
is  apt  to  occur  where  the  circulation  is  poor  and  the  temperature  low,  and 
in  regions  in  which  the  lymph  contains  a  relatively  high  percentage  of 
sodium  chloride,  as  in  the  synovial  sheaths. 

This  theory  has  met  with  opposition  from  various  quarters  and  partic- 
ularly on  the  part  of  Tunnicliffe  and  Rosenheim.  Minkowski  also  holds 
that  it  is  impossible  for  uric  acid  to  circulate,  even  in  normal  blood,  as  the 
quadriurate,  for  in  a  medium  so  rich  in  carbonates  and  phosphates  as  is 
the  blood,  the  quadriurate  must  necessarily  be  rapidly  converted  into  the 
biurate.  Minkowski  thinks  that  uric  acid  normally  circulates  in  the 
blood  in  organic  combination  with  nucleotin-phosphoric  acid.    Others 


GOUT  823 

believe  that  it  is  in  combination  with  thymic  acid,  one  of  the  nuclein 
derivatives. 

Ebstein  holds  that  the  local  manifestations  of  gout  are  due  to  nutri- 
tive tissue  disturbances  which  lead  to  necrosis.  He  found,  after  a  study  of 
many  of  the  affected  tissues  in  gout,  that  one  change  is  common  to  them 
all,  independently  of  the  urate  crystallization,  and  that  is,  a  necrosis  of 
the  parts  in  which  such  deposition  takes  place.  Ke  believes  that  this 
necrosis  is  primary,  and  that  it  is  as  characteristic  as  the  bi urate  deposit. 
Both  changes  must  co-exist  in  any  tissue  in  order  to  constitute  a  true  gouty 
lesion,  and  he  has  found  such  lesions  in  the  kidneys,  in  hyaline  and  fibro- 
cartilage,  and  in  tendons  and  connective  tissue.  He  calls  attention  to  the 
early  stages  of  the  necrotic  process,  in  which  he  finds  no  deposition  of  the 
biurates,  and  consequently  maintains  that  a  nutritive  tissue  disturbance 
is  the  primary  factor,  and  uratic  deposition  a  secondary  one,  in  the  gouty 
process,  the  latter  not  occurring  until  death  of  the  tissue  takes  place. 
Von  Noorden  supports  Ebstein's  views,  and  believes  that  the  tissue  necro- 
sis is  due  to  the  action  of  a  special  ferment. 

In  1784,  Cullen  advanced  the  theory  that  gout  was  primarily  due  to  an 
affection  of  the  nervous  system.  According  to  this  view  there  is  a  basic 
arthritic  stock — a  diathetic  habit,  of  which  gout  and  rheumatism  are  two 
distinct  branches.  The  chief  advocate  of  the  nervous  theory  at  the  present 
day  is  Sir  Dyce  Duckworth,  who  at  first  held  that  disease  of  a  special 
tract  in  the  cord  was  the  cause  of  the  tissue  lesions  in  gout.  Although  he 
no  longer  insists  that  gout  is  due  to  a  lesion  of  any  particular  column  of 
the  cord,  he  just  as  strongly  insists  that  it  is  essentially  of  nervous 
origin.  The  influence  of  depressing  conditions,  mental  and  physical, 
in  precipitating  an  attack  of  gout,  points  strongly  to  the  part  played  by  the 
nervous  system  in  the  etiology  of  the  disease.  The  nervous  theory  has 
not  received  very  general  support. 

In  recent  years  attention  has  been  attracted  to  the  xanthin  or  purin 
bases  as  a  possible  cause  of  gout.  Kolisch  found  that  although  the  uric 
acid  excretion  is  diminished,  yet  the  total  output  of  the  alloxuric  or 
purin  bodies  was  increased.  He  believed  that  the  xanthin  bases  nor- 
mally are  finally  oxidized  into  uric  acid  in  the  kidneys,  but  that  in  gout  the 
kidneys  are  diseased,  and  their  power  to  oxidize  the  xanthin  bases  is  con- 
sequently impaired.  His  results  were  obtained  by  methods  shown  later 
to  be  inaccurate,  and  Siilzer,  Laquer,  and  Magnus-Levy,  failed  to  confirm 
them.  Whatever  part  the  xanthin  bases  may  subsequently  be  shown  to 
play  in  the  etiology  of  gout,  up  to  the  present  they  have  not  been  shown  to 
exert  an  important  influence.  Undoubtedly  some  of  the  xanthin  bases  are 
definitely  toxic.  Kolisch  and  Croftan  have  produced  arterial  and  renal 
lesions  by  injecting  hypoxanthin  into  animals.  I.  Walker  Hall  confirmed 
these  results  and  also  produced  parenchymatous  changes  in  the  liver  by 
long  continued  injections  of  hypoxanthin.  Taylor  has  already  in  Chapter 
XIV  considered  gout  from  the  standpoint  of  an  auto-intoxication. 

It  has  been  claimed  by  some  that  glycocoU  is  found  quite  frequently 
in  the  urine  of  gout  patients,  and  it  has  been  thought  that  it  may  be  a 
factor  in  the  causation  of  the  disease.  As  yet,  too  little  is  known  to  express 
any  definite  opinion  on  this  point.  Its  relationship  to  uric  acid  is  well 
known.  On  heating  the  latter  with  concentrated  mineral  acids  in  sealed 
tubes  to  170°  C,  it  splits  up  into  glycocoll,  carbon  dioxide,  and  ammonia. 


824  CONSTITUTIONAL  DISEASES 

Summary  of  Our  Knowledge  Concerning  the  Chemistry  of  Gout. — It 

will  be  seen  from  the  fore<iX)iiii;'  that  there  is  niueh  divero-enee  of  oj)inion 
regarding  the  true  cause  of  gout.  The  subject  still  awaits  a  definite  eluci- 
dation. Whatever  may  eventually  be  determined  to  be  the  actual  cause  of 
the  disease,  there  is  a  growing  impression  that  uric  acid  plays  only  a 
secondary  part,  and  I.  ^Yalker  Hall,  who  has  been  one  of  the  most  active 
students  of  the  disease,  recently  asserted  that  it  is  in  no  way  an  etiological 
factor.  On  one  point  all  investigators  agree,  and  that  is  that  there  is 
marked  increase  in  the  uric  acid  circulating  in  the  blood.  The  writer's 
conviction  is  that  the  weight  of  evidence  is  in  favor  of  this  increase  being 
due  to  diminished  oxidation  or  destruction  of  uric  acid  in  the  system. 
There  is  general  agreement  that  there  is  always  a  retention  of  uric  acid 
just  before  an  acute  attack,  and  although  investigations  vary  in  the 
results  obtained,  a  marketl  diminution  in  the  uric  acid  excretion  through- 
out the  entire  period  between  acute  attacks  in  chronic  tophaceous  gout 
has  constantly  been  found  by  the  writer.  The  deposition  of  biurates  in 
the  tissues  and  about  the  joints  appears  to  be  due  to  some  factor  other 
than  the  mere  presence  of  an  excess  of  uric  acid  in  the  blood.  Whether 
or  not  a  primary  tissue  necrosis  is  a  necessary  antecedent  to  the  biurate 
deposition,  as  Ebstein  claims,  still  lacks  definite  proof.  There  is  no 
positive  evidence  that  there  is  a  greater  excess  of  uric  acid  in  the  blood 
during  an  acute  exacerbation  of  the  disease  than  in  the  intervals.  In  the 
light  of  recent  investigations  on  the  alkalinity  of  the  blood  in  gout,  it 
seems  impossible  to  attribute  the  deposition  of  biurates  to  diminished 
power  of  the  blood  to  hold  the  uric  acid  in  solution,  owing  to  the  dimin- 
ished alkalinity  of  the  serum,  as  claimed  by  Garrod,  Haig,  and  others. 

Considering  the  fact  that  recent  investigations  have  shown  that  the 
hyperglycemia  of  diabetes  is  probably  due  to  the  absence  of  certain 
sugar-destroying  ferments  or  bodies,  and  accepting  the  view  that  the 
excess  of  uric  acid  in  the  blood  in  gout  is  due  to  deficient  oxidation,  it 
seems  quite  possible,  in  the  light  of  recent  studies,  that  this  excess  may  be 
due  to  the  deficiency  of  a  special  tissue  enzyme.  The  work  of  Jones, 
Schittenhelm,  Burian  and  others,  has  shown  that  certain  of  the  glandular 
organs  produce  the  ferments  guanase,  adenase,  and  oxidase,  which 
oxidize  guanin,  adenin,  and  hypoxanthin  into  xanthin,  hypoxanthin,  and 
xanthin,  respectively.  Another  oxidase  oxidizes  xanthin  into  uric  acid. 
It  is  quite  probable  that  somewhere  in  the  body,  a  ferment  is  produced 
which,  normally,  is  necessary  for  the  proper  destruction  or  oxidation  of 
uric  acid,  and  that  owing  to  some  organ  or  organs  failing  to  produce  this 
ferment,  proper  oxidation  of  uric  acid  does  not  occur  and  the  latter  con- 
sequently accumulates  in  the  blood  in  excess.  The  studies  of  Schitten- 
helm add  considerable  support  to  this  hypothesis.  This  observer  has 
shown,  as  we  have  seen,  that  the  liver,  kidneys,  muscles,  and  bone-marrow 
contain  a  special  oxidase  which  possesses  the  power  of  oxidizing  and 
destroying  uric  acid  and  converting  it  into  urea  and  other  products. 
We  can  conceive  how  certain  factors,  one  of  which  is  believed  to  be 
alcohol,  could  inhibit  the  action  of  this  ferment,  thus  leading  to  dim- 
inished destruction  of  uric  acid  and  its  consequent  increase  in  the  circu- 
lating blood. 

While  the  arthritic  manifestations  of  gout  are  usually  explained  as 
being  due  to  the  mechanical  irritation  of  the  biurates  locally  deposited, 


GOUT  825 

the  uric  acid  theory  does  not  so  satisfactorily  explain  the  nervous  and 
visceral  manifestations  of  the  disease.  There  are  many  who  oppose  this 
view  as  to  the  cause  of  the  joint  pains  in  acute  attacks.  No  other  satis- 
factory explanation  has  been  advanced.  It  seems  more  probable  to  the 
writer  that  the  pain  is  actually  due  to  the  acute  inflammation  which 
occurs,  with  stretching  of  the  peri-articular  tissues  and  consecjucnt 
irritation  of  the  surrounding  nerves.  We  have  no  positive  in(Jication 
that  uric  acid  itself  is  definitely  toxic  in  the  sense  in  which  we  use  the 
term  to  designate  a  chemical  poison.  Animals  have  been  made  to 
ingest  large  quantities  of  uric  acid  with  their  food,  and  urates  in  solution 
have  been  freely  injected  into  their  veins,  without  causing  any  signs  of 
poisoning.  It  may  be  that  some  other  toxic  agent  is  responsible  for  the 
symptoms  of  irregular  gout.  Roberts  thinks,  however,  that  even  in  this 
form,  the  symptoms  may  be  due  to  the  actual  deposition  of  sodium  biurate  in 
the  fibrous  tissues  in  and  about  the  nervous  system  and  in  the  gastro- 
intestinal tract.  He  suggests  that  the  failure  to  microscopically  de- 
monstrate such  deposition  may  be  due  to  insufficient  search  or  to  the 
possibility  of  the  biurates  subsequently  disappearing. 

Pathology. — The  Blood.^ — There  is  always  an  excess  of  uric  acid  as  was 
first  demonstrated  quantitatively  by  Garrod,  in  1848.  He  found  0.025  to 
0.175  grains  of  uric  acid  in  1,000  grains  of  serum.  Klemperer  found  as 
high  as  0.00915  grams  in  100  cc.  of  blood,  and,  in  17  cases,  Magnus- 
Levy  found  the  amount  to  range  between  0.0021  and  0.010  grams  in  the 
same  quantity  of  blood.  The  excess  of  the  uric  acid  is  also  demonstrable 
by  Garrod's  well-known  thread  experiment,  which  may  be  performed 
either  with  the  separated  serum  of  the  drawn  blood  or  with  serum  ob- 
tained by  the  application  of  a  blister.  To  2  drams  of  the  serum,  in  a 
rather  flat  watch  crystal,  add  6  minims  of  moderately  strong  acetic  acid 
for  each  fluid  dram  used.  Mix  well,  and  introduce  one  or  two  ultimate 
fibers  from  a  linen  thread  or  from  a  piece  of  unwashed  linen  fabric.  Set 
aside  in  a  cool  place  for  from  thirty-six  to  sixty  hours  until  the  serum  is 
quite  set  and  almost  dry.  If  uric  acid  be  present  in  excess  (equal  to  at 
least  0.025  grains  of  uric  acid  in  1,000  grains  of  serum  in  addition  to  the 
trace  existing  in  health)  it  will  crystallize  out  on  the  fibers  and,  under  the 
microscope,  will  resemble  the  appearance  of  sugar-candy  on  a  string. 

There  is  no  special  tendency  to  the  development  of  ansemia.  The 
leukocytes  are  not  increased  except  slightly  during  an  acute  attack.  One 
of  our  hospital  cases  with  tophaceous  gout  eventually  died  of  pernicious 
ansemia  with  a  perfectly  characteristic  blood-picture.  Neusser  occasion- 
ally found  that  there  is  an  eosinophilia  and  Chalmers  Watson  has  seen 
numerous  degenerated  myelocytes  during  acute  attacks.  Neusser's  so- 
called  "perinuclear  basophilic  granules,"  which  he  considered  pathogno- 
monic of  a  uric  acid  diathesis,  have  been  shown  by  the  writer  and  others  to 
be  due  to  artifacts  and  to  occur  in  the  blood  of  normal  individuals  with 
the  same  technique.  It  was  also  shown  that  there  was  no  association 
between  the  excretion  of  the  alloxuric  bodies  and  the  relative  abundance  of 
these  granules,  as  he  supposed.  Recent  investigations  tend  to  show  that 
there  is  no  constant  reduction  in  the  alkalinity  as  has  been  held  by 
Garrod,  Haig,  and  others.  In  the  cases  of  saturnine  gout,  the  red  cells  are 
likely  to  manifest  the  basophilic  granular  degeneration  seen  in  lead 
poisoning. 


826  COXSTITUTIOXAL  DISEASES 

The  Joint  Changes. — The  characteristic  lesions  of  gout  manifest  them- 
selves particularly  in  antl  about  the  articulations.  They  are  dejDcndent 
upon  the  deposition  of  uric  acid  in  the  form  of  sodium  hiurate,  and  on  the 
inflammatory  and  degenerative  processes  which  result  therefrom. 

On  examining  a  gout  joint  at  autopsy,  the  articular  surfaces  will  be 
found  studdetl  with  specks,  streaks,  or  patches  of  white,  mortar-like 
material.  Tliis  is  composed  of  sodium  biurate  deposited  as  long  acicular 
crystals.  It  is  likely  to  be  most  abundant  toward  the  central  portion 
of  the  articular  surfaces.  Close  examination  will  show  that  the  sodium 
biurate  is  not  on  the  surface  of  the  cartilages  but  that  it  is  covered  over  by  a 
thin  layer  of  cartilaginous  tissue.  It  seldom  reaches  the  bone  and,  as 
Garrod  pointed  out,  rarely  penetrates  beyond  two-thirds  of  the  depth  of 
the  cartilage.  In  very  advanced,  chronic  cases  there  may  be  actual 
erosion  of  the  cartilage,  but  this  is  rare  as  compared  Avith  arthritis  defor- 
mans. In  the  chronic  cases,  the  biurate  deposit  often  invades  the  capsular 
tissues,  and  may  even  infiltrate  the  skin,  and  lead  to  suppuration  of  a  joint 
tophus.  The  biurate  deposit  in  the  cartilage  can  be  demonstrated  micro- 
scopically by  examining  sections  cut  at  right  angles  to  the  articular  sur- 
face; also  by  the  simpler  method  of  scraping  off  some  of  the  articular 
cartilage  and  teasing  in  salt  solution  and  examining  microscopically.  It 
is  believed  that  the  biurate  is  deposited  from  the  synovial  fluid  of  the 
joint  cavity.  In  the  chronic  cases  there  is  much  thickening  of  the  capsular 
tissues.  In  these  there  maybe  increased  dryness  of  the  joint;  but  if  the 
patient  dies  during  an  acute  attack,  there  is  usually,  particularly  in  the 
knee-joints,  an  excess  of  synovial  fluid,  and  the  synovial  membrane  may 
be  reddened  and  injected.  The  synovial  fluid  is  usually  somewhat  turbid, 
and  contains  a  varying  number  of  polymorphonuclear  leukocytes  and 
occasionally  acicular  crystals  of  sodium  biurate. 

There  is  considerable  diversity  of  opinion,  regarding  the  essential  cause 
of  the  biurate  deposition.  Ebstein  insists  that  there  is  always  a  primary 
tissue-necrosis.  It  seems  more  likely  that,  if  this  view  be  correct,  the 
areas  of  necrosis  result  from  the  toxic  action  of  some  as  yet  unknown 
poison,  or  to  one  of  the  intermediate  purin  bodies.  No  matter  in  what 
part  of  the  body  the  biurates  are  deposited,  he  claims  that  the  tissue- 
necrosis  is  the  primary  factor.  These  necrotic  areas  are  most  liable  to 
occur  in  the  joint  cartilages  and  other  cartilaginous  and  articular  structures 
in  which  the  normal  nutritional  currents  are  slow.  In  support  of  his  view, 
he  states  that  he  has  often  found  areas  in  which  there  was  necrosis  without 
biurate  deposition.  In  these  areas  of  coagulation  necrosis,  the  reaction  is 
always  acid,  so  that  the  conditions  are  favorable  for  the  precipitation  of 
the  uric  acid  in  the  form  of  the  crystalline  biurate.  As  has  been  stated, 
von  Noorden  thinks  this  necrosis  may  be  due  to  a  special  ferment.  His 
and  Mordhorst  claim  that  the  deposition  of  the  sodium  biurate  is  primary, 
and  that  the  tissue  necrosis  is  a  secondary  process.  According  to  Roberts, 
the  biurates  are  deposited  most  abundantly  in  cartilaginous  tissue, 
because  here  the  temperature  is  lowest,  the  circulation  poorest,  and,  in  the 
case  of  the  articular  cartilage,  it  is  bathed  with  the  synovial  fluid  which  is 
rich  in  sodium  chloride,  and  which  he  claims  favors  the  deposition  of 
sodium  biurate.  According  to  Wynne,  the  marginal  outgrowths  about  the 
gouty  joints  are  true  exostoses.  The  bursse  may  be  acutely  inflamed  and 
may  contain  deposits  of  biurate  of  soda. 


GOUT  827 

The  frequency  with  which  biurate  deposits  are  found  in  the  Joints  at 
autopsy  corresponds  closely  with  the  relative  frequency  with  which  the 
gouty  arthritis  is  seen  clinically.  Norman  Moore  has  brought  this  out 
well  in  an  analysis  of  80  autopsies  on  gout  patients.  The  joints  most 
commonly  involved  are  the  metatarso-phalangeal  joints  of  the  big  toes, 
and  frequently  these  are  the  only  ones  affected.  Then  follow  the  tarsal 
joints,  ankles,  knees,  hands,  and  wrists.  The  elbows,  shoulders,  and  hips, 
are  more  rarely  involved.  Among  the  rarest  sites  of  uratic  deposits  are  the 
articulations  of  the  jaws,  larynx,  and  sternoclavicular  joints. 

Situations  in  Which  Tophi  Occur. — Biurate  deposits  occur  in  other 
situations  than  in  the  joints  and  their  neighborhoods.  These  are  termed 
"tophi,"  a  name  derived  from  the  Hebrew,  and  signifying  "concretions." 
They  are  also  known  as  "chalk-stones."  The  commonest  situation  for 
them  to  occur  in  is  on  the  helix  or  anti-helix  of  the  ear.  They  are  also  fre- 
quently found  in  the  tendons  and  aponeuroses.  In  one  case  the  writer  saw 
a  tophus  measuring  3  by  6  cm.,  in  the  tendo  Achillis.  They  are  not  infre- 
quently seen  in  the  subcutaneous  tissue.  The  commonest  seats  of  skin 
tophi  are  the  extensor  surfaces  of  the  fore-arms,  near  the  elbow-joint,  and 
the  neighborhood  of  the  patella.  They  may  be  mistaken  for  the  subcu- 
taneous fibroid  nodules  of  rheumatism.  The  writer  has  observed  a 
patient  with  numerous  tophi  in  the  prepuce;  another  had  a  large  group 
of  them  over  the  sacrum.  They  may  also  occur  in  the  palms  and  soles, 
nose,  and  tarsal  cartilages  of  the  eyes.  Less  common  situations  for  biurate 
deposits  are  the  larnygeal  cartilages,  vocal  cords,  cranial  and  spinal  dura 
mater,  the  pia  mater,  sclerotic  coat  of  the  eye,  the  fibrous  sheathes  of  the 
nerve  trunks,  and  the  aortic  valves.  Enormous  tophi,  which  may  break 
down  and  suppurate,  not  infrequently  occur  about  the  finger  and 
knuckle-joints.  Ebstein  and  Sprague  have  carefully  analyzed  the  tophi, 
and  find  that  they  contain,  on  an  average,  57  per  cent,  of  sodium  biurate, 
and  from  12  to  13  per  cent,  of  calcium  biurate.  Somewhat  similar 
to  these  tophi  in  man,  are  the  deposits  characterizing  "guanin  gout"  in 
hogs.  When  these  animals  are  fed  in  a  certain  way,  one  sees  in  the  mus- 
cles, ligaments,  and  articular  tissues,  small  whitish  deposits  which  are 
made  up  of  guanin.  These  are  frequently  seen  in  Smithfield  and  West- 
phalian  hams. 

The  Kidneys. — Of  the  visceral  lesions  in  gout,  those  of  the  kidneys  are 
the  most  frequent  and  important.  Nephritis  is  extremely  common,  and, 
according  to  Levison,  is  always  present.  Ebstein  has  described  two  types 
of  gout  cases:  First,  the  "primary  renal  gout";  and  second,  the  "primary 
articular  gout."  In  the  former,  the  renal  disease  has  existed  for  some 
time,  and,  subsequently,  articular  manifestations  of  gout  appear.  Such  a 
case  recently  occurred  in  a  colored  man,  aged  twenty-four  years,  admitted 
to  the  Johns  Hopkins  Hospital.  For  several  months  he  had  complained  of 
the  usual  symptoms  of  chronic  nephritis.  There  had  been  no  previous 
arthritic  history.  A  few  days  before  his  death,  he  developed  pain  and 
swelling  of  his  right  big  toe-joint.  This  joint  at  autopsy  showed  the  char- 
acteristic deposits  of  sodium  biurate  in  the  articular  cartilage.  The  kid- 
neys were  much  contracted.  In  the  latter  type,  the  articular  manifestations 
antedate  the  onset  of  the  clinical  symptoms  of  nephritis.  The  form  of 
nephritis  usually  met  with  in  gout,  is  that  characterized  by  granular  degen- 
eration and  marked  atrophy.    It  is  often  spoken  of  as  the  "gouty  kidney." 


82S  CONSTITUTIONAL  DISEASES 

On  the  other  hand,  the  arteriosclerotic  kidney  may  be  met  with.  Here 
the  kidney  is  kirger,  beefy,  red,  and  very  hard.  There  appears  to  be 
no  special  diti'erence  between  the  kidney  of  saturnine  and  that  of  ordi- 
nary gout.  The  gouty  kidney,  on  section,  not  infrequently  shows  white 
deposits  of  sodium  biurate.  In  the  cortical  substance  the  deposit  is 
scanty  and  occurs  in  specks  scattered  irregularly  through  the  tissue.  It 
is,  however,  most  frequently  seen,  and  most  al)un(lant,  in  the  pyramids, 
occurring  in  streaks  running  in  the  directicju  of  the  tubules,  particularly 
toward  the  apices  of  the  pyramids.  In  both  situations,  the  deposit  is 
usually  situated  in  the  intcrtubular  tissue,  but  it  may  also  occur,  as 
Virchow,  Wagner,  and  Lancereaux  have  shown,  in  the  lumena  of  the 
tubules.  When  examined  microscopically,  it  is  seen  to  exist  as  acicular 
crystals,  just  as  in  the  gouty  joints.  These  deposits  were  first  described 
by  Castelnau.  They  are  not  so  frequently  found  as  we  would  be  at  first  led 
to  infer.  Norman  Aloorc  found  them  in  only  12  out  of  80  cases.  Ebstcin 
holds  that  a  tissue  necrosis  antedates  the  biurate  deposition.  Aschoif 
and  jNIinkowski,  on  the  other  hand,  claim  that  they  have  found  the  crystals 
extending  from  the  j)eri})hery  of  the  deposits  into  the  surrounding  healthy 
renal  tissue,  which  showed  no  indications  of  necrosis.  Osier  holds  that 
these  deposits  must  not,  how^ever,  be  always  interpreted  as  meaning  that 
the  individual  has  gout,  as  they  occasionally  occur  without  the  person 
having  had  any  gouty  manifestations. 

Cardiovascular  Lesions. — Arteriosclerosis  is  very  common.  Nearly 
all  cases  of  chronic  gout  show  marked  thickening  of  the  peripheral 
arteries.  Whether  the  arterial  thickening  is  due  to  the  toxic  action  of  the 
excess  of  uric  acid  in  the  blood,  to  that  of  the  products  of  intermediary 
metabolism,  or  to  the  contributory  factors  producing  the  gout — viz., 
alcohol,  lead,  or  excessive  food,  is  difficult  to  determine. 

The  combination  of  nephritis  and  arteriosclerosis  wdth  consequent 
increased  arterial  tension,  frequently  leads  to  hypertrophy  of  the  left  ven- 
tricle. The  arch  of  the  aorta  is  frequently  involved  in  the  arteriosclerotic 
process.  The  orifices  of  the  coronaries  may  be  narrowed,  and  the  coronary 
vessels  themselves  sclerosed.  The  coronary  involvement  renders  the 
subject  liable  to  attacks  of  angina  pectoris.  For  the  same  reason,  myo- 
cardial changes  are  common,  and  death  may  result  from  failure  of  com- 
pensation. Fatty  degeneration  of  the  heart  muscle  occurs.  A  gouty 
pericarditis  is  not  uncommon.  In  rare  instances,  sodium  biurate  deposits 
have  been  found  in  the  aortic  valves. 

Respiratory  System. — Sodium  biurate  deposits  may  occur  in  the  vocal 
cords,  and  in  the  epiglottis  and  laryngeal  cartilages.  In  rare  instances  the 
biurate  crystals  have  been  found  in  the  sputum.  Emphysema  is  very  com- 
mon in  chronic  gout,  and  the  lungs  may  show  a  chronic  bronchitis  at 
autopsy. 

Symptoms. — Acute  Gout. — In  the  initial  attack  there  maybe  no  pre- 
monitory symptoms.  A  previously  healthy  man  of  middle  age  retires 
feeling  perfectly  w'ell.  During  the  night  he  is  aw^akened  with  intense  pain, 
usually  in  the  right  metatarsophalangeal  joint.  By  morning  the  joint  is 
reddened,  slightly  swollen,  and  sensitive  to  the  touch.  The  temperature 
is  moderately  elevated,  reaching  usually  to  between  101°  and  103°  F.  As 
morning  approaches,  the  pain,  which  has  been  agonizing  and  makes  the 
patient  feel  as  though  the  joint  is  being  squeezed  in  a  vise,  gradually  sub- 


GOUT  829 

sides,  and,  beyond  having  a  feeling  of  general  malaise  and  of  anorexia,  he 
experiences  a  fairly  comfortable  day.  The  next  night  the  attack  recurs, 
and  the  pain,  as  Sydenham  says,  "insinuates  itself  with  the  most  exquisite 
cruelty  among  the  numerous  small  bones  of  the  tarsus  and  metatarsus, 
in  the  ligaments  of  which  it  is  lurking."  There  is  a  repetition  of  these 
attacks  each  night  for  a  week  or  ten  days,  constituting  a  so-called  "fit  of 
the  gout."  For  the  first  few  days  the  swelling  of  the  joint  increases,  co- 
incident with  which  there  is  a  gradual  abatement  of  the  intensity  of  the 
pain.  The  skin  over  the  joint  is  reddened  and  shiny.  The  surrounding 
veins  are  slightly  dilated,  and,  toward  the  end  of  the  attack,  there  may  be 
slight  pitting  on  pressure  over  the  joint.  The  inflammation  never  goes  on 
to  suppuration.  With  the  subsidence  of  the  acute  swelling,  the  skin  may 
desquamate.  During  the  acute  febrile  period,  there  is  a  leukocytosis 
which  may  reach  20,000  per  cmm.  In  the  initial  seizure  both  big  toe- 
joints  may  be  involved.  On  the  other  hand,  these  articulations  may 
escape,  and  the  tarsal  and  tarsometatarsal  joints  may  be  first  affected. 
In  these  instances  the  "fit"  generally  lasts  considerably  longer.  After  the 
attack,  the  general  health  maybe  decidedly  improved.  There  may  be  no 
recurrence  of  the  acute  attack  for  years,  or  even  decades.  More  com- 
monly, however,  only  months  elapse,  and  there  is  a  tendency  to  periodical 
recurrences  in  the  spring  and  fall.  Premonitory  symptoms  occasionally 
precede  the  acute  attacks  for  a  number  of  days,  and  the  victim  can  often 
predict  its  onset.  These  symptoms  are  quite  diverse.  The  most  promi- 
nent ones  are  digestive  disturbances — loss  of  appetite,  flatulence,  and 
acidity.  Nocturnal  restlessness,  irritability  of  temper,  and  depression  of 
spirits  ma}'^  also  occur. 

Chronic  Gout. — With  the  progress  of  the  disease,  the  acute  exacerba- 
tions become  more  frequent  and  a  larger  number  of  joints  become  affected. 
The  tarsal-,  ankle-,  knee-,  hand-,  and  wrist-joints  are  the  ones  most  likely 
to  be  involved,  in  the  order  of  frequency  mentioned.  The  elbows,  shoulders, 
and  hips,  are  more  rarely  attacked.  Each  acute  attack  is  supposed  to  be 
occasioned  by  the  sudden  precipitation  of  the  sodium  biurate  in  and  about 
the  joints.  The  periarticular  tissues  become  thickened,  and  densely  in- 
filtrated with  biurates.  The  latter,  particularly  about  the  toe-,  knee-,  finger-, 
and  elbow-joints  may  give  rise  to  large  joint-tophi,  which,  in  the  case  of  the 
knee-  and  elbow-joints,  may  reach  the  size  of  a  walnut.  These  tophi  may 
cause  striking  knob-like  deformities  of  the  knuckle  and  interphalangeal 
articulations.  They  gradually  become  superficial,  and  appear  whitish 
through  the  superimposed  skin.  The  latter,  especially  over  the  knuckle 
and  metatarsophalangeal  joints,  may  become  inflamed  and  actually 
ulcerate,  and  the  contents  of  the  tophi  discharge  as  a  whitish,  chalky 
material,  which,  on  microscopic  examination,  reveals  the  characteristic 
needle-shaped  crystals  of  sodium  biurate.  In  these  cases  of  chronic 
"tophaceous"  gout,  the  commonest  situation  for  the  tophi  is  the  cartilage 
of  the  ear,  in  the  region  of  the  helix  and  antihelix.  They  appear  first  as 
slight  reddish  elevations  in  which,  as  time  goes  on,  the  biurate  can  be 
recognized  with  the  naked  eye  as  a  whitish  "chalk-stone  like"  deposit. 
The  term  "chalk-stone"  is  not  altogether  a  misnomer,  for  Ebstein  and 
Sprague  have  shown  that  tophi  contain  from  12  to  13  per  cent,  of  calcium 
biurate,  although  the  greater  portion,  57  per  cent.,  is  composed  of  sodium 
biurate.    Subcutaneous  tophi  may  occur  about  the  knees  and  along  the 


830  CONSTITUTIONAL  DISEASES 

extensor  surfaces  of  the  forearms,  and  may  be  mistaken  for  rheumatic 
fibroid  nodules.  They  may  also  occur  in  the  palms,  and  soles,  and  over 
the  sacrum,  and  in  the  tendo  Achilles.  Tophi  sometimes  occur  in  the 
tarsal  cartilages  of  the  eye,  in  the  sclerotics,  and  in  the  cartilage  of  the  nose. 
The  bursie  over  the  olecranon  and  patella  may  become  inflamed  and  be 
the  seat  of  sodium  biurate  deposition.  Polyarticular  attacks,  with 
moderate  fever  reiiching  101°  F.  occur  with  frequency,  and  in  the  intervals 
the  unfortunate  victim  is  not  entirely  free  from  pain,  and  always  conscious 
of  joint  disability.  Owing  to  the  lessened  amount  of  synovial  fluid  in  these 
chronic  cases,  audible  creaking  of  the  joints  may  occur,  and  there  is 
sometimes  palpable  crepitation.  The  acute  joint  exacerbations  may  be 
afebrile,  a  feature  which  should  always  lead  the  physician  to  suspect  a 
gouty  origin  for  the  joint  symptoms.  The  pulse  tension  is  increased, 
the  peripheral  arteries  become  sclerosed,  and  hypertrophy  of  the  left 
ventricle  develops.  The  urinary  changes  are  those  of  a  chronic  interstitial 
nephritis  and  will  be  referred  to  later.  Cramps  of  the  calf,  abdominal, 
and  thoracic  muscles,  may  be  most  annoying.  Digestive  disturbances  are 
common.  The  victim  of  chronic  gout  may  possess  marked  mental  and 
bodily  vigor.  Certain  of  the  most  distinguished  members  of  our  pro- 
fession have  been  martyrs  to  the  disease,  notably  the  older  Scaliger, 
Jerome  Cardan,  and  Sydenham,  whose  statement  that  "more  wise  men 
than  fools  are  victims  of  the  affection"  still  holds  good.  Although  the 
subject  of  chronic  gout  is  liable  to  be  carried  off  by  some  terminal  affection 
such  as  urfemia,  pleurisy,  pericarditis,  peritonitis,  and  meningitis,  yet 
the  victims  not  infrequently  live  to  a  good  old  age.  The  question  has  been 
much  discussed  as  to  whether  Heberden's  nodes  ever  occur  in  gout. 
Although  of  rare  occurrence,  it  seems  quite  certain  that  they  do  occur,  for 
Charcot,  Duckworth,  and  Minkowski,  have  described  them  in  cases  of 
unquestioned  gout.  Dupuytren's  contraction  of  the  palmar  fascia  has 
been  described. 

Irregular  Gout. — This  comprises  a  nondescript  group  of  symptoms 
which  have  usually  been  embraced  under  the  terms  lithoeviia,  or  a  uric 
acid,  liihic  acid,  or  gouty  diathesis.  These  irregular  features  are  observed 
in  members  of  gouty  families  who  may  never  have  suffered  from  an  attack 
of  gouty  arthritis.  They  occur,  also,  in  those  who  have  eaten  and  drunk 
too  freely,  without  taking  sufficient  exercise,  and  who  have  been  fortunate 
enough  to  escape  an  acute  attack.  In  families  with  marked  hereditary 
predisposition,  the  daughters  often  escape,  while  one  son  may  have  gouty 
attacks  of  great  severity  even  though  he  lives  a  temperate  life  and  en- 
deavors to  avoid  the  conditions  favoring  the  disorder.  Another  son, 
on  the  other  hand,  has  only  the  irregular  features,  and  never  the  acute 
articular  affection.  While  the  irregular  manifestations  are  more  likely  to 
occur  in  inherited  gout,  they  may  also  occur  in  the  acquired  form.  There 
is  an  unfortunate  tendency  on  the  part  of  many  physicians  to  ascribe 
certain  obscure  symptoms  to  a  so-called  uric  acid  diathesis,  especially  if 
they  find  a  deposit  of  uric  acid  or  urates  in  the  urine,  although  there  is  often 
not  a  vestige  of  evidence  to  justify  this  view.  There  are  certain  health 
resorts  in  this  country  from  which  nearly  every  patient  comes  away  imbued 
with  the  firm  conviction  that  his  blood  is  "filled  with  uric  acid,"  and 
that  this  is  responsible  for  his  various  nervous  features.  The  patients 
are  usually  pleased  with  the  explanation,  and  it  is  a  difficult  task  to  dis- 


GOVT  831 

abuse  their  minds  of  the  fallacy.    Among  the  commonest  manifestations 
of  irregular  gout  are  the  following: 

(a)  Cutaneous  Eruptions. — The  most  distinctive  is  eczema.  The  fav- 
orite seat  is  the  external  ear,  but  the  inflammation  may  spread  to  the  face, 
forehead,  and  back  of  the  neck.  It  may  be  very  obstinate,  and  even  extend 
to  other  parts  of  the  body  in  patients  of  advanced  years.  Symmetrical 
patches  of  psoriasis  may  occur  on  the  legs.  Attacks  of  herpes  zoster  have 
occasionally  occurred.  The  nails  are  often  striated  and  fluted,  or  lined 
vertically.  The  French  have  written  extensively  on  the  skin  manifestations 
of  irregular  gout,  and  speak  of  them  as  the  arthritides. 

(b)  Alimentary  Disorders. — There  may  be  psoriasis  of  the  tongue. 
Notwithstanding  numerous  statements  to  the  contrary,  Duckworth  asserts 
that  no  uratic  deposits  are  met  with  in  connection  with  the  jaws,  teeth,  or 
gums.  It  has  been  held  by  some  that  the  development  of  tartar  on  the 
teeth  is  a  gouty  manifestation.  There  seems  no  justification  for  this  view. 
Some  cases  are  subject  to  frequently  recurring  attacks  of  pharyngitis  with 
great  injection  of  the  vessels.  A  gouty  parotitis  occasionally  occurs. 
Attacks  of  what  is  termed  biliousness,  in  which  the  tongue  is  furred,  the 
breath  foul,  the  bowels  constipated,  and  the  action  of  the  liver  torpid,  are 
not  uncommon  in  gouty  persons. 

(c)  Nervous  Manifestations. — Some  of  the  most  frequent  manifesta- 
tions of  irregular  gout  come  under  this  heading.  Headaches  and  migraine 
attacks  are  common.  Haig  has  laid  special  stress  on  these  symptoms, 
and  he  thinks  that  they  are  due  to  an  excess  of  uric  acid.  Neuralgias  are 
not  uncommon.  Sciatica  is  believed  frequently  to  have  a  gouty  basis. 
Duckw^orth  has  emphasized  the  occurrence  of  hot  or  itching  feet  at  night. 
Plutarch  mentions  that  Strabo  called  this  symptom  "the  lisping  of  the 
gout."     Cramps  in  the  leg  and  abdominal  muscles  may  be  troublesome. 

{d)  Urinary  Disturbances.^  -Many  fallacious  opinions  have  been 
formed  by  physicians  concluding  that  a  person  is  suffering  from  a  uric  acid 
diathesis,  by  finding  deposits  of  uric  acid  and  urates  in  the  urine.  The 
solubility  of  the  latter  is  dependent  upon  so  many  factors,  important 
among  them  being  the  amount  of  urinary  pigment  and  the  percentage  of 
the  various  salts,  that  it  is  entirely  unjustifiable  to  draw  any  definite  con- 
clusions as  to  the  quantity  of  uric  acid  excreted  without  making  actual 
quantitative  analyses.  Uric  acid  precipitation  may  occur,  although  there 
may  be  actual  diminution  in  the  uric  acid  excretion  in  the  twenty-four 
hours.  Individuals  with  a  gouty  habit  are  undoubtedly  prone  to  gravel, 
and  to  uric  acid  calculi.  Duckworth  points  out  that  articular  gout  and 
calculi  rarely  co-exist,  although  they  may  alternate.  Albuminuria  is  very 
common  in  the  gouty  dyscrasia.  Oxaluria  also  occurs.  Hematuria  may 
occur  in  very  old  persons.  Phosphatic  gout  has  been  described.  It  occurs 
without  the  articular  features.  Severe  pain  comes  on  in  the  night,  and 
there  is  spasmodic  dysuria.  Urethritis,  with  a  purulent  discharge,  is  said 
to  occur  either  spontaneously  or  following  a  pure  connection, 

{e)  Ocidar  Manifestations. — Hutchinson  has  called  attention  to  hot 
and  itching  eye-balls  as  a  frequent  sign  of  masked  gout.  Associated  or 
alternating  with  this  symptom  there  may  be  attacks  of  episcleral  con- 
gestion. The  writer  observed  repeated  attacks  of  unilateral  conjunctivitis 
in  a  gouty  patient,  who  for  years  had  not  had  any  articular  symptoms. 
These  would  occur  together  with,  or  independently  of,  a  gouty  pharyngitis. 


832  CONSTITUTIONAL  DISEASES 

(/)  Cardiac  Manifestations. — A  peculiar  paroxysmal  disturbance  of  the 
circulation  is  sometimes  witnessed,  in  which  the  heart -beats  are  very 
rapid  and  a  condition  is  produced  which  Roberts  terms  the  "runaway 
heart."  There  may  be  attacks  of  false  angina  pectoris,  in  which  there  are 
no  manifestations  of  cardiac  disease 

(g)  Pulmonary  Fcainrcs. — Greenhow  has  pointed  out  that  persons  of 
the  gouty  habit  aVe  liable  to  suffer  from  chronic  bronchitis.  Asthmatic 
paroxysms  may  also  occur.  The  prevalence  of  emphysema  is  well  recog- 
nized. 

The  Urine  in  Gout. — During  the  acute  paroxysms  the  urine  is  scanty, 
high  colored,  and  is  generally  stated  to  contain  a  deposit  either  of  urates 
or  uric  acid.  In  the  writer's  experience  in  hospital  work,  such  a  deposit  is 
the  exception  rather  than  the  rule.  There  is  usually  a  trace  of  albumin, 
and  there  may  be  a  mild  glycosuria.  Careful  search  will  usually  show  afew 
hyaline  or  granular  casts.  Quantitative  analyses  will  always  show  a 
marked  reduction  in  the  amount  of  uric  acid  below  the  usual  level  for  two 
or  three  days  before  the  acute  attack.  Twenty-four  or  forty-eight  hours 
after  the  onset  of  the  acute  symjjtoms,  the  uric  acid  curve  rises,  and  the 
amount  may  reach  0.7  to  1 .0  gram ,  the  u])per  limit  for  normal.  As  the  acute 
symptoms  subside,  the  curve  falls  to  0.4  gram,  the  lower  limit  for  normal, 
or  usually  below  tliis.  In  chronic  gout,  the  urine  is  usually  increased  in 
quantity,  ))ale,  of  low  specific  gravity,  and  always  contains  traces  of  albu- 
min and  hyaline  and  granular  casts.  Although  some  have  failed  to  find  a 
constant  reduction  of  uric  acid  in  the  intervals  between  the  acute  attacks 
in  these  cases,  the  writer's  analyses  have  practically  always  shown  a  very 
marked  reduction,  often  not  more  than  0.1  or  0. 2  gram  being  precipitated 
in  the  twenty-four  hours.  In  one  or  two  cases,  he  has  failed  to  find,  on 
certain  days,  any  precipitation  of  uric  acid  as  ammonium  urate,  with 
Folin's  modification  of  the  Ho])kins  quantitative  method.  Many  hold 
that  there  is  no  corresponding  increase  in  the  excretion  of  the  phosphoric 
acid  with  that  of  the  uric  acid  during  the  acute  attack,  but,  in  some  of 
the  cases  followed,  the  writer  found  a  striking  parallelism  in  the  curves  of 
the  two  acids.  If  the  uric  acid  be  derived  from  nuclein  destruction  a 
correspondence  in  the  curves  would  rather  be  expected. 

Complications. — Cardiovascular. — Arteriosclerosis  is  extremely  com- 
mon and  is  always  found  at  autopsy  in  the  chronic  cases.  Owing  to  the 
increased  tension,  hypertrophy  of  the  left  ventricle  occurs.  In  due  time 
this  may  give  way  to  dilatation,  causing  palpitation,  irregular  heart  action, 
and  eventually  a  condition  of  asystole.  Myocarditis  is  very  common  in 
the  obese  cases.  This  is  probably  induced  by  the  atheroma  involving  the 
coronary  arteries,  and  may  be  the  eventual  cause  of  the  patient's  death. 
Owing  to  the  coronary  disease,  true  anginal  attacks  may  occur.  A  ter- 
minal pericarditis  is  not  an  uncommon  event,  but  this  is  usually  attributed 
to  the  renal  lesion  rather  than  directly  to  the  gout  itself.  Aneurism  and 
apoplexy  may  occur. 

Phlebitis  and  venous  thrombosis  are  well  recognized  as  occasionally 
of  gouty  origin.  The  French  are  inclined  to  the  view  that  many  instances 
of  so-called  idiopathic  thrombosis  of  the  veins  are  due  to  a  gouty  dyscrasia. 

Renal. — A  chronic  interstitial  nci)hritis,  and  small  granular  kidneys,  are 
almost  invariably  present  in  the  chronic  form  of  the  disease,  and  the 
majority  of  gout  patients  die  of  uraemia. 


GOUT  833 

Retrocedent  Gout. — This  term  is  applied  to  a  group  of  serious  internal 
symptoms,  oecurring  coincidently  with  a  rapid  disappearance,  or  im- 
provement, of  the  joint  manifestations.  They  may  be  so  grave  as  to  cause 
death,  and  may  be  considered  among  the  complications  of  the  disease. 
With  a  sudden  cessation  of  the  joint  inflammation  there  may  be  severe 
gastro-intestinal  symptoms— pain,  vomiting,  diarrhoea,  and  great  depres- 
sion, and  death  may  occur  during  such  an  attack.  On  the  other  hand 
there  may  be  cardiac  manifestations — dyspnoea,  precordial  pain,  and 
irregular  heart  action.  Cerebral  features,  such  as  delirium,  coma,  or 
apoplexy,  may  occur,  but  in  a  majority  of  cases  these  symptoms  are 
probably  urtemic. 

Of  the  eye  complications,  an  iritis  is  recognized  as  being  of  gouty  origin. 
Glaucoma  occurs.  Hutchinson  has  described  a  hemorrhagic  retinitis. 
This  may  be  of  renal  origin,  but  it  is  especially  characterized  by  being 
unilateral,  and  affecting  the  left  eye  most  frequently.  A  suppurative 
panophthalmitis  has  also  been  described. 

Glycosuria  and  Diabetes. — Glycosuria  is  comparatively  common  in 
gout.  It  may,  in  certain  cases,  bo  dignified  by  the  name  of  mild  diabetes 
mellitus.  It  occurs,  usually,  in  the  obese  gout  patients^  The  glycosuria 
may  alternate  with  arthritic  manifestations  (diabetes  alternans).  Lecorche 
observed  23  cases  of  transitory  or  permanent  glycosuria  in  150  cases  of 
gout.  The  etiology  of  the  glycosuria  is  difficult  to  explain,  but  Min- 
kowski thinks  that,  owing  to  the  prevalence  of  arteriosclerosis  in  gout, 
there  may  be  sclerotic  changes  in  the  pancreas,  as  a  result  of  the  arterial 
disease,  corresponding  to  the  arteriosclerotic  diabetes  described  by  Fleiner, 
Hoppe-Seyler,  and  others. 

Diagnosis. — In  the  majority  of  cases  of  the  acute  form  of  the  disease, 
no  great  difficulty  should  arise.  The  predilection  for  the  local  inflamma- 
tion to  attack  the  metatarsophalangeal  and  the  tarsal  joints  is  very 
characteristic.  The  marked  reddening,  and  the  shiny  appearance  of  the 
skin,  together  with  the  intensity  of  the  pain,  is  extremely  suggestive.  Be- 
fore the  disease  has  definitely  reached  the  chronic  stage,  it  must  be  remem- 
bered that  the  joint  inflammation  may  be  polyarticular,  and  many  of  these 
cases  are  diagnosed  as  acute  rheumatism.  Careful  inquiry  regarding 
heredity,  habits  as  to  eating  and  drinking,  together  with  the  occupation, 
will  often  give  the  proper  clue.  The  examination  of  the  blood  for  an 
excess  of  uric  acid  is  undoubtedly  of  value.  Quantitative  determinations 
are  too  complicated,  and  the  Garrod  thread-test  suffices.  A  positive 
test  practically  indicates  gout,  as  the  only  other  conditions  in  which  we 
meet  with  an  excess  of  uric  acid  in  the  blood  are  pneumonia  and  leuksemia, 
with  which  there  can  be  no  confusion.  Unless  the  uric  acid  curve  can  be 
followed  before,  during,  and  after,  the  subsidence  of  the  acute  attack, 
the  writer's  own  feeling  is  that  the  urinary  examination  gives  little  aid  in 
making  a  differential  diagnosis. 

It  is  in  the  chronic  form,  with  occasional  acute  exacerbations,  that  the 
correct  nature  of  the  arthritis  is  often  overlooked.  This  is  particularly  the 
case  if  tophi  have  not  yet  appeared;  but  many  cases  go  begging  for  a  diag- 
nosis even  when  these  are  present,  owing  to  the  failure  of  the  physician  to 
search  regularly  for  tophi  in  the  ears  in  all  cases  of  acute  or  chronic  joint 
affections.  The  tophi,  as  we  know,  are  commonest  in  the  cartilaginous 
portions  of  the  ear  in  the  vicinity  of  the  helix  and  antihelix.     They  are 

63 


834  CONSTITUTIONAL  DISEASES 

usually  small,  superficial,  and  whitish  in  appearance.  They  may,  however, 
be  more  deeply  seated  and  the  biurate  deposits  may  not  be  seen  with  the 
naked  eye.  Microscopic  examination  of  the  contents  shows  the  character- 
istic needle-shaped,  acicular  crystals  of  sodium  biurate.  The  presence 
of  these  crystals  is  pathognomonic  of  gout.  Not  to  be  confused  with  the 
tophi,  are  Woolncr's  tip  or  the  Darwinian  tubercle,  which  is  more  devel- 
oped in  some  of  us  than  in  others,  small  fibroid  nodules  on  the  margin  of 
the  ear,  and  small  sebaceous  cysts.  The  latter  is  the  only  one  to  give  rise 
to  any  real  confusion,  and  the  finding  of  oil  droplets  and  epithelial  cells, 
with  the  absence  of  biurate  crystals  in  the  contents,  easily  differentiates  the 
two.  Where  there  are  large  biurate  accumulations  about  the  toe-,  finger-, 
knee-,  or  elbow-joints,  the  diagnosis  of  the  affection  is  manifest  at  first 
sight.  It  must  be  recalled  that  subcutaneous  tophi,  clinically  indistin- 
guishable from  rheunuitic  fibroid  nodules,  may  occur  over  the  extensor 
surfaces  of  the  foreai'ms  and  about  the  knees,  and  may,  to  the  uninitiated, 
be  confirmatory  of  a  diagnosis  of  rheumatism.  It  is  well  in  any  such 
doubtful  cases  to  excise  one  of  these  nodules  and  examine  microscopically. 
The  presence  of  sodium-biurate  deposits  in  them  points  definitely  to  gout. 
A  feature  of  diagnostic  importance  is  the  fact  that  an  attack  of  acute  gouty 
arthritis  may  be  afebrile.  Any  polyarthritis,  with  acute  manifestations 
and  unaccompanied  by  fever,  should  always  cause  a  strong  suspicion  that 
it  is  gouty  in  origin.  In  these  chronic  cases,  the  habits  of  life  and  the 
history  of  the  situations  of  the  initial  attack  of  arthritis  is  most  important. 
If  there  be  an  arthritic  family  history,  if  the  patient  has  indulged  freely  in 
fermented  beverages,  or  has  had  an  occupation  subjecting  him  to  possible 
lead  infection,  and  if  the  initial  or  early  attacks  have  been  limited  to  the 
metatarsophalangeal  or  tarsal  joints,  the  chances  are  strongly  in  favor  of 
the  disease  being  gout.  The  x-ray  photograph  may  be  of  some  assist- 
ance. Where  there  are  periarticular  deposits  of  biurates  in  considerable 
masses,  these  will  be  recognized  as  shadows  in  the  photogragh.  Where 
this  is  the  case  one  will  be  reasonably  sure,  without  the  photograph,  that  the 
periarticular  thickening  is  due  to  biurate  depositions.  The  weak  feature 
in  the  diagnostic  value  of  the  Rontgen  rays,  is  that  they  are  practically  of  no 
assistance  just  in  those  cases  where  they  would  be  of  the  most  value, 
namely,  where  the  biurate  deposits  are  limited  to  the  articular  cartilages. 
In  these  cases,  the  a:-rays  fail  to  reveal  the  existence  of  the  deposition, 
either  in  the  photographic  plate  or  in  the  reproduction. 

As  our  knowledge  of  chronic  articular  affections  has  increased,  the 
opinion  is  becoming  more  firmly  established  that  there  is  no  such  condi- 
tion as  chronic  articular  rheumatism.  An  acute  rheumatic  arthritis,  when 
it  subsides,  practically  never  leaves  any  deformity  or  limitation  in  func- 
tional activity.  Consequently,  when  deformity  or  impaired  motion  super- 
venes upon  one  or  more  attacks  of  acute  arthritis,  we  can  be  reasonably 
certain  that  we  are  not  dealing  with  a  rheumatic  affection,  but  rather  with 
gout  or  arthritis  deformans.  It  is  with  the  latter  affection  that  the  greatest 
difficulty  in  the  differential  diagnosis  is  likely  to  occur.  In  arthritis  de- 
formans, however,  certain  features  aid  us  in  the  differentiation.  In  the 
case  of  deformities  of  the  hands,  there  is  a  greater  tendency  to  ulnar  de- 
flection of  the  fingers.  A  most  important  differential  point  is  the  almost 
constant  occurrence  of  atrophy  of  the  dorsal  interossei  muscles  of  the 
hands,  producing  a  depressed  appearance  over  the  metacarpal  region. 


GOUT  835 

Heberden's  nodes  point  toward  arthritis  deformans,  although,  as  has 
been  already  stated,  they  have  been  in  rare  instanees  described  in  cases  of 
undoubted  gout.  The  tendency  of  the  laity,  and  also  of  many  physicians, 
is  to  incorrectly  consider  these  enlargements  of  the  terminal  finger-joints 
as  a  manifestation  of  gout.  Where  the  larger  joints  are  involved  in 
arthritis  deformans,  such  as  the  knee,  wrist,  or  elbow,  the  deformity  is 
more  likely  to  be  of  a  fusiform  shape  with  considerable  muscular  atrophy 
above  and  below.  Needless  to  say,  tophi  do  not  occur  in  this  disease. 
The  rr-rays  are  of  undoubted  value  in  differentiating  the  two  affections 
when  actual  joint  deformity  has  occurred.  Osteophytic  growths,  or 
atrophy  of  the  ends  of  the  bones  and  of  the  joint  surfaces,  point  respect- 
ively to  the  hypertrophic  and  atrophic  forms  of  arthritis  deformans.  It 
should  be  recalled,  however,  that  Wynne  has  described  bony  out- 
growths about  the  joints  in  gout.  The  joint  distortions  of  arthritis  defor- 
mans are  very  common  in  women  while  those  of  gout  are  rare. 
Garrod's  uric  acid  thread-test  should  be  tried,  and  a  positive  result  would 
indicate  chronic  gout.  The  frequently  used  term  "rheumatic  gout" 
should  be  abandoned.  The  disease  for  which  it  stands  has  nothing  to  do 
with  gout  and  should  be  called  arthritis  deformans. 

A  chronic  arthritis,  accompanied  by  marked  arteriosclerosis  and  a 
urinary  picture  of  chronic  interstitial  nephritis,  should  strongly  suggest 
gout  as  its  origin. 

The  diagnosis  of  the  irregular  forms  of  gout  in  which  there  have  been 
no  articular  manifestations,  often  presents  great  difficulty  and  is  subject 
to  much  uncertainty.  The  existence  of  a  family  history  of  gout  is  very 
important  in  arriving  at  the  basal  cause  in  these  cases. 

The  writer's  personal  conviction  is  that  gout  in  this  country  is  much 
more  prevalent  than  is  generally  supposed.  Many  cases  of  the  acute,  and 
particularly  of  the  chronic,  form  are  mistaken  for  rheumatism,  owing  to* 
the  failure  of  the  physician  to  ascertain  the  family  history,  the  patient's 
habits,  the  history  of  the  early  arthritic  attacks,  and  to  search  for  evidences 
of  tophi  in  the  ears  or  elsewhere.  It  is  important  to  enter  a  protest  against 
the  tendency  in  certain  quarters  to  ascribe  nearly  every  obscure  symptom, 
usually  those  of  nervous  or  gastric  origin,  to  a  gouty  diathesis.  The  idea 
that  migrain  attacks,  accompanied  though  they  may  be  by  a  precipitation 
of  uric  acid  or  urates  in  the  urine,  are  due  to  a  uric  acid  dyscrasia,  is  based 
on  evidence  that  is  far  from  convincing. 

Prognosis. — Once  manifestations  of  gout  have  made  their  appearance, 
they  are  likely  to  recur  at  intervals  throughout  subsequent  life.  It  occa- 
sionally happens,  however,  that  a  patient,  who  in  earlier  years  has  been  sub- 
ject to  recurring  attacks  of  arthritis,  may  never  show  any  manifestations 
after  the  fiftieth  or  sixtieth  year.  This  may,  in  part,  be  a  result  of  treat- 
ment, particularly  as  regards  the  habits  of  living,  but  it  occasionally  occurs 
spontaneously,  without  the  aid  of  therapeutic  measures.  It  is  the  later 
fact  that  should  make  us  rather  conservative  in  drawing  conclusions  re- 
garding the  effect  of  any  line  of  treatment.  A  fatal  termination  is  unusual 
in  the  acute  stages  of  the  disease,  although  it  may  occur  from  the  severity 
of  the  symptoms  resulting  from  retrocedent  or  "metastatic"  gout.  The 
duration  of  life  is  not  likely  to  be  materially  shortened,  so  long  as  the 
disease  maintains  its  regular  character  with  distinct  arthritic  manifesta- 
tions.   Often  when  these  appear  to  play  a  much  less  prominent  part  in  the 


836  CONSTITUTIOXAL  DISEASES 

gouty  picture,  visceral  complications  are  likely  to  arise  which  may  hasten 
the  patient's  death.  The  fatal  termination  in  chronic  gout  cases  is  usually 
due  to  uraemia,  myocarditis  with  dilatation  of  the  hearty  or  to  pericarditis. 
As  we  well  know,  the  victims  of  regular  gout  often  live  to  an  advanced 

Treatment. — Until  we  know  with  positive  certainty  the  actual  basal 
cause  for  gout,  the  treatment  of  the  disease  must  necessarily  be  largely 
empirical.  There  is,  as  we  have  seen,  a  steadily  growing  belief  that  the 
symptoms  of  gout  are  not  directly  traceable  to  the  action  of  uric  acid. 
The  pathological  findings  indicate,  however,  that  uric  acid  and  its  salts 
play  a  conspicuous  part  in  the  lesions.  We  have  no  positive  proof  that 
uric  acid  in  itself  is  toxic,  and  investigators  are  inclined  to  interpret  the 
excess  of  uric  acid  in  the  blood,  and  the  deposition  of  sodium  biurate  in 
the  tissues  as  secondary  manifestations  and  to  be  rather  the  result  than 
the  cause  of  the  disease.  Just  what  part  the  products  of  intermediary 
purin  metabolism  play  in  the  actual  etiology  remains  to  be  seen.  That 
purin  metabolism  is  markedly  disturbed  is  generally  recognized,  and  its 
best  indication  is  the  constant  occurrence  of  an  excess  of  uric  acid  in  the 
circulating  blood.  Subsequent  investigations  may  teach  us  what  influ- 
ences favor  or  retard  the  action  of  the  various  purin  enzymes  which  we 
have  previously  discussed.  The  various  therapeutic  measures  we  have 
been  accustomed  to  use  in  the  treatment  of  gout  have  been  directed  mainly 
toward  influencing  puv'in  metabolism,  and  particularly  with  the  object 
in  view  of  reducing  the  excess  of  uric  acid  in  the  blood.  It  is  conceivable 
that  this  reduction  may  be  brought  about  in  one  or  more  of  the  following 
ways:  (1)  diminishing  the  formation  of  uric  acid;  (2)  increasing  its 
elimination;  (3)  increasing  the  rapidity  of  its  oxidation  in  the  body; 
(4)  increasing  its  solubility  in  the  blood  and  tissue  juices. 

Prophylaxis  in  Members  of  Gouty  Families. — In  families  in  which 
there  is  a  marked  history  of  hereditary  gout,  something  may  be  done  to 
lessen  the  liability  of  individual  members  to  develop  active  manifestations 
of  the  disease.  I3y  temperate  living,  abstaining  from  alcohol,  and  eating 
moderately,  the  risks  are  materially  diminished.  An  active  outdoor  life, 
with  plenty  of  exercise  and  regular  hours,  will  do  much  to  keep  an  inborn 
tendency  to  the  disease  in  abeyance. 

The  treatment  of  the  disease  after  actual  manifestations  have  made 
their  appearance  may  be  discussed  under  various  headings :  Hygienic, 
dietetic,  alkalis  and  mineral  waters,  medicinal,  local  measures,  and 
operative  treatment. 

Hygienic. — Gout,  as  we  know,  prevails  chiefly  among  well-to-do  indi- 
viduals who  are  not  forced  to  make  a  livelihood  by  following  occupations 
requiring  even  the  average  amount  of  physical  exercise.  Many  manifest  a 
tendency  to  obesity  and  frequently  lead  sedentary  lives.  It  is  most  im- 
portant, therefore,  to  encourage  in  these  persons  a  more  active  outdoor 
life  requiring  physical  exercise  in  moderation.  This  must  not  be  over- 
done, and  must  be  confined  within  the  limits  of  fatigue,  for  we  know  that 
an  acute  attack  may  be  precipitated  by  excessive  physical  exertion.  The 
patient  should  be  encouraged  to  do  a  certain  amount  of  walking  each  day, 
and  a  particularly  useful  exercise  is  horseback  riding,  owing  to  the 
beneficial  effect  it  has  on  the  intestinal  functions.  Golf  can  be  highly 
recommended,  as  it  gets  the  patient  into  the  open  air,  is  not  too  violent, 


GOVT  837 

and  commands  a  certain  fascination  for  individuals  of  all  ages  As  an 
adjunct  to  outdoor  exercise,  certain  indoor  gymnastics  may  be  with 
advantage  prescribed,  such  as  the  use  of  dumb-bells,  Indian  clubs,  and  the 
various  forms  of  resistance  movements.  Massage  will  increase  the 
muscular  tone,  stimulate  the  circulation,  and  tend  to  improve  the  general 
metabolic  functions.  The  skin  functions  should  be  increased  by  system- 
atic bathing.  In  the  sthenic  cases  cold-baths  may  be  used,  and,  where 
there  is  a  tendency  to  obesity,  with  no  contra-indications  in  the  way  of 
valvular  or  myocardial  disease,  an  occasional  Turkish  bath  may  be 
taken  with  advantage.  The  bowels  should  be  carefully  regulated.  The 
patients  should  dress  warmly,  avoid  rapid  changes  in  temperature,  and 
be  careful  not  to  have  the  skin  suddenly  chilled. 

Dietetic. — The  regulation  of  the  food  is  undoubtedly  a  most  important 
factor  in  the  treatment.  Meat  is  the  article  of  diet  that  has  been  supposed 
to  possess  the  most  baneful  influence,  and  over  which  there  has  been  the 
most  discussion.  We  have  had  the  most  diverse  advice  as  to  what  re- 
strictions in  this  direction  should  be  made.  Wollaston,  a  century  ago,  and 
Haig,  of  the  present  day,  advise  a  complete  exclusion  of  the  meat  and  insist 
on  the  efficacy  of  a  strict  vegetable  diet.  Armstrong  and  Wainwright 
go  to  the  other  extreme  and  recommend  the  "Salisbury"  or  exclusive 
red  meat  diet.  Von  Mering  and  Pfeiffer  take  an  intermediate  course  and 
advise  against  any  restriction  of  the  meats,  even  advising  them  to  be  given 
in  moderate  excess.  This  remarkable  difference  of  opinion  has  been,  in 
large  part,  due  to  the  fact  that  the  true  source  of  the  uric  acid  was  not 
known  until  quite  recent  years.  So  long  as  the  erroneous  view  prevailed, 
that  uric  acid  was  a  mere  antecedent  of  urea,  it  was  natural  that  there 
should  be  a  tendency  to  restrict  the  richest  nitrogen-containing  ingredient 
of  the  food.  We  now  know  that  by  far  the  largest  proportion  of  uric 
acid  is  derived  from  the  "endogenous"  purins  of  the  body,  and  a  much 
smaller  proportion  from  the  "exogenous"  purins  of  the  food.  It  was 
also  claimed  that  the  red  meats  and  game  were  especially  to  be  avoided; 
but  recent  investigations,  by  Kaufmann  and  Mohr,  show  that  there  is  no 
greater  uric  acid  output  when  a  person  is  fed  on  red  and  dark  meats  than 
when  he  is  given  white  meats  in  the  same  amounts.  If  the  former  are  in 
any  way  more  injurious,  this  is  probably  referable  largely  to  the  fact  that 
they  are  less  easily  digested.  They  are  supposed  by  some  to  be  slightly 
richer  in  the  extractives  belonging  to  the  xanthin  series,  but  investigations 
have  not  shown  this  to  be  the  case.  The  balance  of  evidence  at  the  pre- 
sent day  is  against  the  exclusion  of  meats,  and  in  favor  of  their  being 
allowed  in  moderate  amounts.  As  many  gout  patients  are  excessive  meat 
eaters,  it  is  often  advisable,  from  time  to  time,  to  limit  the  meats  to  one 
meal  a  day. 

The  proteid  foods  that  are  considered  particularly  injurious,  are  those 
rich  in  cell  nuclei  and,  consequently,  containing  an  abundance  of  purin 
bodies.  These  comprise  the  thymus  (sweet  breads),  liver,  kidney,  and 
brain.  Weintrand,  Umber,  and  Rosenfeld,  have  found  that  they  cause  a 
marked  increase  in  the  uric  acid  excretion,  and  in  the  amount  of  uric  acid 
sediment. 

The  meat  extracts  are  to  be  avoided,  owing  to  their  richness  in  nitrog- 
enous extractives  and  salt.     Straus  and  Eitner  found  that  the  uric  acid 


838  CONSTITUTIONAL  DISEASES 

excretion  was  increased  one  to  one  and  a  half  times  after  the  giving  of 
50  grams — a  very  hirgc  dose — of  Liebig's  meat  extract. 

Fresh  fish  may  be  permitted  in  moderation,  bnt,  weight  for  weight,  it  has 
been  shown  that  they  canse  just  as  hirge  a  uric  acid  output  as  do  meats. 
Salt  fish  should  be  avoided.  Fish  roe  and  caviar  should  be  forbidden, 
owing  to  their  richness  in  nuclein,  although  in  the  latter  it  is  in  the  form  of 
paranuclein. 

Eggs  constitute  the  most  valuable  ])roteid  food  for  gout  patients,  in 
that  they  are  free  from  purin  bodies.  JNIilk,  for  the  same  reason,  is  also 
most  useful.  There  is  no  scientific  basis  for  the  belief  by  some  that 
cheese  should  be  excluded  from  the  diet.  According  to  the  analyses  of 
Rosenfeld  and  Orgler,  casein  does  not  cause  an  increase  in  the  uric 
acid  excretion.    Cheese  may  therefore  be  permitted  in  moderation. 

Starchy  foods  may  be  freely  allowed.  An  exclusive  starch  and  vege- 
table diet  has  its  advocates  still,  but  their  number  is  gradually  diminishing. 
Bread,  rice,  potatoes  and  other  garden  vegetables,  may  form  a  liberal 
portion  of  the  dietary.  Cucumbers  and  tomatoes  had  better  be  avoided. 
In  Germany,  particularly,  the  vegetable  albumins  have  been  more  or  less 
extensively  used  as  a  proteid  food,  and  as  a  partial  substitute  for  bread  in 
gout.    Of  these,  alearonat  and  roborat  have  been  most  extensively  used. 

Until  recent  years  the  prevailing  belief  had  been  that  fruits  were 
harmful.  It  was  thought  that  the  acids  contained  in  the  fruits  were 
injurious.  Since  the  time  of  Wohler,  however,  it  has  been  held  that 
the  acid  combinations  in  the  fruits  are  oxidized  in  the  system  into  car- 
bonates and  consequently  fruit  must  be  considered  an  alkaline  nourish- 
ment. The  best  opinion  at  the  present  day  favors  the  free  use  of  fruits. 
The  experience  in  any  individual  case  is  the  best  teacher  in  this  regard, 
however,  for  certain  fruits  such  as  bananas  and  strawberries,  particularly 
the  latter,  are  liable  to  excite  joint  pains,  and  to  cause  pharyngeal  symp- 
toms. 

Fats,  in  the  form  of  butter  particularly,  may  be  allowed  with  freedom; 
and  butter  in  large  quantities  has  been  advocated  by  Ebstein. 

All  highly  seasoned  foods  should  be  forbidden.  Pepper,  paprika,  and 
mustard,  should  not  be  permitted  in  dressings.  Their  only  injurious 
effect  is  through  impairment  of  the  digestive  functions.  Vinegar  should 
be  avoided.  Sir  William  Roberts,  who  maintains  that  the  sodium  salts 
are  injurious,  in  that  they  diminish  the  solubility  of  the  urates  and  favor 
their  deposition,  advises  strongly  against  the  use  of  sodium  chloride  in  the 
food.     He  recommends  potassium  chloride  as  a  substitute. 

It  will  be  seen  from  the  foregoing  that  the  most  diverse  views  have  pre- 
vailed concerning  the  proper  diet  in  gout.  No  set  rules  can  be  laid 
down.  The  diet  in  each  individual  case  must  be  carefully  considered. 
In  general  terms  it  may  be  said  that  the  proteid  foods,  particularly  those 
rich  in  nuclein  or  purin  derivatives,  should  be  limited  but  not  excluded. 
The  general  conviction  at  the  present  day  is  that  quantity  plays  a  more 
important  part  than  quality,  in  gout.  This  is  the  conclusion  recently 
arrived  at  by  Minkovrski,  who  has  carefully  reviewed  the  subject.  The 
duty  of  the  physician  is  to  see  that  the  patient  does  not  overeat,  and  to 
keep  his  digestive  functions  in  the  best  possible  condition. 

The  majority  of  gout  patients  are  better  off  without  any  alcoholic  bev- 
erages.    Individual  experience  soon  teaches  the  victim  that  his  general 


GOOT  839 

"health  is  better  and  that  he  is  freer  from  attacks  by  totally  abstaining 
from  alcohol.  The  fermented  beverages  are  those  most  liable  to  occasion 
a  lighting  up  of  the  arthritic  manifestations.  The  mere  indulgence  in  a 
glass  of  beer  or  wine  not  infrequently  excites  in  a  few  hours,  or  even  min- 
utes, twinges  of  pain  in  the  joints.  When  alcohol  is  indicated,  as  it  some- 
times is  in  the  asthenic  cases  with  cardiac  symptoms,  whisky  or  brandy 
may  be  prescribed  and  does  least  harm.  On  the  other  hand  the  richer 
wines,  such  as  port,  sherry,  Madeira,  champagne,  and  Burgundy,  and 
strong  ales  and  stout,  are  very  likely  to  provoke  symptoms.  In  Germany 
and  England,  where  wine-drinking  is  commoner  than  in  this  country, 
there  is  a  tendency  to  rather  greater  leniency  in  the  use  of  wine, 
and  the  lighter  forms,  such  as  the  Moselle  wines,  are  permitted  in 
moderation. 

There  seems  no  just  reason  why  coffee,  tea,  and  cocoa,  should  be  ex- 
cluded from  the  dietary,  as  has  been  advised  by  some.  It  was  held  that 
the  purin  derivatives  they  contain — caffeine,  adenin,  theobromine,  and 
theophyllin— might  be  a  source  for  increased  uric  acid  formation,  Rost, 
Albanase,  and  others,  have  shown  that  caffeine  and  theobromine  are  ex- 
creted, in  part  unchanged,  in  the  urine,  and  in  part  they  are  converted  into 
heteroxanthin,  but  they  have  not  been  shown  to  be  oxidized  into  uric  acid. 

The  gout  patient  should  be  induced  to  drink  freely  of  water,  par- 
ticularly on  an  empty  stomach  early  in  the  morning  and  before  the  various 
meals.  There  is  no  positive  proof  that  the  drinking  of  water  itself 
causes  any  material  increase  in  the  uric  acid  elimination,  but  experience 
has  proved  the  beneficial  effect  of  the  procedure. 

Alkalis  and  Mineral  Waters. — Although  alkalis  have  been  very  highly 
recommended  on  many  sides  in  the  treatment  of  gout,  owing  to  their 
supposed  effect  in  increasing  the  alkalinity  of  the  blood  and  consequently 
rendering  the  contained  uric  acid  combinations  more  soluble  and  more 
readily  excreted,  there  has  in  recent  years  been  a  growing  skepticism 
of  their  efficiency.  Freudberg  has  shown  that,  in  the  doses  in  which 
they  are  usually  given  in  gout,  it  is  extremely  doubtful  whether  the  alka- 
linity of  the  blood  is  at  all  increased.  A  serious  fallacy  also  arises  from 
concluding  that,  because  an  alkaline  salt  increases  the  solubility  of  uric 
acid  in  a  test-tube,  it  is  also  going  to  have  the  same  effect  in  the  circu- 
lating blood,  where  the  medium  is  much  more  complex  and  where  the 
uric  acid  combination  is  entirely  different. 

Since  Garrod  confirmed  the  observation  of  Lipowitz  that  lithium  urate 
was  very  soluble  in  water,  and,  in  1858,  first  recommended  the  use  of  lith- 
ium carbonate  in  the  treatment  of  the  disease,  the  various  lithium  salts 
have  been  held  in  high  favor.  Lithium  carbonate  and  lithium  citrate,  in 
an  effervescing  tablet  of  5  grains,  dissolved  in  a  tumbler  of  water  and  ad- 
ministered 4  or  6  times  daily,  are  still  popular  remedies.  Potassium 
citrate,  or  carbonate,  in  20  to  30  grain  doses  (gm.  1 .3  to  2)  4  times  daily, 
may  be  given.  Roberts  and  Bain  advise  strongly  against  the  use  of 
sodium  salts,  as  they  claim  that  they  are  much  less  powerful  uric  acid 
solvents  than  the  potassium  preparations.  The  urates  of  soda  are  also 
held  to  be  less  soluble  than  those  of  potash.  These  various  alkalis  are  un- 
doubtedly beneficial,  but  it  is  generally  conceded  that  their  salutary  action 
is  due  rather  to  the  liberal  quantities  of  water  with  which  they  are  admin- 
istered than  to  the  effect  of  the  drugs  themselves. 


840  CONSTITUTIONAL  DISEASES 

Mineral  waters  have  ahvays  played  an  important  part  in  the  treatment  " 
of  gout.    All  forms  may  be  said  to  be  beneficial,  but  the  good  effects  are 
due  more  to  the  water  than  to  the  contained  salts.    As  Osier  says,  "Much 
of  the  humbuggery  of  the  profession  still  lingers  about  mineral  waters, 
more  particularly  about  the  so-called  lithia  waters." 

It  is  a  curious  fact,  notwithstanding  that  Roberts  and  others  have  theo- 
retically demonstrated  the  injurious  influence  of  sodium  chloride  on  the 
gouty  individual,  that  it  is  just  those  continental  springs  which  contain  this 
salt  in  the  largest  quantities  to  which  gout  patients  flock  from  all  quarters 
of  the  world.  Roberts  points  out  that  an  acute  attack  is  often  precipitated 
very  soon  after  a  "cure"  is  begun  at  one  of  these  springs;  and  he  attrib- 
utes this  to  the  fact  that,  owing  to  the  excess  of  sodium  chloride  in  the 
blood,  the  latter  becomes  surcharged  with  sodium  biurate,  which  suddenly 
becomes  precipitated  in  and  about  the  joints,  setting  up  an  acute  attack. 
Curiously  enough,  such  an  explosion  is  usually  followed  by  a  period  of 
much  improved  health.  This  Roberts  attributes  to  the  temporary  freeing 
of  the  circulation  of  the  excess  of  uric  acid.  The  springs  that  contain  the 
alkahne  carbonates  and  alkaline  sulphates  are  also  in  rej:)ute,  and  their 
beneficial  action  is  in  large  part  due  to  the  salutary  effects  of  these  salts 
on  the  digestion. 

The  mineral  springs  best  suited  for  gouty  patients  in  this  country  are 
those  of  Saratoga,  Bedford,  and  White  Sulphur;  in  England,  Buxton,  Bath, 
and  Strathpeffer;  in  France,  Aix-les-Bains  and  Contrexeville;  in  Ger- 
many, the  Sauerling  spring  of  Carlsbad,  Wildbad,  and  Hamburg.  The 
drinking  of  water  at  home  in  large  quantities,  and  on  an  empty  stomach, 
is  beneficial  but  not  so  much  so  as  at  one  of  these  springs,  where  the  acces- 
sories to  the  "cure"  mean  so  much.  The  modified  diet,  freedom  from 
business  worries  and  cares,  regular  hours,  proper  exercise,  baths,  douches, 
etc.,  are  important  adjuncts. 

Medicinal  Management  of  the  Acute  Attack. — The  patient  should  be 
kept  in  bed,  where  he  is  usually  quite  willing  to  remain  owing  to  the  sever- 
ity of  the  pain.  A  mild  saline  laxative  should  be  administered  at  the  out- 
set The  affected  joint,  where  conditions  permit,  as  in  the  case  of  that  of 
the  big  toe,  should  be  elevated,  and  wrapped  in  thick  layers  of  raw  cotton 
surrounded  by  oiled  silk.  In  this  way  the  joint  is  protected  from  acciden- 
tal pressure,  and  the  wool  acts  as  a  poultice,  inducing  local  sweating,  and 
also  swelling,  which  tends  to  relieve  the  acuteness  of  the  pain.  The  use 
of  warm  or  cold  applications  locally  must  depend  entirely  upon  the  rela- 
tive relief  experienced  by  the  patient  in  any  individual  case.  Local  ano- 
dynes may  be  tried  when  the  pain  is  severe.  A  lotion  of  laudanum  and 
water  in  various  proportions  may  be  applied.  Whisky  and  water,  applied 
quite  warm,  is  a  favorite  remedy.  Ichthyol  and  lanolin,  10  grains  to  the 
ounce,  may  be  tried.  Blisters,  and  counter-irritation  by  the  use  of  the 
cautery,  are  rather  to  be  avoided,  although  the  latter  may  give  some  relief. 
Some  have  claimed  that  the  length  of  an  attack  may  be  much  shortened 
by  beginning  early  to  induce  motion  of  the  joint  by  either  active  or  passive 
means.  Few  subjects  are  willing,  however,  to  consent  to  such  heroic 
measures.  Baking  in  the  dry  oven  may  ameliorate  the  pain.  It  is  worth 
while  to  try  the  effect  of  passive  hypersemia  on  the  pain  by  the  application 
of  a  tourniquet  or  Esmarch's  bandage  about  the  extremity  above  the 
joints,  for  periods  of  five  minutes  several  times  during  the  day,  as  recently 


GOVT  841 

recommended  by  Bier  and  others  in  painful  joint  affections.  In  certain 
instances  this  has  given  great  rehef. 

Colchicum  is  the  drug  most  likely  to  give  relief  from  the  pain.  This  is 
so  prompt  in  many  instances  that  it  is  often  referred  to  as  a  specific,  in 
much  the  same  sense  v\^ith  which  we  use  the  word  in  connection  with  qui- 
nine and  mercury.  It  was  first  introduced,  in  1763,  by  Storck,  who  recom- 
mended its  use  in  gout  and  rheumatism,  and  also  as  a  diuretic  and  drastic 
in  dropsical  conditions,  although  it  is  said  to  have  been  known  to  the 
Greek  and  Arabian  physicians  of  the  sixth  century,  as  a  remedy  for  gout, 
under  the  name  of  hermodactyl.  The  drug  may  be  administered  either 
as  the  wine  or  the  tincture  of  the  seeds,  preferably  the  former,  in  20  minim 
(cc.  1)  doses  every  two  hours  for  4  doses,  and  then  every  four  hours  until 
the  pain  is  relieved,  unless  untoward  physiological  effects  manifest  them- 
selves. The  relief  to  the  pain  is  usually  very  prompt,  but  how  it  is  effected 
is  not  at  all  well  understood.  It  must  be  discontinued  on  alleviation  of  the 
pain  because  it  is  not  known  to  have  any  direct  action  on  the  gouty  pro- 
cess. Its  active  principle,  colchicin,  is  also  in  use.  The  administration  of 
colchicum  may  be  abused  and  harm  done.  When  given  in  excess,  it  causes 
vomiting,  purgation,  and  cardiac  depression.  It  sometimes  happens  that 
colchicum  fails  to  give  relief.  In  these  cases  the  salicylic  acid  preparations 
may  be  tried.  Although  not  so  likely  to  give  early  relief  to  the  pain  as  in 
rheumatism,  yet  the  salicylates,  which  were  first  recommended  in  gout  by 
Germain  S6e,  are  held  in  high  repute  by  some  clinicians.  They  are  known 
to  increase  the  total  output  of  nitrogen  and  materially  to  augment  the  ex- 
cretion of  uric  acid.  It  is  not  agreed,  however,  that  their  beneficial  effect 
is  due  to  this  action.  They  may  be  given  as  sodium  salicylate,  oil  of  gaul- 
th^eria,  or  aspirin.  The  latter,  the  acetic  ester  of  salicylic  acid,  has  gained 
favor,  and  has  the  advantage  over  the  ordinary  salicylates  in  being 
less  injurious  to  the  stomach.  It  may  be  given  in  10  to  20  grain  (gm. 
0. 6  to  1.3)  doses  every  two  or  four  hours,  until  pain  is  relieved.  Antipy- 
rine  or  phenacetin  may  be  tried  for  the  pain,  but  must  be  used  with 
caution.  In  certain  cases  where  the  pain  is  excruciating  and  does  not 
yield  to  the  usual  remedies,  a  hypodermic  injection  of  morphia  should 
be  administered.  It  is  customary  to  give  the  patient  alkalis  during  the 
acute  attack.  Their  efficacy  is  doubtful.  The  citrate,  acetate,  or  bi- 
carbonate of  potash,  in  20  to  30  grain  (gm.  1.3  to  2)  doses  every  four 
hours,  administered  in  large  quantities  of  water,  should  be  tried.  Any 
benefit  obtained  is  probably  due  rather  to  the  water  than  to  the  alkali. 

The  diet  is  very  important  during  the  acute  attack.  It  should  be  as 
purin-free  as  possible.  A  diet  consisting  of  milk,  eggs,  butter,  white  bread, 
rice,  sago,  and  cheese,  is  free  from  nucleins.  For  the  first  day  or  two,  when 
the  fever  is  high,  it  is  well  to  restrict  the  patient  to  milk  and  barley-water. 
As  the  acute  symptoms  gradually  subside,  eggs  and  other  members  of  the 
above  list  may  be  added,  and  when  the  fever  entirely  disappears  small 
amounts  of  the  white  meats,  such  as  chicken,  etc.,  may  be  permitted. 

When  the  acute  symptoms  have  disappeared,  gentle  massage  to  the 
affected  joint  should  be  started,  and  active  and  passive  motion  encour- 
aged. If  the  patient's  means  will  permit,  he  should  be  sent  to  one  of  the 
mineral  springs  for  a  "cure,"  where  the  accessories  are  fully  as  important 
in  the  treatment  as  the  drinking  of  the  waters.  Where  this  is  not  possible, 
a  simple  bitter  tonic  should  be  prescribed  before  meals.   A  common  course 


842  CONSTITUTIONAL  DISEASES 

to  pursue  is  to  give  the  patient  a  prescription  containing  5  to  10  minims 
(cc.  0.3  to  0.6)  of  "wine  of  colchieum  Avith  the  same  number  of  grains  of 
potassium  iodide,  or  20  grains  (gm.  1.3)  of  pota.ssium  acetate  or  citrate 
after  each  meal  and  at  bedtime,  for  two  or  three  weeks.  The  patient 
should  be  induced  to  drink  freely  of  water  before  meals  and  on  retiring, 
to  restrain  his  appetite  within  reasonable  bounds,  and  to  indulge  in  some 
daily  exercise. 

The  Uric  Acid  Solvents. — Hardly  a  year  passes  without  one  of  these 
much  vaunted  remedies  being  introduced  to  the  medical  profession.  They 
almost  invariably  fail  to  justify  the  claims  made  for  them.  Just  as  in  the 
case  of  the  alkalis,  this  is  due  to  these  solvents  failing  to  act  in  a  com- 
plicated medium  like  the  blood-serum  as  they  do  in  a  test-tube. 

Of  the  organic  bases  claimed  to  be  uric  acid  sc)lvents,  the  first  put  on 
the  market  was  piperazin  (diethylenediamin).  With  uric  acid  it  forms 
pi])erazin  urate,  which  is  soluble  in  Avater  in  the  proportion  of  1  to  50, 
while  lithium  urate  is  soluble  in  1  to  368,  and  uric  acid  itself  in  1  to  38,000. 
It  w'as  concluded  that  it  would  be  an  ideal  remedy  for  keeping  the  uric 
acid  of  the  blood  in  an  easily  soluble  form,  and  also  for  causing  a  solution 
of  the  biurate  deposits  in  the  tissues,  and  of  uric  acid  calculi  in  the  kidneys 
or  bladder.  Experience  has  shown,  however,  that  its  administration  is 
not  followed  by  any  increase  in  the  uric  acid  output.  This  failure  is 
probably  explained  by  the  observation  that  when  several  salts  are  added 
to  uric  acid  in  a  test-tube  the  dissolving  action  of  the  piperazin  is  markedly 
reduced.  The  salts  of  the  blood  act  in  the  same  way.  The  other  solvents 
closely  related  to  piperazin  constitutionally,  lycctol  and  lysidin,  which 
had  a  temporary  vogue,  particularly  on  the  Continent,  have  failed  to  give 
the  results  claimed  for  them,  for  the  same  reason.  Piperazin-water  is  still 
in  use,  but  it  is  the  water  rather  than  the  piperazin  that  gives  rise  to  any 
beneficial  results  that  follow  its  administration. 

Urotropin  (hexamethyltetramine)  was  introduced  into  the  therapy  of 
gout  in  1898,  by  Nicolaier.  He,  with  Tollens,  His,  and  others,  demon- 
strated that  formaldehyde  formed  diformaldehyde  urate  with  uric  acid, 
which  is  soluble  in  water  in  the  proportion  of  1  to  300  to  1  to  400.  When 
urotropin  is  administered  to  an  individual  it  yields  formaldehyde  in  the 
organism,  which  in  part  is  excreted  in  the  urine  as  diformaldehyde  urate, 
— the  greater  part,  however,  in  other  combinations.  The  hope  that 
urotropin  would  increase  the  uric  acid  excretion  was  not  borne  out  by  the 
analyses  of  Rosenfeld  and  Orgler,  who  found  the  uric  acid  actually 
diminished,  and  by  Schreiber,  Avho  found  it  unchanged.  The  effect  of  the 
drug  in  gout,  therefore,  is  very  doubtful,  although  Nicolaier  and  Flexner 
claim  to  have  seen  benefit  in  a  few  cases.  Any  beneficial  effect  it  may 
have  in  the  treatment  of  uric  acid  calculi  may,  in  part  at  least,  be  referred 
to  the  antiseptic  action  of  the  formaldehyde  it  produces  in  the  system. 

Urea  has  been  used,  but  the  results  have  been  far  from  encouraging. 
Being  a  diuretic  it  may  do  some  good,  but  there  is  no  scientific  basis  for 
its  use. 

One  would  naturally  think  that  the  nuclein  bases,  or  any  allied  com- 
pounds, would  be  the  last  remedies  to  be  tried  in  gout  therapy,  knowing  as 
we  do,  that  uric  acid  is  largely  derived  from  them.  One  of  the  allied  com- 
pounds, thymic  acid,  which  is  claimed  to  be  "base-free,"  has  been  tried 
by  Minkowski,  who  found  in  one  case  that  the  uric  acid  excretion  was 


GOVT  843 

increased  and  that  there  was  apparently  a  diminution  in  the  size  of  some 
of  the  tophi. 

The  general  conclusion  to  be  drawn  from  the  experience  with  these 
various  uric  acid  solvents  is  that  they  are  practically  all  failures  so  far  as 
any  direct  effect  is  produced.  Their  possible  beneficial  action  results 
from  the  fact  that  the  patients  can  be  induced  to  drink  more  water  in  this 
way  than  without  medication. 

Remedies  to  Increase  the  Rapidity  of  Uric  Acid  Oxidation.— O-ry/^r/i 
inhalations  have  been  tried,  but  the  analyses  of  Honigmann  and  Krafft 
show  that  there  is  no  diminution  of  the  uric  acid  excretion,  and  no  evidence 
to  point  toward  its  increased  oxidation  in  the  system.  Thyroid  tablets 
and  spermin  have  been  used  for  the  same  purpose,  and  with  the  same 
results.  From  what  is  now  known  concerning  the  action  of  various 
enzymes  in  transforming  the  various  purin  bases  one  into  another,  and  of 
the  action  of  a  special  oxidase  in  destroying  uric  acid,  we  may  look 
forward  with  hope  that  some  therapeutic  means  may  yet  be  discovered  to 
influence  their  action. 

Local  Measures. — These  have  already  been  considered  in  the  manage- 
ment of  the  acute  attack. 

Operative  Procedures. — It  occasionally  happens  that  surgical  measures 
are  indicated.  When  joint  tophi  become  inflamed,  and  spontaneously 
open  and  discharge  biurates,  a  persistent  discharging  sinus  may  result. 
In  these  cases  eradication  of  the  tophus  is  advisable.  The  bursee  some- 
times become  inflamed,  swollen,  and  painful,  and,  in  some  instances,  free 
opening  of  them  gives  great  relief. 

Riedel  has  recently  operated  on  2  cases  with  gouty  arthritis  limited 
to  one  of  the  great-toe  joints.  A  mistaken  diagnosis  was  made  in  both 
instances,  the  arthritis  being  thought  to  be  due  to  a  suppurative  process. 
At  operation,  however,  it  was  found  that  the  arthritis  was  of  gouty 
origin.  The  joint  capsule  was  completely  removed  without  interfering 
with  the  bone,  and  the  edges  of  the  operation  incision  were  brought  to- 
gether without  the  use  of  sutures  In  both  instances  the  patients  lived  for 
years  with  no  recurrence  of  arthritic  attacks,  death  resulting  from  other 
causes.  On  the  basis  of  these  2  cases,  Riedel  recommends  the  ablation 
of  the  capsular  tissues  in  those  instances  in  which  the  arthritis  has  been 
confined  to  a  single  joint.  On  such  limited  experience,  it  does  not  do  to 
draw  any  definite  conclusions  as  to  the  advisability  of  operative  pro- 
cedures. The  removal  of  the  affected  joint  cannot  eradicate  the  metabolic 
disturbance  causing  the  disease.  Further,  we  know  that  patients  often  go 
for  years  without  recurrences  of  the  arthritic  symptoms. 

As  to  the  use  of  electricity  in  the  treatment  of  the  disease,  it  may  be  noted 
that  Remak  and  Benedikt  claim  to  have  obtained  good  results  by  the  use 
of  the  constant  current  locally  applied  to  the  aft'ected  joint,  both  in  the 
acute  as  well  as  in  the  chronic  form.  Labatut,  Jourdanet,  and  Levison, 
have  recently  reported  beneficial  results  by  the  use  of  electrical  endosmo- 
sis,  or  kathaphoresis,  with  lithion,  in  the  treatment  of  the  joints  and  skin 
tophi.  The  galvanic  current,  with  the  electrodes  moistened  with  a  con- 
centrated solution  of  lithion  chloride,  or  carbonate,  is  passed  through  the 
affected  joint  or  tophus,  or  is  given  in  the  form  of  an  electric  lithion  bath. 

General  Management  of  the  Ohronic  Oases. — The  regulation  of  the 
diet  stands  first  in  importance.   As  we  have  seen,  it  is  generally  agreed  that 


S44  CONSTITUTIONAL  DISEASES 

reduction  of  the  total  food  intake  is  of  more  importance  than  the  special 
restriction  of  any  one  of  the  three  varieties  of  foodstuifs.  In  the  case  of 
the  proteids,  those  that  are  most  easily  digested,  such  as  eggs,  fish,  and  the 
white  meats,  are  preferable.  Those  rich  in  nuclein,  such  as  sweetbreads, 
kidneys,  liver,  and  brain,  should  be  avoided.  If  any  change  be  made,  the 
vegetables  should  be  increased  at  the  expense  of  the  proteids.  The  pa- 
tient should  be  regular  in  his  meals. 

Plenty  of  exercise,  of  the  character  already  outlined,  should  be  taken. 
Worry,  and  all  unnecessary  psychical  disturbance,  must  be  avoided.  In 
the  case  of  podagra,  special  care  must  be  taken  to  secure  a  properly  fitting 
shoe.  The  individual  should  be  warmly  clad.  The  digestion  should  be 
looked  after,  and  any  tendency  to  constipation  counteracted. 

The  majority  of  patients  do  not  require  anything  medicinally,  excepting 
during  the  acute  exacerbations.  They  must  be  persuaded  to  drink  several 
glasses  of  water  daily  on  an  empty  stomach.  As  it  is  difficult  to  get  patients 
to  do  this,  the  object  can  be  more  easily  secured  by  having  them  take 
some  alkali,  such  as  a  5  grain  tablet  of  effervescent  carbonate  or  citrate  of 
lithia  dissolved  in  a  glass  of  water,  several  times  daily. 

Where  the  patient's  means  will  permit,  it  is  well  to  send  him  to  one  of 
the  mineral  springs  for  a  few  weeks'  "cure"  each  year,  where  the  acces- 
sories of  the  cure  mean  as  much  as  the  drinking  of  the  water  itself. 

Treatment  of  the  Complications. — In  cases  complicated  by  diabetes  the 
carbohydrates  should  be  restricted.  The  glycosuria  is  of  a  mild  type  and 
generally  yields  readily  to  dietetic  treatment. 

Where  there  are  evidences  of  a  serious  ?iep/in7r5,  the  proteids  should  be 
partially  cut  down.  If  urtemic  manifestations  supervene,  as  they  often 
do,  the  usual  measures  for  this  complication  should  be  tried. 

In  the  cases  with  an  increasing  tendency  to  obesity,  the  fats  and  carbohy- 
drates should  be  cut  down,  and  proteids  permitted  in  larger  amounts  than 
would  be  allowed  in  the  average  case. 

The  cardiac  complications  require  especial  attention.  In  the  cases 
with  evidences  of  myocardial  weakness,  the  usual  cardiac  stimulants  and 
tonics  are  indicated.  If  the  condition  be  not  a  too  serious  one,  and  the 
patient's  circumstances  permit,  a  course  of  baths  at  the  Nauheim  Springs, 
in  Germany,  may  help  the  cardiac  features,  and  will  also  tend  to  alleviate 
the  ordinary  gouty  symptoms.  Where  the  patient  cannot  be  sent  away, 
a  substitute  may  be  made  for  the  Nauheim  baths  by  the  use  of  the  Triton 
Effervescent  Salts,  prepared  in  this  country.  Still  the  writer  knows  of 
patients  with  cardiac  disease  who  have  actually  been  injured  by  this 
treatment  and  feels  that  the  greatest  caution  must  be  used  in  advising  it. 


CHAPTER  XXXII. 

OBESITY. 

By  JAMES  M.  ANDERS,  M.  D. 

Synonyms. — Lipomatosis  universalis;  adiposity;  corpulency;  fat- 
ness. 

Definition. — Obesity  is  a  metabolic  disorder,  commonly  assuming  the 
form  of  hypernutrition,  and  is  chai'acterized  anatomically  by  an  exces- 
sive amount  of  bodily  fat;  it  assumes  clinical  importance  v^hen  the  fat 
deposits  throughout  the  body  become  burdensome  or  produce  impair- 
ment of  the  functions,  as  shown  by  disinclination  to  muscular  exercise,  pal- 
pitation, dyspnoea,  and  other  features.  The  condition  is  associated  with, 
and  dependent  on,  a  variety  of  underlying  affections;  so  that  it  may  be 
rightly  regarded  as  a  symptom  rather  than  a  pathological  entity.  The 
far-reaching  importance  of  due  attention  to  this  fact  in  the  treatment  of 
obesity  is  exemplified  in  the  success  which  attends  the  removal  of  the  caus- 
ative states. 

Historical. — As  early  as  the  sixth  century,  Coelius  Aurelenius  applied, 
although  Avithout  justification,  the  term  polysarcia  to  this  disorder.  The 
Greeks  and  Romans  adopted  hygienic  means,  principally  mechanical, 
against  the  development  of  obesity, '  and  in  their  lighter  literature  as 
well  as  that  of  Persia,  Japan,  and  China,  frequent  allusions  are  made  to 
the  "overweighted  and  irascible  victims  of  gout,"  ardent  votaries  of  fash- 
ion and  the  pleasures  of  the  table.  The  subject  of  corpulency  occupied 
the  mind  of  Hippocrates,  who  likewise  discoursed  lengthily  on  a  fatty  diet- 
Later,  Celsus  made  important  contributions  to  the  prophylaxis  of  obesity; 
and  this  disease  constituted  one  of  the  principal  humors  of  Galen's  system. 

The  older  authors  entertained  a  just  appreciation  of  the  serious  compli- 
cations and  sequelse  of  obesity,  and  the  burden  of  their  instructions  in  the 
absence  of  therapeutic  resources  had  to  do  with  prophylactic  measures. 
They  noted  with  painful  interest  that  important  lives  were  shortened  from 
the  thoughtless  enjoyment  of  vinous  potations  and  over-indulgence  in  eat- 
ing. The  writers  of  antiquity,  however,  and  this  is  especially  true  of  those 
of  the  middle  ages,  manifested  a  total  ignorance  of  the  nature  of  the  meta- 
bolic processes  involved  in  nutritional  disorders;  and  their  methods  of 
treatment  consisted  of  external  measures  alone,  such  as  out  of  door  exer- 
cise, sea  baths,  and  active  hand-rubbing  of  the  body,  either  respectively  or 
unitedly. 

In  1718,  Rhotonet,  a  Parisian  surgeon,  "excised  nine  pounds  of  fat  from 
the  abdomen  of  a  well-known  person  and  thus  relieved  her"  (Oertel). 
During  the  seventeenth  and  eighteenth  centuries,  numerous  papers  were 
published  on  obesity,  but  no  real  advances  in  knowledge  either  of  the  patho- 
genesis or  treatment  of  the  condition  were  accomplished.     No  definite 

845 


846  CONSTITUTIOXAL  DISEASES 

scientific  investigations  into  the  nature  and  causes  of  the  disease  were 
undertaken  until  the  nineteenth  century,  when  J.  V.  Liebig  prosecuted 
valuable  labors  in  connection  with  the  origin  of  overfatness.  From  that 
time  on,  our  knowledge  of  the  subject  of  adipose  tissue  and  nutrition  was 
elaborated,  not  wholly,  but  princij)ally,  by  the  labors  of  M.  v.  Pettenkofer, 
Harvey,  Voit,  J.  jSlunk,  Vogel,  Toldt,  Virchow,  Flemming,  Leyden,  Unna, 
von  Noorden,  Ebstein,  antl  Oertel. 

These  authors  have  experimentally  established  the  origin  of  fat  from 
carbohydrates,  albumin,  and  fats,  and,  moreover,  have  elucidated  the 
causes  and  jiathological  processes  involved  in  nutrition,  hypernutrition 
(fatness),  and  subnutrition  (leanness).  Perhaps  most  disagreement  exist- 
ing between  investigators  in  this  field  has  reference  to  the  histological 
relations  of  adipose  tissues.  A  few  epoch-making  events  stand  out 
prominently.  Thus,  Leyden  showed  the  important  and  far-reaching 
connection  between  coronary  artery  disease  and  certain  myocardial 
lesions  met  with  in  fatty  overgrowth.  Another,  and  practically  a  first,  step 
in  advance  in  our  therapeutic  resources,  was  the  introduction  of  thyroid- 
feeding  in  the  treatment  of  this  disease. 

The  recent  literature  of  nutrition  has  attained  to  considerable  propor- 
tions and  among  the  most  valuable  researches  on  the  subject  are  those  of 
]Moleschatt,  Ranke,  Voit,  and  Forster,  whose  combined  studies  have 
given  us  an  accurate  determination  of  the  food  requirements  under  normal 
conditions.  ]\Ietabolic  investigations  have  also  proved  that  obesity  may 
result  from  inordinate  stimulations  of  the  physiological  functions  due  to 
over-alimentation  as  well  as  by  all  the  processes  which  tend  to  slow  the  or- 
ganic oxitlations. 

Varieties. — Two  leading  forms  are  recognized:  the  plethoric  and  the 
anfemic.  These  may  merge  into  a  third,  or  hydrtemic,  form,  and  there 
are  many  transitions  between  the  two  typical  varieties.  The  anaemic 
variety  reaches  the  hydrgemic  stage  much  earlier  than  the  plethoric, 
and,  according  to  personal  experience  and  observation,  only  a  fragment  of 
the  cases  composing  the  plethoric  group  merge  into  the  terminal  stage  of 
the  disorder.  These  differences  in  the  general  course  and  tendencies  of 
the  different  varieties  of  obesity  will  become  evident  on  noting  the  causes 
to  which  they  are  attributed.  A  division  of  the  cases  of  obesity  into  gen- 
eral and  local  should  also  be  attempted  in  practice  (vide  infra). 

Etiology. — Certain  predi.sposi?] g  causes  should  be  prominently  men- 
tioned,— heredity,  age,  sex,  sedentary  occupation,  temperament,  enforced 
rest,  habit,  and  climate. 

Predisposing  Causes. — Heredity. — Heredity  was  clearly  traceable  in 
330  (or  60.7  per  cent.)  of  543  cases  occuring  in  the  writer's  experience,  and, 
in  some  instances,  through  several  generations;  it  caimot  be  said  to 
depend  upon  the  indolence  of  ancestors  so  much  as  upon  peculiarities  of 
the  digestive  and  assimilative  powers.  In  this  group,  a  history  of  gout 
among  the  antecedents  is  also  commonly  observed.  Thus,  podagra  due 
to  heredity  or  in  actual  association  with  the  obesity  was  noted  in  235  (or 
43.2  per  cent.)  of  this  series  of  543  cases.  "Rheumatism"  was  present 
in  104  (or  35.5  percent.)  of  the  cases.  These  figures  indicate  a  close  and 
vital  connection  between  gout  ("rheumatism"),  and  obesity. 

Hereditary  disposition  to  gout  having  been  established  beyond  perad- 
venture,  may  serve  to  explain  why  heredity  is  commonly  noted  in  obesity. 


OBESITY  847 

In  general  terms,  it  may  be  said  that  gouty  subjects,  in  whom  a  moderate 
degree  of  obesity  is  frequently  associated,  manifest  a  reduced  oxidizing 
energy,  as  evidenced  by  a  low  haemoglobin  content  of  the  erythrocytes.  In 
many  instances  of  the  sort  the  red  corpuscles  are  normal  or  even  increased, 
while  the  haemoglobin  percentage  may  be  as  low  as  70.  Per  contra,  the 
assumption  advanced  by  Oertel,  that  "persons  whose  albumin-bearing 
tissue,  especially  muscular  and  glandular  tissue,  exhibits  a  strong  power 
of  growth,  in  order  to  satisfy  the  cellular  vital  requirement,  are,  therefore, 
less  liable  to  become  obese  than  others  whose  hereditary  constitution 
lacks  this  energy  of  growth  and  nutrition,"  is  fully  confirmed  by  the 
observations  of  the  writer.  Again,  granted  that  a  preformed  fatty  tissue 
exists  as  an  independent  organ,  inherited  qualitative  peculiarities  would 
account  for  the  predisposition  to  an  abnormal  accunuilation  of  fat  in  some 
cases  at  least.  This  view  is  supported  by  the  fact  that  the  definite  parts 
showing  normally  the  largest  fat  deposits,  are  primarily  those  in  which 
excessive  or  abnormal  accumulations  principally  occur. 

Hereditary  predisposition  manifests  itself  early  in  life  by  the  appearance 
of  well-marked  corpulency,  but  it  may  not  show  itself  until  a  later  period 
or  until  some  trivial  exciting  cause  becomes  operative.  An  inherited  taint 
is  more  commonly  observed  in  females  than  males.  Atavism  may  occur. 
With  Kisch,  Oertel,  and  others,  the  writer  agrees  that  heredity  is  not 
more  pronounced  in  the  same  sex  (e.  g.,  from  father  to  son,  and  mother  to 
daughter,)  since  his  collective  investigations  tend  to  disprove  this  claim. 

Age. — ^The  general  tendency  to  an  abnormal  accumulation  of  fat  is  more 
pronounced  at  certain  periods  of  life  than  others;  but  this  variability  may 
not  be  dependent  on  the  age  per  se,  inasmuch  as  it  is  difficult  to  disassociate 
the  influence  of  habit,  alimentation,  and  many  other  factors.  In  young 
infants,  a  marked  degree  of  obesity  may  occur,  and  in  many  cases  it  is  prin- 
cipally ascribable  to  the  milk  and  farinaceous  articles  of  food  consumed  in 
the  diet.  This  form  of  infantile  corpulency  is  apt  to  disappear  subse- 
quently, although  it  may  reappear  later  on  in  life,  especially  when  a 
radical  change  in  the  habits  occurs. 

On  the  other  hand,  in  a  certain  proportion  of  the  cases  of  obesity  com- 
mencing at  birth,  a  slow  and  gradual  increase  in  the  amount  of  fatty  tissue 
may  take  place  during  childhood  and  adolescence.  In  the  majority  of 
instances,  however,  corpulency  develops  later  in  life,  in  the  male  during  the 
period  between  forty  and  fifty  years,  and  in  the  female  during  the  two 
decades  between  thirty  and  fifty  years.  The  favoring  influence  of  puberty 
apart,  during  adolescence,  a  period  of  life  in  which  enormous  quantities  of 
nutritive  material  are  demanded  by  the  organism,  the  tendency  is  toward 
a  decrease  of  adipose  tissue.  Again,  in  advanced  years,  when  retrograde 
metabolic  processes  occur,  the  conditions  favoring  an  abnormal  accumula- 
tion of  fat  are  missing. 

Sex. — Obesity,  under  normal  conditions  of  life,  is  more  common  by 
far  in  the  female  than  in  the  male.  Personal  experience  and  observa- 
tions confirm  the  view  that,  owing  to  the  lower  percentage  of  haemoglobin 
in  women  in  comparison  with  men,  the  oxidizing  energy  is  correspond- 
ingly diminished,  and  hence  a  greater  tendency  to  transformation  of  the 
carbohydrates  into  fat  is  the  natural  consequence.  In  the  causation  of 
obesity,  a  prominent  role  is  ascribable  to  childbirth.  The  condition  dated 
from  the  puerperium  in  16.2  per  cent,  of  the  writer's  series  in  females,  and 


848  CONSTITUTIOXAL  DISEASES 

from  miscarriage  in  5.3  per  cent.  In  multipara,  each  subsequent  preg- 
nancy increased  the  general  tendency  to  obesity,  in  some  cases  at  least. 

Other  factors  expressly  favorable  to  the  development  of  an  abnormal 
amount  of  fat  in  the  female  are:  The  more  quiet,  inactive  life,  the  greater 
tendency  to  indulgence  in  fat-forming  articles  of  diet,  puberty,  and  the 
menopause  (slight).  With  reference  to  the  menopause,  Tilt's  statistics 
are  significant:  Hb  studied  382  cases  in  women  in  whom  the  menstrua- 
tion had  completely  ceased  for  five  years,  and  found  that  121  had  grown 
heavier,  171  had  retained  their  former  weight,  while  90  had  become 
lighter.  When  the  menoj)ause  leads  to  greater  corpulence  it  is  mani- 
fested especially  by  the  ac(juisition  of  an  evihowpoint.  While  the  aniemic 
type  of  the  disease  is  more  connnon  in  the  chlorotic  female,  more  cases 
of  the  plethoric  type  are  met  with  in  the  male. 

Temperament,  Occwpation  and  Enforced  Rest. — The  indolent,  sluggish, 
luxury-  and  rest-loving,  phlegmatic  individual  is  disposed  to  corpulency. 
This  fact  affords  a  satisfactory  explanation  why  obesity  is  so  commonly 
observed  among  certain  races — southern  Italians,  Orientals,  South 
Pacific  Islanders,  Dutchmen,  and  certain  African  races.  Similarly  the 
inhabitants  of  low  countries  of  the  temperate  and  arctic  regions, 
living,  as  they  do,  under  conditions  favorable  for  the  development  of 
the  phlegmatic  temperament,  are  prone  to  abnormal  fat-deposition.  In 
phlegmatic  persons  there  is  an  additional  factor  of  importance;  they  are 
quite  generally  inclined  to  consume  large  quantities  of  fat-forming  sub- 
stances. 

The  occupation  may  exert  no  inconsiderable  effect,  a  sedentary  life 
favoring  the  development  of  corpulency.  Any  calling  in  which  the  re- 
quired muscular  activity  is  at  a  minimum  predisposes  to  adiposity.  The 
condition  often  dates  from  longer  or  shorter  periods  of  enforced  rest — 
e.g.,  following  accidents  and  illness;  the  hemiplegic  is  often  obese  owing 
to  muscular  inactivity.  Following  such  acute  infectious  diseases  as  typhoid 
fever,  pneumonia,  acute  articular  rheumatism,  and  the  like,  adiposity, 
especially  of  the  anaemic  form,  not  uncommonly  develops.  The  writer's 
notes  indicate  that  this  is  a  rather  potent  factor;  thus,  out  of  a  total  of 
543  cases,  43  (or  7.9  per  cent.)  followed  an  acute  illness.  Among  inci- 
dental predisposing  causes  should  be  mentioned  congenital  anomalies 
and  monstrosities  (idiots,  cretins,  acephali). 

Exciting  Causes  of  Obesity. — Obesity  is  especially  dependent  on  the 
habitual  ingestion  of  abnormally  large  amounts  of  fat-making  food,  and 
the  intemperate  use  of  alcoholic  beverages — sweet  wines,  beer,  ale,  and 
porter,  in  particular, — with  or  without  deficient  exercise.  The  source  of 
the  fat  is  considered  to  be  the  fats  and  carbohydrates  taken  as  food, 
although  probably  it  is  derived  to  a  considerable  extent  also  from  the 
albuminoids.  "One  product  of  the  decomposition  of  albuminoid  sub- 
stances is  invariably  fat"  (Striimpell).  A  striking  illustration  of  an  in- 
crease of  adipose  tissue  from  proteids  is  seen  in  the  present-day  method 
of  treating  cases  of  tuberculosis  with  milk  and  raw  eggs.  An  excessive 
diet  of  starches  and  sugars  acts  indirectly  as  a  fat-producer  by  lessening 
the  oxidation  of  the  fats  and  proteids  which  may  be  ingested,  because 
the  carbohydrates  themselves  are  so  readily  oxidized.  Hence  excessive 
indulgence  in  any  one  of  the  several  varieties  of  diet  may  produce  the 
condition. 


OBESITY  849 

Intemperance  in  the  use  of  alcohol  plays  an  important  role  by  inducing 
hypernutrition.  In  such  subjects,  however,  there  may  be  observed  an  im- 
paired appetite  for  the  articles  of  food  that  enter  into  the  everyday 
dietary,  and  poor  digestion.  Alcohol  is  readily  oxidized  in  the  system, 
thus  allowing  the  fat  previously  present  to  remain  undisturbed.  Alcohol 
also  prevents  tissue-waste;  and  finally,  certain  beverages,  as  beer,  contain 
starches  in  considerable  amount.  It  has  been  estimated  that  a  person 
taking  habitually  5  or  6  glasses  of  beer  daily,  would  consume  b\  ozs. 
(150  gm.)  of  starch,  or  about  one-half  of  the  required  amount,  in  the 
same  period. 

The  intemperate,  on  account  of  physical  torpor  which  is  the  necessary 
result  of  his  habits,  is  notably  disinclined  to  pursue  muscular  exercise. 
Neither  has  he  sufficient  endurance  to  adopt  the  proper  forms  of  exer- 
cise to  maintain  healthy  nutrition  Familiar  illustrations  of  the  effects 
of  intemperance  in  this  regard  are  afforded  by  inn-keepers,  fjrewers,  and 
the  inhabitants  of  certain  countries,  like  Germany  and  Bavaria,  in  which 
beer-drinking  is  in  vogue. 

In  this  connection  emphasis  should  be  placed  upon  the  occurrence  of 
localized  depositions  of  fat  as  a  pathological  process,  probably  dependent 
on  the  same  laws  which  produce  general  obesity. 

Special  Pathology. — The  most  obvious  change  is  the  decided  increase 
in  the  adipose  tissue  throughout  the  body.  The  fat  deposits  are  most 
marked  in  localities  in  which  fatty  tissue  \z  normally  present,  as  under 
the  skin,  in  the  panniculus  adiposus,  and  the  mammary  regions;  they 
also  occur  in  the  various  internal  organs  and  tissues  that  are  altogether, 
or  almost,  free  from  fat  in  healthy  individuals. 

The  physiological  amount  of  fat  has  been  estimated  by  Beclard  and 
Quesnay  at  no  more  than  5  to  6  per  cent,  of  the  whole  weight  in  adults, 
while  the  proportion  of  fat  in  the  new-born  varies  between  9  and  18  per 
cent.  The  normal  fluctuations  are  greater  in  women  (to  whom  the 
higher  figures  also  pertain)  than  in  men,  and  a  moderate  increase  of  fat 
beyond  the  percentages  given  above,  after  the  fiftieth  year,  may  be  re- 
garded as  a  physiological  condition.  The  variations  in  the  amount  of 
fat  that  occurs  within  the  limits  of  health  are  dependent  on  age,  climate, 
and  family  and  racial  characteristics. 

The  deposition  of  fat  which  always  occurs  in  the  connective  tissue 
greatly  increases  the  bulk  or  dimensions  of  the  body.  The  round  face, 
"double  chin,"  bulky,  deep  chest,  large  waist,  conspicuous  and  some- 
times pendulous  abdomen,  and  short,  thick,  cylindrical  limbs,  are  familiar 
appearances .  Again,  the  trunk  is  often  disproportionate  to  the  extremities. 
Children  may  be  obese,  and  the  disorder  is  rarely  congenital.  It  is  to 
be  observed  that  corpulency,  "fatty  infiltration,"  and  "fatty  degenera- 
tion," are  not  synonymous  terms. 

The  various  viscera,  more  particularly  the  heart,  are  overlaid  with  fat, 
and  the  interstitial  connective  tissue  may  be  the  seat  of  fatty  infiltration. 
In  subpericardial  overfatness,  as  seen  in  extreme  general  obesity,  par- 
ticularly of  the  anaemic  variety,  fatty  infiltration  of  the  intermuscular 
tissue  of  the  heart  may  supervene.  Out  of  103  cases,  lasting  for  periods 
ranging  from  a  few  to  many  years,  of  extreme  adiposity  that  have  oc- 
curred in  the  writer's  experience,  only  5  cases  gave  clinical  proof  of  the 
54 


850  CONSTITUTIONAL  DISEASES 

existence  of  tnie  fatty  infiltration.^  On  the  other  hand,  in  cases  of  exces- 
sive obesity  this  morbid  process  (infiltration)  is  limited  to  a  thin  layer 
of  the  intermuscular  fibrous  tissue,  situated  directly  beneath  the  epicar- 
dium;   but  it  is  not  to  be  confounded  with  true  fatty  infiltration. 

In  exceptional  instances  fatty  infiltration  may  terminate  in  fatty  de- 
generative change  of  the  muscle  cells.  In  extreme  grades  muscular 
atrophy  from  compression  by  infiltrated  fat  ("pressure  atrophy")  may 
also  ensue.  In  this  article,  however,  we  are  concerned  only  with  the 
alterations  that  belong  to  "fatty  overgrowth."  Ilyjicrtrophic  dilatation 
of  the  heart  is  frequently  present  in  high  degrees  of  plethoric  adiposity, 
owing  to  an  enlarged  volume  of  blood,  and  the  arteries  may  show  fatty 
changes  in  the  intima  and  media,  and  later  those  of  arteriosclerosis. 
The  arterial  changes  may  lead  to  the  development  of  chronic  inter- 
stitial nephritis,  which  thus  becomes  a  late  complication  of  obesity.  The 
veins  are  often  the  seat  of  larger  or  smaller  varicosities.  The  kidneys 
and  Ivngs  may  be  enlarged  owing  to  fat  deposits  and  fatty  infiltration. 
Additionally,  passive  congestion  and  oedema  of  the  lungs,  secondary  to 
the  cardiac  weakness,  may  be  found  at  autopsy.  Of  the  viscera,  the 
liver  alone  is  the  seat  of  normal  fat  deposits,  but  in  obesity  these  accumu- 
lations may  cause  enlargement  of  the  organ.  The  stomach  may  be  dilated, 
and  a  catarrhal  gastritis  and  enteritis  is  sometimes  observed. 

The  blood  changes  vary  with  the  different  forms  of  corpulency,  hence 
they  will  be  considered  separately  :  (1)  In  the  plethoric  variety  the  mass 
of  blood  is  abnormally  large.  The  whole  blood  shows  an  increase  in 
specific  gravity,  fluctuating,  however,  between  1.062  and  1  070,  and  that 
of  the  serum  between  1.032  and  1.035.  There  are  cases  in  which  the 
number  of  red  cells  reaches  an  extraordinary  degree.  In  one  of  the 
writer's  patients  the  red  cells  numbered  6,800,000  per  cmm. 

Pathogenesis. — Fats  conserve  the  albumin  in  metabolism  by  furnish- 
ing heat  and  force  during  their  combustion — an  important  chemico-physio- 
logical  function.  By  thus  favorably  aftecting  the  metabolic  processes,  they 
at  once  rise  to  an  important  position  in  connection  with  the  general  nutrition, 
and  a  certain  proportion  of  systemic  fat  is  naturally  essential  for  the  preser- 
vation of  health.  (See  also  Pathology,  supra.)  The  origin  or  m^de  of 
formation  of  the  excessive  fat  accumulations  is  a  subject  that  is  imperlectly 
understood.  In  the  plethoric  form  of  the  complaint,  obesity  most  prob- 
ably results  from  the  ingestion  of  an  excessive  amount  of  fat-producing 
carbohydrates  and  their  complete  transformation  owdng  to  an  abnor- 
mally active  digestion  and  assimilation.  Per  contra,  in  the  ansemic  variety 
a  deficiency  in  the  oxidizing  power  of  the  system  may  be  assumed  to 
exist  and  constitute  the  principal  factor  in  bringing  about  the  condition. 
Under  these  circumstances,  a  normal  proportion  of  carbohydrates  in  the 
aliment  used  will  fail  to  be  destroyed  on  account  of  deficient  oxidation. 
Obesity,  therefore,  may  be  said  to  be  dependent  on  disturbance  of  cell- 
activity;  and  the  overuse  of  carbohydrates  leads  ofttimes  directly  to  an 
excessive  manufacture  of  fats.  The  liberal  consumption  of  proteids  may 
also  result  in  a  fat-forming  residue,  which,  if  not  destroyed  by  oxidation, 
miiy  produce  adiposity.  The  disturbance  of  the  metabolic  processes 
that  leads  to  deposition  of  fat,  may  be  transmitted  through  heredity. 

*  The  American  Journal  of  the  Medical  Sciences,  April,  1901. 


OBESITY  851 

According  to  Toldt,  "fatty  tissue"  is  regarded  as  a  special  organ; 
this  "preformed  adipose  tissue"  may  undergo  an  increase  as  the  result  of  a 
proliferative  process.  Again,  connective  tissue  cells,  which  penetrate 
between  the  elements  of  organs,  may  be  transformed  to  "fatty  tissue," 
forming  the  condition  known  as  fatty  infiltration;  but  this  does  not  usually 
fall  within  the  scope  of  physiological  conditions.  OerteP  correctly  states 
that  the  fat  arising  from  this  process  is  most  damaging  to  the  physiological 
functions  of  the  vital  organs. 

Histology. — Microscopically,  dincrences  in  the  size  and  number  of  the 
fat-globules  are  exhibited.  Thus,  in  the  plethoric  form  of  polysarcia  the 
fat-globules  are  large,  being  distended  with  droplets  of  fat;  their  cell  envel- 
ope and  nuclei,  however,  are  quite  indistinct.  When  numerous,  the  fat- 
vesicles  are  closely  packed  and  their  surfaces  are  faceted  by  mutual 
pressure.  They  are  round,  or  ovoid,  or  (less  commonly)  oblong  when 
sparsely  scattered  through  the  connective  tissue.  On  the  other  hand,  in 
cases  of  the  anaemic  or  hydraemic  variety  of  corpulency  in  which  the  fat- 
masses  are  soft  and  doughy  to  the  feel,  the  cells  are  less  completely  filled 
with  larger  or  smaller  droplets,  and  the  cell  membrane  and  nucleus  are 
easily  distinguishable. 

The  process  of  fatty  infiltration  begins  with  the  appearance  of  a  small 
droplet  within  the  cell  envelope;  this  grows  larger  until  "the  cytoplasm 
forms  a  mere  capsule  about  it  and  the  nucleus  is  crowded  and  flattened  in 
consequence."  Microscopic  sections,  stained  in  the  usual  manner,  do  not 
show  the  presence  of  fat-globules,  but  in  the  spaces  previously  occupied 
by  them  vacuoles  are  seen. 

Symptoms. — Owing  to  the  insidiously  progressive  character  of  the 
affection,  and  the  absence  of  all  characteristic  prodromes,  it  is  exceedingly 
difficult  to  fix  the  date  of  the  onset  as  a  clinical  entity.  At  first,  slight 
inconvenience,  a  sense  of  burdensomeness,  and  dyspnoea  during  walking 
or  working,  are  the  principal  subjective  manifestations,  and,  indeed,  no 
other  symptoms  may  be  complained  of  for  years.  Later,  with  the  slow 
and  gradual  development  of  the  disease,  and  involvement  of  the  various 
viscei'a,  both  the  number  and  intensity  of  the  clinical  features  are 
increased.  Marked  breathlessness  on  exertion,  due  to  the  hampering  of 
the  action  of  the  heart  and  lungs  by  massive  chest-walls,  fat-overgrowth 
and  the  upward-crowded  diaphragm,  are  among  the  earliest  conspicuous 
features.  The  symptoms  presented  by  individual  patients  will  vary 
according  to  the  stage  at  which  they  come  under  observation.  Again, 
the  two  leading  varieties — -plethoric  and  anaemic — of  obesity  present 
diametrically  opposed  conditions  of  the  blood  as  a  basis  for  the  abnormal 
fat  accumulations,  and  hence  both  the  external  appearances  and  the  sub- 
jective manifestations  are  quite  dissimilar.  For  these  reasons  the  two 
typical  forms  demand  separate  consideration. 

1.  Plethoric  Form. — In  this  variety  there  is  hypernutrition  of  all  the 
tissues.  Such  patients  often  partake  of  large  quantities  of  beer  or  other 
fluid  during  meals  and  the  appetite  is  abnormally  keen.  In  addition  to  the 
excess  of  fat,  which  is  symmetrically  distributed  throughout  the  body  as  a 
rule,  the  muscles,  including  those  of  the  myocardium,  are  vigorous  and 
voluminous.    The  blood  shows  a  condition  of  abnormal  richness  both  in 

*  "Obesity,"  Twentieth  Century  Practice  of  Medicine,  vol.  ii,  p.  658, 


852  CONSTITUTIOXAL  DISEASES 

erythrocytes  and  hiipmoglobiii.  In  a  nnnibor  of  patients  the  crvthrocytes 
are  over  6,000,000  and  the  h;enioglobin  over  110  per  cent. 

Physical  tSigns. — The  general  aj^pearance  indicates  robust  health  and 
unusual  vigor  of  constitution.  The  complexion  is  florid,  the  skin  soft, 
smooth  and  in  some  cases  the  face  looks  congested;  the  lips,  conjunctivae, 
and  other  mucous  membranes  present  a  rosy  hue.  The  neck  is  massive, 
the  abdomen  prominent,  and  the  girth  decidedly  increased.  The  sweat- 
glands  are  unusually  active.  But  though  the  systole  is  aI)nornially  strong, 
the  impulse  is  felt  indistinctly  on  account  of  fatty-overgrowth  and  the 
subcutaneous  tlepositions  of  fat.  liater,  as  the  result  of  myocardial  weak- 
ness, and  often  before  this  in  extreme  cases,  the  im])ulse  may  be  lost,  both 
to  inspection  and  ])alpation.  The  pulse  is  slow  and  of  high  tension;  this 
causes  arteriosclerosis  with  its  usual  consequences — cerebral  hyperemia, 
cardiac  asthma,  chronic  interstitial  nephritis,  anginal  seizures,  and 
finally  apo])lexy.  The  vigorous  contractions  of  the  heart,  due  to  muscular 
overgrowth,  sooner  or  later  grow  feeble  as  the  result  of  cardiac  failure, 
the  pulse  declines  in  fulness  and  volume  and  finally  becomes  small  and 
arrhythmic.    Bradycardia  is  a  not  infrequent  concomitant  {vide  infra). 

Indications  of  cardiac  enlargement  are  present.  In  well-marked 
corpulency,  however,  it  is  always  difficult,  and  sometimes  impossible,  to 
establish  the  boundary  lines  of  dulness  by  percussion.  The  heart  sounds 
remain  clear  for  a  long  period,  but  with  the  progressive  development  of 
the  condition  become  indistinct.  Murmurs  may  be  audible,  most  com- 
monly in  the  aortic  zone;  they  are  probably  not  due  to  chronic  valvulitis, 
but  to  either  a  roughened  condition  of  the  intima  of  the  aorta  or  to  relative 
incompetency,  other  indications  of  a  dilated  heart  being  then  in  associa- 
tion. Again,  the  bruit  may  rarely  be  h;emic  in  origin  or  "due  to  an  abnor- 
mal, relaxed  state  of  the  heart  muscle,  or  to  weakness  or  insufficiency  of  the 
papillary  muscles."^ 

In  advanced  cases,  arteriosclerosis,  affecting  particularly  the  aortic  arch 
and  the  coronaries,  is  an  associated  lesion  of  comparative  frequency. 
Forchheimer  noted  it  in  39  out  of  122  cases  of  fatty  overgrowth  found 
in  the  literature  prior  to  1889.  Of  these,  atheroma  of  the  aorta  occurred 
in  21,  and  similar  lesions  of  the  coronaries  in  14  cases.  When  atheroma 
occurs,  accentuation  of  the  second  aortic  sound  is  noted,  and  in  cases 
showing  involvement  of  the  coronaries  arrhythmia  is  conspicuous. 

In  many  cases  the  condition  does  not  proceed  beyond  a  moderate  grade 
of  obesity,  and  the  patient  enjoys  good  general  health.  He,  however, 
does  not  resist  well  the  inroads  of  the  acute  infections,  and  his  fat-laden 
viscera  are  likely  to  show  degenerative  changes  at  a  premature  period 
of  life. 

In  another  contingent  of  cases  belonging  to  this  variety,  the  condition, 
if  unchecked,  leads  to  a  marked  increase  of  the  general  bulk  of  the  body 
and  various  grotesque  malformations.  The  features  are  broad  and 
coarse,  and  some  of  the  facial  lineaments  are  obliterated.  Indeed,  the 
natural  folds  of  the  skin  everywhere  may  be  substituted  by  those  formed 
of  huge  layers  of  fat.  The  fat-deposits  are  most  prominent  about  the  neck, 
and  the  double  and  triple  chin  arc  readily  noted;  also  over  the  trunk  and 
particularly  the  abdomen,  which  may  be   markedly  pendulous.     The 

'See  Schroetten,  Ziemssen's  Hand-book,  vol.  i,  p.  26. 


OBESITY  853 

maximum  weight  among  the  writer's  patients  was  412  pounds,  and 
Weinberger  observed  a  boy  aged  ten  years  weighing  266  pounds.  The 
bodily  movements  become  slow  and  clumsy,  and  the  gait  wabbling,  heavy, 
and  somewhat  uncertain.  At  last  locomotion  may  be  impossible,  partly 
from  the  increasing  weight  of  the  fat  and  partly  from  the  extreme  feeble- 
ness of  the  tissues,  particularly  those  of  the  heart. 

In  some  cases  the  muscular  power  diminishes  rapidly,  the  appetite  fails, 
profuse  sweatings  occur,  and  signs  of  general  venous  stasis  may  be  observed. 
In  the  majority,  however,  venous  engorgement  develops  more  insidiously. 
Cough,  distress  of  respiration,  and  asthmatic  seizures,  especially  at  night, 
signal  the  passive  hyperemia  of  the  respiratory  mucous  membrane.  The 
symptoms  of  a  gastric  catarrh,  dependent  on  stasis  in  the  mucous  membrane 
of  the  stomach,  are  in  evidence,  and  with  these  the  characteristic  features 
of  gastrectasis  may  be  combined.  Great  thirst  and  bulimia  may  be  ob- 
served in  some  cases  at  least.  From  analogous  changes  in  the  intestines, 
there  is  often  constipation  which  may  alternate  occasionally  with  diarrhoea. 
The  passive  congestion  of  the  kidneys  is  shown  by  a  tendency  to  oliguria 
with  albuminuria,  and  the  presence  of  hyaline  and  a  few  granular  casts. 

As  elsewhere  stated,  the  poisonous  products  of  tissue-metabolism  are  not 
eliminated  in  the  normal  ratio.  Indeed,  in  one  female  patient,  aged  forty- 
two  years,  presenting  marked  obesity,  weighing  225  pounds,  although 
otherwise  feeling  in  good  health,  the  daily  renal  output  was  diminished  one- 
half  from  the  health  standard.  The  amount  of  food  ingested  was  plus. 
Sexual  desire  is  in  abeyance  and  azoospermia  is  not  uncommon. 

In  the  last  stage  of  the  plethoric  kind  of  obesity,  malleolar  oedema  merg- 
ing into  progressive  dropsy  may  arise.  As  the  result  of  judicious  treatment 
the  arterial  pressure  may  steadily  rise  and  at  the  same  time  all  of  the  clinical 
phenomena  dependent  on  the  venous  stasis  gradually  disappear.  In  the 
end,  however,  owing  to  fatty  changes  taking  place  in  the  myocardium, 
permanent  results  are  out  of  the  question,  and  a  fatal  termination  is  reached 
amid  the  signs  and  symptoms  of  advanced  cardiac  dilatation.  Death  may 
also  come  suddenly  from  cardiac  paralysis. 

2.  Anaemia  Form. — This  leading  type  is  characterized  by  and  dependent 
on  ansemia,  often  of  chlorotic  type.  Cases  of  the  plethoric  form  merge 
into  this  variety;  it  may,  however,  require  many  years  for  this.  It  is  to  be 
noted  that  while  extreme  degrees  of  the  ansemic  form  of  overfatness  may 
be  encountered,  the  fatty  depositions  do  not  reach  the  gigantic  propor- 
tions of  the  opposite  variety.  Muscular  exercise  is  difficult  and  early 
induces  exhaustion,  accompanied  by  distress  of  breathing  and  cardiac  pal- 
pitation. 

''I'he  symptoms  are  in  a  measure  those  characterizing  the  anaemias  in 
general,  together  with  a  peculiarly  marked  increase  of  fatty  depositions  in 
the  usual  places  of  predilection.  The  writer  has  the  records  of  a  blood 
examination  in  nineteen  cases.  In  the  majority  of  the  instances  the  blood 
changes  were  of  the  chlorotic  type.  The  haemoglobin  percentage  varied 
greatly— from  33  to  83  per  cent. — the  average  being  about  70  per  cent. 
In  about  35  per  cent,  of  the  cases,  however,  the  erythrocytes  and  haemo- 
globin were  reduced  about  equally  More  or  less  poikilocytosis  was 
commonly  found;  and  also  an  occasional  normoblast  and  a  considerable 
leukocytosis  (the  count  ranging  from  11,000  to  31,000  per  cmrn.)  was 
present  in  about  25  per  cent,  of  the  cases. 


854  CONSTITUTIONAL  DISEASES 

The  phys^ical  signs  are  at  variance  with  tliose  found  in  the  plethoric 
form.  Inspection  shows  pallor  of  the  bodily  surface  and  the  visible  mucous 
membrane.  The  skin  is  inclined  to  free  perspiration,  and,  in  advanced 
cases  may  become  wrinkled.  "The  skin  is  often  irritated  (intertrigo)  by  the 
excessive  sweating,  and  by  the  friction  of  cutaneous  surfaces  in  the  folds  of 
fat,  as  imder  the  breast,  at  the  abdominal  and  inguinal  folds,  and  around 
the  scrotinn  and  labia.  This  may  be  followetl  by  eczema.  Painful  excoria- 
tions, pruritus,  acne  rosacea  (in  alcoholics),  and  alopecia,  are  also  not  un- 
conmion."  To  the  feel,  the  subcutaneous  fat-cushions  are  soft  and  flabby, 
and  the  muscles  are  lacking  in  firnmess  and  strength.  Irregular,  circum- 
scribed fat-masses,  in  the  subcutaneous  tissue,  ranging  in  size  from  a  split 
bean  to  a  hen's  egg,  are  sometimes  palpable.  Apart  from  the  augmented 
peripheral  blood-tension,  which  is  common  to  the  anaemias,  the  signs  of 
cardiac  insufficiency  become  more  or  less  conspicuous  w  ith  the  ])rogressive 
development  of  the  condition,  and  at  last,  as  the  result  of  falling  arterial 
pressure,  dropsy  su])ervenes.  In  two  instances  under  personal  observation 
marked  anasarca  finally  develojied.  The  characteristic  ha^mic  murmurs, 
as  well  as  the  bruit  dc  (liable  in  the  cervical  veins,  are  often  heard. 

While  it  is  generally  conceded  that  the  principal  factor  in  the  production 
of  this  form  of  obesity  is  the  antemic  condition  of  the  blood,  or,  in  other 
words,  that  it  is  dependent  on  the  feeble  oxidation  resulting  from  the  greatly 
reduced  hffimoglobin-content  of  the  erythrocytes,  it  is  to  be  recollected  that 
greatly  impaired  nutrition  with  associated  anaemia  and  defective  combustion 
of  fat  may  likewise  arise  from  habitual  muscular  inactivity  coupled  to  the 
employment  of  insufficient  nourishment.  As  stated  under  Etiology,  most 
cases  of  ana?mic  obesity  occur  in  females,  and  it  often  originates  in  an  attack 
of  chlorosis  during  the  "teens."  It  is  probable  that  recovery  in  manychloro- 
tic  females  is  incomplete,  and  thus  the  foundation  is  laid  for  the  future 
development  of  the  anjemic  type  of  corpulency.  This  is  especially  true  of 
cases  of  chlorosis  characterized  by  anomalies  (hypoplasia)  of  the  blood- 
vessels and  genitalia.  In  such  instances  the  menses  may  be  both  scanty 
and  irregular,  and  dysmenorrhoea  may  form  the  burden  of  complaint. 

The  appetite  is  impaired  and  capricious;  in  most  cases  carbohydrates 
are  preferred  to  proteids.  The  tongue  is  furred  and  the  breath  often 
foul.  Intestinal  flatulence  with  more  or  less  constipation  is  the  general 
rule.  The  daily  quantity  of  urine  voided  is  small,  due  to  diminished 
arterial  pressure.  Slight  albuminuria  is  often  found  and  is  to  be 
ascribed  to  passive  hyperjemia  of  the  renal  vessels  in  the  majority  of 
instances,  since,  with  improved  tonus  of  the  circulation  as  the  result  of 
the  use  of  cardiac  stimulants,  the  albumin  usually  disappears.  Attacks 
of  intercurrent  diseases  are  badly  borne. 

Complications  and  Sequelae. — These  have  for  the  most  part  been 
stated,  but  their  enumeration  here  will  serve  to  emphasize  the  marked 
effect  which  they  sometimes  j^roduce  on  the  general  course  of  the  affection. 
Among  the  principal  complications,  often  the  precursors  of  the  terminal 
stage,  are  bronchitis,  pulmonary  congestion,  anginal  attacks,  cardiac 
asthma,  hernia,  albuminuria,  glycosuria,  arteriosclerosis,  oedema,  cerebral 
hemorrhage,  and  Cheyne-Stokes  respiration.  It  should  be  stated  that 
the  cardiac  asthma,  which  is  sometimes  a  troublesome  concomitant,  is 
dependent  on  pulmonary  congestion  as  the  result  of  "light"  breathing 
and  feeble  heart  action  during  sleep. 


OBESITY  855 

The  writer  has  seen  the  vascular  tension  apparently  increased,  due  to 
stimulation  of  the  vasoconstrictors  despite  a  progressive  loss  of  con- 
tractile energy  of  the  left  ventricle.  Severe  attacks  of  angina  are 
also  observed.  Thompson  says,  "Such  attacks  may  appear  as  a  result 
of  sudden  dilatation,  or  be  apparently  unprovoked."  The  arterial  pres- 
sure, however,  slowly  and  gradually  falls,  as  before  stated,  with  the 
progress  of  the  disease,  as  shown  by  the  diminished  secretion  of  urine 
and  the  sphygmographic  tracings. 

From  the  writer's  studies,  true  fatty  infiltration  may  occur  as  a  sequel 
of  fatty  overgrowth,  but  it  is  extremely  rare  (vide  supra). 

Circumscribed  Obesity. — In  many  cases  the  fat-depositions  are  not 
distributed  regularly  over  the  entire  body,  but  are  confined  to  circimi- 
scribed  portions^or  example,  the  abdominal  parieties,  the  mammary 
regions,  and  the  hips.  In  other  patients  the  fat-content  is  in  excess  in 
the  trunk,  while  other  parts  of  the  body — the  extremities — are  about 
normal.  Williams^  points  out  that  localized  superfluous  fat-deposits  are 
due  to  lack  of  exercise  of  the  underlying  nuiscles,  and  attributes  the 
"abdomenia  figure"  to  insufficient  exeicise  of  the  muscles  of  the  abdo- 
men. The  precise  causes  for  the  localization  of  the  depositions  of  fat 
in  certain  portions  of  the  body  are  difficult  to  determine.  The  increased 
thickness  of  the  fatty  layer  in  the  abdominal  wall  may  be  due  to  multiple 
pregnancies.  Again,  in  cases  of  obesity  in  which  the  reduction  process 
is  too  rapidly  carried  on,  marked  inequalities  in  the  distribution  of  the 
fatty  layer  may  be  observed. 

Diagnosis. — This  is  not  difficult  in  the  majority  of  instances,  but  it 
should  include  the  particular  variety  of  obesity  present — for  example, 
whether  anaemic  or  plethoric.  Care  must  also  be  exercised  In  detecting 
associated  conditions,  as  gout,  anasarca,  arteriosclerosis,  and  the  like; 
also  the  complications  and  sequelae.  Myxedema  should  not  be  mistaken 
for  polysarcia,  but  this  mistake  has  occurred.  In  both  affections  the 
general  bulk  of  the  body  is  greatly  Increased,  but  in  myxoedema  the  skin 
is  thick,  firm,  and  inelastic;  it  Is  dry  and  rough  and  the  facial  lines  of 
expression  are  obliterated.  Again,  In  the  latter  disease  the  physiognomy 
is  altered  to  a  remarkable  extent,  while  the  lips,  tongue,  nostrils,  and 
mouth,  are  all  thickened  by  infiltration.  Moreover,  in  myxoedema  the 
voice  Is  monotonous,  slow,  and  has  a  leathery  tone. 

Prognosis. — The  prognosis  will  depend  principally  upon  the  degree, 
variety,  and  prevailing  complications  of  each  individual  case.  In  the 
earlier  stages  of  the  plethoric  type,  particularly  in  cases  In  which  there  is 
not  a  history  of  strong  hereditary  predisposition,  but  the  Ingestion  of  too 
much  fat-making  food  is  the  principal  cause,  the  outlook  Is  positively 
favorable  under  appropriate  treatment.  In  more  advanced  cases,  with 
associated  arteriosclerosis,  particularly  of  the  coronarles,  stenocardia,  and 
oedema,  the  prognosis  may  be  of  the  utmost  gravity. 

On  the  whole,  it  Is  less  favorable  In  the  anaemic  or  hydrsemic  form  than 
in  the  plethoric.  Many  of  the  former  variety,  however,  are  curable  in 
proportion  to  the  removability  of  the  cause — the  anaemia.  The  tendency 
to  relapse  In  all  cases,  even  those  In  which  an  apparent  cure  has  been 
effected,  must  be  recollected.     In  general,  the  results  of  treatment  will 

^"Some  Aspects  of  Obesity,"  The  Practitioner,  May,  1904. 


856  CONSTITUTIOXAL  DISEASES 

depend  upon  the  degree  of  care  and  cooperation  which  the  patient  is 
wilUng  to  exercise.  Conversely,  the  effect  of  treatment  upon  the  strength 
and  nutritive  equihbriuni  of  tiie  patient  bears  upon  the  prognosis.  Med- 
ical officers  of  life  assurance  comi)anies  recognize  obesity  as  an  indication 
of  impaired  health,  and  when  the  boilv-weight  is  decidedly  dispropor- 
tionate to  the  height  of  the  individual,  the  risk  is  usually  declined.  Such 
subjects  bear  serious  illnesses  of  all  forms,  accidents,  and  surgical  opera- 
tions, badly. 

Oertel's  experimental  test,  the  comparison  of  the  fluids  regularly  taken 
and  of  the  quantity  of  urine  regularly  secreted  within  the  twenty-four 
hours,  supplied  a  most  reliable  indication  in  cases  of  anjcmic  obesity  with 
heart-inefficiency,  hydncmia,  or  oedema.  The  patient  takes  as  much 
fluid  as  he  is  accustomed  to,  during  two  days,  and  the  amount  of  urine 
secreted  is  carefully  measured.  During  the  next  two  days  the  fluids  taken 
are  reduced  to  a  volume  of  from  700  to  1,000  cc,  according  to  the  ])atient's 
size,  and  the  urine  again  estimated.  If  now  the  quantity  of  urine  secreted 
shows  an  increase  over  that  of  the  previous  two  days,  we  may  draw  the 
inference  that  both  the  heart-power  and  the  function  of  the  kidneys  are  in 
a  responsive  condition,  and  therefore  the  prognosis  is  comparatively 
better  than  if  the  reverse  as  to  the  quantity  of  urine  secreted  should 
obtain. 

In  the  writer's  experience,  the  effect  of  physical  exercise  upon  the  circu- 
lation and  respiration  has  formed  a  reliable  criterion  in  the  individual  case. 
When  physical  exertion  induces  early  breathlessness,  thoracic  oppression, 
and  palpitation,  and  the  pulse  becomes  small  ("thready")  and  irregular, 
the  outlook  is  gloomy. 

Modes  of  Death. — Among  the  commoner  causes  of  death  are:  Angina 
pectoris  (from  involvement  of  the  coronaries),  apoplexy,  syncope,  uraemia, 
cardiac  dilatation,  intercurrent  acute  infections,  and  necessary  major 
operations.  Of  the  rarer  modes  of  death  may  be  mentioned  rupture  of 
the  heart,  cerebral  thrombosis,  hemorrhagic  infarctions,  cardiac  asthma, 
carbuncles  (to  which  subjects  of  obesity  are  liable),  and  pulmonary  con- 
gestion or  oedema. 

Treatment. — Prophylaxis. — A  child  of  a  mother  suffering  from 
anaemic  obesity  should  be  nourished  by  a  suitable  wet-nurse  who  is  not 
predisposed  by  heredity  to  this  form  of  polysarcia.  In  the  earlier  years 
of  persons  showing  a  hereditary  disposition  to  corpulence,  the  fat-forming 
(farinaceous)  substances  must  be  greatly  restricted  in  the  dietary.  The 
proportions  of  fat  and  proteid  allowed  will  depend  upon  the  amount  of 
muscular  activity.  Physical  exercise  should  be  advised  and  encouraged, 
but  it  is  to  be  carefully  regulated.  Cool  bathing  is  a  useful  prophylactic 
measure  if  carried  on  systematically  and  regularly.  If  anaemia  be  asso- 
ciated with  a  pronounced  tendency  to  obesity  during  childhood  or  adoles- 
cence, suitable  forms  of  iron  should  additionally  be  administered. 

At  middle  life,  in  those  disposed  to  corpulency,  all  imprudences  in 
eating  and  drinking  should  be  cautioned  against,  and  the  quantities  of 
various  articles  of  food  and  the  time  of  eating  regulated.  Outdoor  sports 
and  gymnastics  should  also  be  gauged  accordingly.  Prophylactic  meas- 
ures, however,  must  have  reference  to  the  special  indications  presented 
by  individual  cases.  For  example,  the  inclination  to  corpulency  may  be 
overcome  by  instituting  measures  preventive  of  the  development  of  gout. 


OBESITY  857 

Attention  to  the  condition  of  the  blood  and  blood-making  organs  has  also 
proved  effective.  As  a  rule,  however,  the  dietetic-mechanical  treatment 
under  strict  surveillance  must  be  combined. 

The  treatment  of  confirmed  obe.ntij  may  be  conveniently  discussed  under 
three  heads:  (a)  the  dietetic  treatment;  (h)  the  mechanical  manage- 
ment (to  increase  oxidation) ;  (c)  the  medicinal  measures.  There  are  few 
diseases  that  the  physician  is  called  upon  to  treat  in  which  it  is  so  vitally 
important  to  adapt  the  treatment  to  special  cases  as  in  obesity,  and,  as 
Grocco  wisely  states,  it  must  be  varied  from  day  to  day  to  respond  to 
indications  as  they  arise.  If  the  dominating  etiological  influence  is  re- 
movable, this  should  be  accomplished  in  the  first  instance  and  then  atten- 
tion given  to  the  minor  factors.  Cases  that  present  complications  of 
various  kinds  may  prohibit  the  exercise  of  the  rule  mentioned  above.  The 
foregoing  remarks  apply  particularly  to  moderate  grades  of  the  plethoric 
variety  of  obesity.  On  the  other  hand,  in  well-marked  cases  in  plethoric 
patients  and  in  the  anaemic  type,  a  more  complex  group  of  indications  is 
presented,  and  usually  two  of  the  elements  of  treatment  indicated  above, 
(a)  and  (6),  are  prime  requisites.  Finally,  that  method  must  be  selected 
which  invigorates  while  at  the  same  time  it  involves  neither  injury  nor 
weakening  of  the  patient. 

Dietetic  Treatment. — The  dietetic  treatment  is  all-important.  The 
diet  chosen  must  maintain  the  equilibrium  of  the  metabolic  processes. 
Broadly  speaking,  the  principal  variation  from  the  ordinary  dietary  con- 
sists in  a  restriction  of  the  fat-forming  food,  or  carbohydrates.  The  carbo- 
hydrates should  not  be  totally  withdrawn,  since  the  ingestion  of  large 
amounts  of  proteid  foods,  which  are  difficult  of  complete  metamorphosis, 
may  excite  digestive  disturbances,  gouty  manifestations,  and  even  chronic 
interstitial  nephritis.  It  is  the  writer's  almost  invariable  custom  to  allow 
a  limited  proportion  both  of  carbohydrates  and  fat,  and  thus  accomplish 
two  objects:  (1)  a  slow  consumption  of  the  previous  fat-depositions; 
(2)  maintenance  of  the  normal  metabolic  processes. 

The  principal  systems  of  dietary  are  known  by  the  names  of  Banting, 
Ebstein,  and  Oertel.  In  so-called  "Bantingism,"  sugars,  fats,  and  starches, 
are  greatly  restricted  in  the  dietary;  water,  however,  is  not  reduced,  and 
wines  and  spirituous  liquors  are  allowed.  Sir  Dj^ce  Duckworth^  has  well 
said  that  as  a  system  "Bantingism"  is  both  unphysiological  and  im- 
practical. In  subjects  of  a  rheumatic  or  gouty  diathesis  Banting's  heavy 
proteid  and  alcohol  dietary,  since  it  fails  to  secure  complete  elimination 
of  waste  products,  which  are  now  in  excess  of  the  normal,  is  wholly  con- 
tra-indicated. A  brief  reference  may  be  made  to  the  Salisbury  treatment, 
which  in  many  respects  is  similiar  to  the  Banting,  and  consists  in  permit- 
ting large  quantities  of  animal  food  (withholding  carbohydrates  alto- 
gether) and  large  amounts  of  /ree  hot  water  to  wash  out  the  increased 
nitrogenous  metabolic  products  from  the  system. 

In  Ebstein 's  diet-list  the  proteids  are  diminished,  and  carbohydrates 
greatly  restricted,  while  fat  is  freely  permitted.  It  is  assumed  that  fat  does 
not  increase  stored  fat,  while  at  the  same  time  it  tends  to  impair  the  ap- 
petite; and,  being  less  readily  oxidized  than  the  carbohydrates,  it  inter- 
feres less  with  the  metabolism  of  the  proteids.    Saccharine  matter  and 

* "  Obesity,"  Allbutt's  System  of  Medicine,  vol.  v,  p.  617. 


858  CONSTITUTIONAL  DISEASES 

potatoes  are  strictly  forbidden.    The  following  is  an  illustration  of  Eb- 
stein's  dietary: 

Breakfast,  6  a.  m.  in  summor,  7:30  a.  m.  in  winter. — White  bread,  well  toasted 
(rather  less  than  2  ounces),  and  well  covered  with  butter.  Tea,  without  milk  or 
sugar,  8  or  9  ounces. 

Dinner,  2  p.  m. — Soup  made  with  beef-marrow.  Fat  meat,  with  fat  sauce,  4  to 
5  ounces.  A  moderate  quantity  of  asparagus,  spinach,  cabbage,  peas,  or  beans. 
Two  or  three  glasses  of  light  white  wine.  After  the  meal,  a  large  cup  of  tea  without 
milk  or  sugar. 

Supper,  7:30  p.m. — An  egg,  a  little  roast  meat,  with  fat.  About  an  ounce  of 
bread,  well  covered  with  butter.    A  large  cup  of  tea,  without  milk  or  sugar. 

The  Ocrtel  method  of  feeding,  more  particularly  with  modifications  to 
which  attention  will  be  called  hereafter,  is  especially  adapted  for  some 
cases  of  obesity  with  feeble  hearts.  This  author  allows  more  fat  than 
Banting,  but  less  fat  and  more  (about  double  the  quantity)  proteids  and 
carbohydrates  than  Ebstein.  The  amount  of  free  water  permitted  daily 
is  only  one  pint;  about  one  pint  additional  in  other  food  is  allowable. 
His  diet-table  for  obesity  is  appended: 


Albumin 

Fat 

Carbohydrates 

Calories 

Minimum 

156 

25 

75 

1180 

Maximum 

170 

45 

120 

1608 

Oertel  also  offers  a  special  diet  list  in  circulatory  disturbances,  com- 
bined with  graduated  exercise  and  a  marked  reduction  of  the  amount  of 
liquid  taken;  it  comprises  three  parts: 

1.  The  reduction  of  the  amount  of  liquid  taken  with  meals  and  dur- 
ing the  intervals,  the  total  for  each  day  being  3G  ounces  (1,064  cc). 
Frequent  bathing  (including  the  Turkish  bath  in  suitable  instances)  and 
pilocarpine  are  employed  to  promote  free  diaphoresis. 

2.  The  diet  is  composed  largely  of  proteids,  as  follows : 

Morning. — A  cup  of  coffee  or  tea,  with  a  little  milk — about  6  ounces  (178  cc.) 
altogether;  bread,  3  ounces  (93  cc). 

Noon. — Three  to  4  ounces  (90  cc.  to  120  cc.)  of  soup;  7  to  8  ounces  (218  cc. 
to  248  cc.)  of  roast  beef,  veal,  game,  or  poultry;  salad  or  a  light  vegetable;  a 
little  fish;  1  ounce  (32  cc.)  of  bread  or  farinaceous  pudding;  3  to  6  ounces  (93  cc. 
to  186  cc.)  of  fruit  for  dessert.  No  liquids  at  this  meal,  as  a  rule;  but  in  hot 
weather  6  ounces  (178  cc.)  of  light  wine  may  be  taken. 

Afternoon. — Six  ounces  (178  cc.)  of  coffee  or  tea,  with  as  much  water.  An 
ounce  of  bread  as  an  indulgence. 

Evening.- — One  or  two  soft-boiled  eggs,  1  ounce  (32  cc.)  of  bread,  perhaps  a 
small  slice  of  cheese,  a  little  salad,  and  fruit;  6  to  8  ounces  (178  cc.  to  236  cc.) 
of  wine,  with  4  or  5  ounces  (120  cc.  to  148  cc.)  of  water  (Yeo). 

3.  Graduated  exercises,  as  walking,  the  distance  to  be  undertaken 
each  day  to  be  carefully  specified  and  frequently,  though  gradually,  in- 
creased. A  like  plan  is  to  be  pursued  with  reference  to  the  degree  of 
inclination.  This  is  the  most  important  part  of  the  system,  since  it  in- 
vigorates the  heart  muscle. 

The  "mechanical"  part  of  the  Oertel  method  also  tends  to  consume 
the  superflous  fat  of  the  patient's  body,  and  stimulate  the  elimination  of 
fluid  through  the  skin  and  kidneys,  at  the  same  time  oxidizing  the  food 
ingested  so  that  further  deposition  of  fat  is  prohibited.  It  has  gained  an 
enviable  reputation  in  Europe  (c.  g.,  Germany,  Austria,  and  Switzer- 


OBESITY  859 

land,)  where  special  sanataria  for  its  administration  have  been  estab- 
lished. At  these  "Terrain  curorte"  are  to  be  found,  "heaUh  paths"  of 
four  different  grades,  differing  in  slopes  from  5°  to  20°.  The  majority  of 
these  paths  are  provided  with  colored  sign-boards  giving  distances  and 
elevations,  so  that  the  exercise  prescribed  by  the  physician  can  be  system- 
atically and  accurately  followed. 

A.  W.  Perry^  has  wel!  said  that  there  are  cases  in  which  an  excessive 
kmount  of  water  (serum)  in  the  tissues  is  practically  the  sole  cause  of  the 
corpulency.  He  recommends  Rankc's  normal  diet;  namely,  meat,  280 
gm.;  fat,  100  gm.;  bread,  400  gm.;  and  the  limitation  of  the  amount 
of  fluid  ingested,  allowing  only  300  or  400  cc.  more  of  water  to  be 
taken  daily  in  drink  and  food  than  the  daily  amount  of  urine  secreted.  In 
order  to  carry  out  this  method  the  percentages  of  water  in  different  forms 
of  food  prepared  ready  to  be  eaten  must  be  carefully  estimated.  These 
are,  "(Numbers  indicate  percentages  of  water) :  Soup,  91.6;  boiled  meat, 
70;  roast  mutton,  74;  roast  beef,  59;  roast  veal,  78;  dried  meat,  40; 
fish,  white,  74;  pudding,  48;  mushes,  80;  bread,  hard,  30;  bread,  soft, 
40;  carrots,  boiled,  82;  spinach,  83;  peas,  69.5;  lettuce,  97;  fresh 
fruits,  85;  string  beans,  88;  celery,  84;  asparagus,  94;  milk,  87;  cream, 
65;  cheese,  35;  baker's  toast,  1.18;  crackers,  7.50;  potatoes,  boiled,  70; 
turnips,  boiled,  82.5;  cabbage,  85." 

Labbe  and  Furet^  recommend  a  regimen  from  which  salt  is  entirely 
eliminated,  in  connection  with  the  ingestion  of  fluids  in  abundance. 
The  organism,  in  order  to  maintain  its  molecular  composition,  rejects  the 
excess  fluid,  which  carries  off  excrementitious  products. 

Among  other  systems,  those  of  Weir  Mitchell,  Sir  Dyce  Duckworth, 
Strumpell,Yeo,  Dujardin-Beaumetz,  and  von  Noorden,  may  be  mentioned. 
These  may  serve  as  useful  guides  in  some  cases,  but  a  detailed  statement 
is  not  possible.  Finally,  it  must  be  recollected  that  there  is  no  single 
dietary  for  obesity  but  for  the  individual  patient. 

In  all  patients  presenting  themselves  for  treatment,  the  physician  should 
pay  special  attention  to  the  condition  of  the  urine,  blood,  heart,  and  arteries, 
as  well  as  to  the  previous  family  and  personal  history.  Under  any  system 
of  dietetic  treatment  the  patient  should  be  weighed  accurately  at  brief 
intervals.  The  food  should  also  be  weighed  and  measured  at  first,  but 
the  patient  soons  learns  to  estimate  by  bulk  the  requisite  quantity  of  each 
article  permitted.  Attention  to  details  is  essential  to  success,  and  the 
effect  of  treatment  upon  the  general  health  must  be  noted.  Fat-reduction 
must  always  be  slowly  progressive.  If  the  case  is  one  of  plethoric  obesity, 
a  judicious  rearrangement  of  the  food,  e.  g.,  a  moderate  increase  of  the 
proteid  substances  and  a  corresponding  diminution  of  the  carbohydrates, 
is  indicated.  Muscular  exercise,  so  far  as  possible  in  the  open  air,  must 
also  be  enjoined — walking,  horseback  riding,  bicycling,  rowing,  swim- 
ming. These  measures  usually  accomplish  a  successful  reduction  even  in 
well-established  examples  of  the  condition.  The  majority  belong  to  this 
type,  and  the  writer  is  in  the  habit  of  ordering  the  following  dietary,  with 
modifications  to  suit  the  peculiarities  of  individual  cases: 

^  California  State  Journal  of  Medicine,  November,  1903,  p.  358. 
^  Revue  de  Medecine,  1905.    No.  9,  p.  674. 


860  CONSTITUTIOXAL  DISEASES 

Morning  Meal. — Fruit — as  an  orange,  or  2  peaches,  or  one-half  a  grapefruit 
(without  sugar),  or  a  sour  apple,  fine  wheat-bread,  IJ  ounces  (gm.  40);  a  soft- 
boiled  egg:  milk,  1  ounce  (28  cc);  saccharine,  ^  grain  (gm.  0.03);  coffee,  4i 
ounces  (120  cc). 

Noon  Meal  or  Luncheon. — Caviare,  2  drams  (gm.  S);  lamb  chops,  sweetbread, 
boiled  ham  (cold),  or  fowl  or  game  in  season,  3  to  4  ounces  (gm.  90  to  120); 
salad,  1  ounce  (gm.  30)  (with a  small  amount  of  French  dressing);  cheese,  1  dram 
(gm.  4);  bread,  rye  or  bran,  h  ounce  (gm.  15);  fruit  (except  strawberries  and 
bananas),  or  (instead  of  the  latter),  water,  4  ounces  (125  cc). 

Evening  Meal  or  Dinner. — Soup  (clear),  3  ounces  (85  cc);  fish,  2  ounce 
(gm.  60);  roast  or  broiled  beef,  lamb,  veal,  or  game  or  poultry,  4  to  5  ounces 
(gm.  125  to  150);  one  or  two  of  the  following  green  vegetables:  spinach,  string 
beans,  green  peas,  celery  (stewed),  asparagus,  raw  sliced  tomatoes,  Brussels 
sprouts,  li  ounces  (gm.  42).  For  Dessert,  may  take  jDlain  rice  i:)udding,  junket, 
cup  custards  (all  sweetened  with  saccharine),  or  fruit  (except  strawberries  and 
bananas)  either  raw  or  cooked,  4  to  5  ounces  (gm.  125  to  150.).  May  take  4  to  5 
ounces  (125  to  140  cc.)  of  water  when  fruit  is  not  used. 

No  fluid  is  to  be  taken  at  meals  except  as  indicated  above,  but  a  glass  of 
water  on  rising,  and  three  hours  after  food,  is  permitted.  During  the 
warm  season,  particularly  if  the  sweat-glands  are  active,  an  additional 
glass  of  water  may  be  occasionally  allowed.  It  is  unwise  to  restrict  fluids 
too  greatly  in  any  cases  in  which  the  proteids  are  given  in  abnormally 
large  amounts,  since  it  allows  of  an  accumulation  in  the  system  of  the 
products  of  nitrogenous  metabolism.  That  more  than  the  quantity  of 
fluid  above  specified  is  also  demanded  in  cases  of  obesity  associated  with 
a  gouty  tendency  is  not  a  baseless  assumption. 

In  cases  of  anaemic  obesity,  the  restriction  of  fluids  may  be  more  rigidly 
enforced.  This  is  even  more  true  of  cases  presenting  a  hydrtemic  or  even 
dropsical  tendency.  The  rule,  in  such  instances,  is  to  favor  concentration 
of  the  blood  by  not  allowing  more  than  32  ounces  of  fluid  per  diem.  In 
any  given  instance  in  which  increasing  weakness  of  the  heart,  with  an 
impeded  circulation,  naturally  diminishes  the  excretion  of  water  by  the 
cutaneous  and  renal  routes,  the  circulatory  system  must  receive  unusual 
and  careful  attention  and  the  consumption  of  fluid  must  be  limited.  In 
this  form  of  the  aft'ection  (ansemic),  the  appetite  is  often  impaired,  and 
the  dietary  suited  to  the  needs  of  the  patients  is  exceedingly  difficult  to 
enforce.  They  often  insist  upon  being  allowed  to  partake  of  light  lunches 
between  meals  and  on  retiring,  and  the  writer  endorses  such  a  course. 
Among  the  best  dishes  for  the  purpose  are  a  cup  of  hot  broth  or  bouillon 
with  part  of  a  French  roll,  a  glass  of  milk  with  a  graham  wafer,  a  thin 
sandw  ich  of  scraped-beef  or  chicken,  or  the  like. 

The  value  of  highly  nutritious  blood-making  food — tender  meats, 
milk,  eggs,  green  vegetables,  fruits — in  this  form  of  obesity  is  undoubted, 
and  indicated  first  of  all,  but  the  quantity  of  proteid  food  must  not  be 
excessive.  The  great  difficulty  in  these  cases  is  to  accomplish  the  decom- 
position of  proteids  by  muscular  exercise,  such  subjects  being  lethargic 
and  strongly  averse  to  physical  exertion.  Fatty  food  which  does  not  in- 
hibit the  disposal  of  the  nitrogenous  materials  to  the  same  extent  as  the 
carbohydrates  should  be  somewhat  more  restricted  even  than  indicated 
in  the  dietary  given  above.  The  superior  value  of  this  method  has 
received  adequate  verification  from  personal  experience.  A  light  acid 
wine,  as  dry  Moselle,  Rhine,  or  claret,  in  definite  quantity — four  ounces 
(120  cc.) — at  dinner,  is  useful. 


OBESITY  861 

The  Mechanical  Treatment.— To  increase  oxidation  by  exercise  is, 
next  to  an  appropriate  dietary,  the  most  important  element.  The  special 
form  of  exercise,  and  also  the  duration  and  frequency,  must  be  carefully 
adjudged  for  the  individual  patient.  One  of  the  principal  uses  of  exercise 
is  to  maintain  an  appropriate  proportion  of  albumin  in  the  body,  but 
"not  only  the  fat  but  organic  albumin  is  likewise  used  up  by  muscular 
activity"  (Oertel).  Physical  exercise  also  promotes  the  destruction 
of  the  fat  already  warehoused  in  the  system,  and,  moreover,  it 
invigorates  cardiac  action  and  induces  deeper  breathing.  Muscular 
exercise,  however,  should  not  be  too  violent,  particularly  in  the  cases 
manifesting  circulatory  disturbances  or  evidences  of  fatty  infiltration  of 
the  heart.  The  writer's  best  results  have  been  from  walking  out  of  doors, 
later  by  increasing  the  pace,  and,  finally,  climbing  exercises  either  at  home 
or  at  open-air  health-resorts,  combined  with  gymnastics  for  the  arms  and 
trunk.  Reference  was  previously  made  to  the  "health-paths"  when 
speaking  of  the  treatment  of  fatty  overgrowth.  These  paths  should  have 
an  incline  ranging  between  5°  and  20°.  The  amount  of  exercise  should 
be  measured  by  the  use  of  a  good  pedometer. 

It  is  all-important  to  make  the  minutest  study  of  the  patient's  cardio- 
vascular system,  and  to  observe  the  effect  of  the  muscular  exercise.  For 
example,  if  the  case  be  one  of  the  anaemic,  or  hydreemic  type,  or  presents 
some  complication,  then  the  patient  must  begin  with  short  walks  on  the 
level,  to  be  slowly  and  gradually  increased  as  the  force  of  the  heart  and 
strength  of  the  patient  permit;  and  it  is  desirable  to  distribute  the  exercise 
over  both  the  morning  and  afternoon  hours  if  this  is  practicable.  On  the 
other  hand,  in  instances  of  the  plethoric  form  of  the  affection,  a  greater 
amount  of  physical  exercise  and  even  walks  up  inclines  of  moderate 
degree  may  be  taken  from  the  commencement.  Striimpell  remarks :  "In 
dealing  with  cases  of  obesity  in  which  the  condition  is  due  less  to  over- 
feeding than  to  lack  of  muscular  exercise,  it  might  be  decidedly  advisable 
to  lay  the  most  stress  upon  the  increase  in  muscular  activity."  The  so- 
called  "resistance  exercises,"  introduced  by  the  Schotts  in  the  treatment 
of  chronic  cardiac  diseases,  may  be  employed  in  the  anaemic  or  hydrsemic 
varieties  of  obesity  in  which  cardiac  dilatation  is  associated.  After  marked 
signs  of  improvement  in  the  cardiovascular  system  and  the  respir- 
atory forces  has  been  brought  about,  then  suitable  gymnastics  and 
walking  exercises  may  be  substituted.  Great  care  must  be  exercised  in 
prescribing  the  mechanical  treatment  in  obese  patients  who  have  atherom- 
atous vessels.  Complications  and  intercurrent  affections  must  be 
relieved  by  appropriate  treatment.  When  oxidation  cannot  be  sufficiently 
promoted  by  muscular  exercise,  a  course  of  rather  deep  massage,  with  a 
view  to  increasing  the  muscular  system  and  stimulating  the  circulatory 
and  eliminative  organs,  is  the  best  substitute.  With  massage  the  Swedish 
movements  may  be  combined. 

Although  to  a  lesser  extent  than  the  muscular  exercise,  balneotherapy 
also  promotes  oxidation.  When  no  contra-indications  exist,  cold-  or  salt- 
water baths  followed  by  active  hand-rubbing  by  the  patient  himself  may 
be  advised.  These  baths  should  be  brief  and  the  temperature  of  the  water 
not  too  low  at  the  start.  If  gouty  manifestations  are  prominent,  hot  baths 
are  to  be  employed  preferably,  since  they  increase  elimination  through  the 
skin,  while,  on  the  other  hand,  cold  ablutions  tend  to  increase  the  suffering 


862  CONSTITVTIOXAL  DISEASES 

of  the  patient.  Bornstein  advises  daily  hot  baths  in  obesity,  as  they  induce 
freer  eliniination  through  the  skin  and  kichievs.  It  is  important  to  main- 
tain etiieient  exeretion  of  the  ])ro(hiets  of  eombustion  by  constant  attention, 
not  only  to  the  skin,  but  also  to  the  bowels  and  kitlneys. 

The  treatment  of  associated  diseases,  many  of  which  stand  in  the  rela- 
tion of  cause,  is  highly  important, — more  especially  gout  and  rheumatism. 
It  is  decidedly  inadvisable  to  institute  the  usual  reduction  treatment  when 
gout  and  obesity  are  combined,  and  such  a  course  aggravates  the  first- 
named  disease.  The  most  brilliant  results  in  such  cases  are  obtained  by 
ada])ting  the  treatment  princijjally  to  the  gouty  element,  although  some  of 
the  measures  employed  favorably  influence  the  obesity,  e.  g.,  the  physical 
exercise.  To  rearrange  appropriately  the  dietary  for  these  combined 
cases  is  extremely  difficult.  On  the  other  hand,  there  are  numerous 
conditions  and  diseases  associated  with  obesity  in  which  the  reduction 
treatment  is  called  for  and  should  precede.  It  is  well  known  that  diseases 
of  the  circulatory  system,  in  particular,  are  unfavorably  influenced  by 
even  a  moderate  degree  of  corpulency.  The  same  is  true  to  a  lesser  extent 
of  bronchitis,  asthma,  and  chronic  interstitial  nejihritis. 

Medicinal  Treatment. — A  number  of  watering-places,  particularly 
JNIarienbad  and  Carlsbad,  enjoy  an  enviable  reputation  for  the  treatment 
of  obesity.  From  a  thera])eutic  standpoint,  however,  a  suitable  dietary, 
muscular  exercise,  and  other  details,  are  equally  important  with  the 
waters  ingested.  The  spas  are  adapted  especially  to  the  plethoric  form 
of  the  complaint,  but  not  to  the  anaemic.  In  the  latter  form,  mild  aperient 
waters,  containing  iron,  are  often  serviceable.  Neither  should  patients 
presenting  marked  cardiovascular  disturbances  resort  to  these  spas. 
Such  a  course  of  treatment  is  not  to  be  pursued  except  under  the  strict 
surveillance  of  a  resident  practitioner  who  is  competent  to  arrange  an 
appropriate  regimen.  Personal  observations  lead  to  the  inference  that  the 
beneficial  effects  from  the  spa  treatment  are  rarely  permanent.  In  mild 
grades  of  plethoric  obesity,  such  places  as  Hamburg,  Kissingen,  Brides- 
les-Bains,  and  Vichy,  abroad,  and  Saratoga  and  Virginia  Hot  Springs,  at 
home,  may  be  recommended. 

On  the  whole,  the  medicinal  treatment  is  neither  satisfactory  nor  suc- 
cessful. As  stated  above,  hjematinics  are  useful  in  the  antemic  variety. 
Some  of  the  complicating  affections  call  for  special  therapeutic  agents, — as 
gout,  rheumatism,  circulatory  disturbances,  and  the  like.  Certain  reme- 
dies recommended  in  the  treatment  of  this  disease  are  harmful — e.  g., 
Phytolacca  berry.  Thyroid-feeding  has  come  into  more  or  less  favor. 
Leichtenstein,  Wendelstadt,  Ewald,  and  others,  have  reported  successful 
results  in  a  number  of  instances,  especially  in  those  exhibiting  the  anae- 
mic, flabby,  "myxoedematoid"  form  of  obesity.  The  loss  of  weight  was 
from  2  to  3  pounds  (1  to  1.5  kgm.)  in  one  week,  and  as  high  as  20 
pounds  in  two  to  four  weeks.  In  a  number  of  selected  cases  belonging  to 
this  category  the  use  of  thyroid  extract  (desiccated)  in  small  doses  caused 
a  progressive  loss  of  weight  without  injury  to  the  general  health;  but  it 
quite  as  often  fails.  In  the  majority  this  loss  is  not  maintained  after  the 
reduction  of  10  to  15  pounds  has  been  accomplished.  The  commencing 
dose  should  be  small  and  then  slowly  and  gradually  increased,  but  it  is 
not  advisable  to  exceed  gr.  v  (0.324)  thrice  daily.  It  is  wise  to  guard 
the  heart  by  combining  smalj  doses  of  strychnine  or  digitalis. 


OBESITY  863 

In  this  connection  it  should  be  pointed  out  that  a  myxoedematous  con- 
dition is  not  uncommonly  associated  with  the  anjcmic  form  of  obesity.^ 
Thyroidin,  the  active  principle  of  the  thyroid  gland,  and  iodothyrin, 
give  results  that  are  in  every  way  comparable  to  those  of  thyroid-feeding, 
according  to  Baumann  and  Ross  as  well  as  personal  experience.  Jeozy- 
kowski  treated  10  cases  of  corpulence  by  thyroidin  in  doses  of  from  5  to  8 
grains  (0.3  to  0.5  gm.)  per  diem.  In  one  patient  more  than  40  pounds 
(18.1  kgm.)  were  lost  in  two  months,  and  in  another  30  pounds  (13.6 
kgm.)  in  three  months.  Symptoms  of  thyroidism — restlessness  and 
tachycardia  in  particular— are  the  signal  either  for  a  reduction  in  the 
dosage  of  thyroid  extract  or  its  temporary  withdrawal. 

The  cathartic  mineral  waters  are  indicated  in  cases  in  which  there  has 
been  gormandizing  with  disturbance  of  the  portal  system,  and  in  many 
cases  of  plethoric  obesity,  in  the  earlier  stages,  in  connection  with  a  suit- 
able restriction  of  the  dietary.  When  saline  laxatives  are  employed  the 
other  fluids  must  be  correspondingly  reduced.  The  heart  and  blood- 
vessels must  always  receive  the  minutest  attention,  and  any  circulatory 
disturbance  must  be  promptly  met;  it  is  often  necessary  in  advanced 
cases,  with  or  without  oedema,  to  resort  to  digitalis  or  strychnine.  In  a 
certain  proportion  of  cases  the  dietetic-mechanical  treatment  of  obesity, 
even  with  gradual  loss  of  weight,  is  attended  with  marked  nervous  dis- 
turbance, usually  assuming  the  form  of  restlessness  and  abnormal  exci- 
tability. It  is  important,  when  such  symptoms  arise,  to  carry  on  the 
treatment  still  more  slowly,  when  they  may  disappear;  but,  if  they  do 
not,  then  it  should  be  discontinued. 

Treatment  of  Local  Obesity. — The  best  method  is  a  course  of  local 
massage  combined  with  a  mild  general-reduction  cure.  Allard^  recom- 
mends the  employment  of  a  vibrating  ball  controlled  by  an  electric 
motor  in  circumscribed  obesity;  this  method  of  treatment  has  proved 
efficient  in  a  limited  number  of  cases.  When  the  abdomen  is  the  seat 
of  the  localized  overfatness  it  is  well  to  estimate  the  element  of  intestinal 
distention,  and  gastrectasis,  from  which  such  patients  commonly  suffer, 
and  to  direct  appropriate  measures  to  these  conditions  when  present. 
Moreover,  the  massage  exercises  a  beneficial  effect  in  overcoming  the 
atony  of  the  intestines,  thus  diminishing  the  girth  measurement. 

^"Some  Respiratory  Conditions  Dependent  Upon  Gout  and  Obesity,"  by  the 
writer,  The  Philadelphia  MedioalJournal,  October  26,  1901. 
'Revue  dc  therapeutic,  1905,  No.  6,  p.  191. 


CHAPTER  XXXIII. 

RICKETS. 
By  GEORGE  F.  STILL,  M.  A.,  M.  D.  (Cantab.),  F.R.C.P. 

"The  most  recent  and  ordinary  name  of  this  disease,"  wrote  Glisson 
in  1650,^  "is  The  Rickets,  but  who  baptised  it  and  upon  what  occasion 
and  for  what  reason,  or  whether  by  chance  or  atlvice  it  was  so  named,  is 
very  uncertain."  GHsson  regarded  the  rickets  in  his  time  as  "absolutely 
a  new  Disease  and  never  described  by  any  of  the  Ancient  or  Modern 
Writers  "  "It  became  first  known,"  he  says,  "about  thirty  years  since  in 
the  Counties  of  Dorset  and  Somerset  lying  in  the  Western  part  of  Eng- 
land." The  term  "Rachitis"  or  "Rachites"  he  suggests  as  an  alterna- 
tive, not  because  he  thinks  that  there  is  any  evidence  that  "Rickets"  was 
a  corruption  of  the  Greek  term,  but  because  he  thinks  that  "they  that  are 
expert  in  the  Greek  and  Latin  tongues  may  peradventure  expect  a  name 
from  us  whereof  some  reason  may  be  given."  The  word  Rachitis,  he 
explains,  was  selected  by  himself  and  some  of  his  friends  because  the 
spine  (pax'-^)  '^^'^s  "the  first  and  principal  among  the  parts  affected  in 
this  evil." 

In  Germany,  the  disease  has  been  known  as  "die  Englische  Krank- 
heit,"  a  term  which  must  be  taken  to  indicate  rather  the  source  of  the 
original  description  of  the  disease,  than  any  distinguishing  prevalence  of 
rickets  in  England  or  among  English-speaking  people. 

Up  to  recent  times,  certain  conditions  were  included  vmder  the  name  of 
rickets  which  are  now  believed  to  be  entirely  distinct  pathologically.  The 
disease  which  is  now  called  infantile  scurvy  (Barlow's  disease),  was 
formerly  described  as  acute  rickets,  hemorrhagic  rickets,  or  scurvy 
rickets;  and  under  the  head  of  foetal  rickets  was  classed  the  disease 
which  is  now  known  as  achondroplasia. 

Rickets  will  be  [described  here  under  three  heads:  (1)  congenital  or 
foetal  rickets,  (2)  ordinary  rickets  as  seen  in  the  first  two  or  three  years  of 
life,  and  (3)  late  rickets. 

Congenital  and  late  rickets  are  (in  the  ojiinion  of  most  observers) 
extremely  rare;  moreover,  there  is  still  some  doubt  whether  the  condi- 
tions described  by  these  names  are  in  all  cases  identical  pathologically 
with  the  common  rickets  of  infancy.  It  will  be  convenient,  therefore,  to 
describe  the  common  form  of  rickets  first,  for  it  is  in  this  form  that  the 
characteristics  of  the  disease  have  been  most  carefully  observed. 

Geographical  Distribution. — There  is  a  general  consensus  of  opinion 
that  rickets  is  more  prevalent  in  temperate  zones  than  in  very  hot 
or  very  cold   countries,    but    this   vague    generalization    rests    on    no 

'Treatise  on  the  Rickets.     TransL  Phil  Armin.,  165L 

864 


RICKETS 


865 


firm  basis.  Statistical  evidence  is  lacking  with  regard  to  many  parts  of 
the  world,  and  even  such  statistics  as  are  available  are  often  of  little 
value  for  purposes  of  comparison,  inasmuch  as  some  observers  have 
failed  to  state  the  age  limits  to  which  their  figures  refer,  and  others  have 
given  no  indication  of  the  evidence  which  has  been  accepted  as  estab- 
lishing the  presence  of  rickets.  It  must  be  remembered  als(j  that  statistics 
have  almost  always  been  taken  from  hospitals  or  dispensaries  and  there- 
fore refer  only  to  sick  children  and  to  the  poorer  classes,  not  to  the  child 
population  in  general. 

With  these  limitations,  the  following  figures  may  be  quoted  as  indicat- 
ing, at  any  rate,  the  widespread  occurrence  of  rickets : 


Place. 

Age. 

Frequency. 

Observer. 

New  York   (Tene- 

1-16 months. 

13  out  of  67, 

Long  &  Steele 

ments) 

or  19.4% 

(Fi-eeman). 

New  York  (Hospi- 

Up to  2  yrs. 

60  out  of  66, 

Freeman, 

tal) 

or  91%. 

Philadelphia 

Up  to  5  yrs. 

28  per  cent. 

Parry. 

Boston  (U.  S.  A.) 

Under  2  yrs. 

79.5% 

Morse, 

Buffalo 

Up  to  3  yrs. 
(Italians) 

70%. 

Snow. 

Buflfalo 

Up  to  3  yrs. 
(other  nationalities) 

11-12%. 

1 

Snow. 

London 

Up  to  3  yrs. 

44.6%. 

Still.  _ 

Manchester 

(sick  children) 

30.3%. 

Ritchie. 

Edinburgh 

Up  to  3  yrs. 

"Rather  more 
than  50%." 

J.  Thomson. 

Paris 

Children 

One-third. 

Marfan. 

Berlin 

Up  to  3  yrs. 

65.8%. 

Cohn. 

Prague 

Up  to  5  yrs. 

31%. 

Ritter. 

St.  Petersburg 

Children 
(moderate  rickets) 

60-80%. 

lonkowsky. 

Moscow 

Children 

80%. 

Kissel. 

Christiania 

Up  to  3  yrs. 

19.9%. 

Quisling. 

Christiania 

Children 

32%. 

Johannessen. 

It  is  clear  that  rickets  has  a  wide  distribution  in  the  northern  hemisphere 
and,  although  figures  are  lacking  for  the  southern  hemisphere,  the  dis- 
ease is  known  to  be  prevalent  in  Australia,  South  Africa,  and  South 
America.  It  has  been  stated  that  it  is  almost  unknown  in  the  tropics  but 
the  accuracy  of  this  statement  is  doubtful.  Recently  during  a  boundary 
investigation  in  Africa,  cases  of  severe  rickets  were  seen  among  the 
natives  of  the  Gold  Coast  Colony,  5°  to  11°  north  of  the  Equator,  and 
rickets  is  known  to  be  prevalent  in  the  West  Indies.  It  is  also  believed 
that  in  very  cold  regions,  such  as  Greenland,  the  disease  is  very  rare.  In 
China,  Japan,  India  and  Thibet,  rickets  is  said  to  be  an  exceedingly  rare 
disease  (Palm) ;  but  such  statements  must  be  received  with  caution,  for 
it  seems  probable  that  many  observers  have  included  only  such  cases  as 
showed  curvature  of  bones  and  other  symptoms  which  are  only  met  with 
in  severe  degrees  of  rickets. 

Rickets  is  said  to  be  much  more  prevalent  in  moist  climates  than  in  dry 
(Palm),  and  in  low-lying  districts  .'than  in  altitudes:  it  is  said  to  be  rare 
at  an  elevation  of  more  than  2,000  feet  (about  .75  km.)  above  the  sea 
(Rehn),  but  both  Baginsky  and  Monti  observed  rickets  to  be  frequent  in 
places  2,000  to  4,000  feet  (.75  to  1.25  km.)  above  the  sea. 

55 


866  CONSTITUTIONAL  DISEASES 

It  is  generally  lieUl  that  rickets  is  a  disease  chiefly  of  cities  and  large 
towns  and  no  doubt  this  view  is  correct,  but  in  Enghuul,  certainly,  rickets 
is  very  common  in  country  districts  also,  anil  it  seems  likely  that  investiga- 
tion would  show  this  to  be  the  case  in  other  parts  of  the  world.  A  col- 
lective enquiry  by  Norwegian  physicians  showed  that  in  Norway  out  of 
615  cases  of  rickets,  359  were  from  towns,  256  from  the  country;  but  as 
no  statistics  are  forthcoming  of  the  relative  proportions  of  town  and 
country  child-population,  it  is  difficult  to  obtain  any  conclusive  evidence 
as  to  the  relative  frequency  of  rickets  in  town  and  country. 

Probably  the  social  conditions  of  town  life  are  of  much  more  importance 
in  the  etiology  of  rickets  than  any  geographical  limits.  This  has  been 
well  illustrated  by  the  increase  in  the  frequency  of  rickets  which  has  been 
noticed  in  Melbourne  since  the  great  influx  of  population  attracted  by  its 
commercial  prosperity  some  fifteen  years  ago.  In  1885,  rickets,  even  in  its 
slightest  manifestations,  was  extremely  rare  at  the  Children's  IIos})ital  in 
Melbourne.  In  1895,  rickets  had  become  ({uite  a  common  disease.  This 
increase  corresponded  with  an  increase  of  poverty  and  extended  use  of 
cheap  artificial  food  |)reparations  for  infant  feeding  (Snowball). 

Season. — Season  plays  little  if  any  part  in  the  production  of  rickets, 
but  several  observers  have  noticed  a  special  frequency  of  rickets  among 
hospital  patients  during  the  v/inter  months.  This  has  been  attributed  to 
confinement  in  ill-ventilated  rooms,  but  it  is  not  proved  that  rickets  has 
its  onset  more  at  one  time  of  the  year  than  another  and  there  is  an  obvious 
reason  why  rachitic  children  should  be  brought  for  treatment  during  the 
winter  months — a  large  proportion  of  the  rickety  children  are  not  brought 
for  rickets,  but  for  respiratory  complications  and  these  are  much  com- 
moner in  the  cold  season  than  in  the  warm. 

Age  and  Sex. — The  onset  of  rickets  is  so  insidious  that  any  exact 
determination  of  the  age  at  which  it  begins  is  usually  impossible.  It 
rarely  begins  after  the  age  of  three  years,  and  probably  seldom  before  the 
age  of  three  months:  among  hospital  out-patients  the  second  year  of 
life  shows  the  largest  proportion  of  rickets.  Out  of  1,662  cases  of  rickets, 
1,268  were  between  one  and  two  years  old  (Comby).  Some  statistics  of 
consecutive  ]:)atients  under  the  age  of  three  3'ears  taken  from  the  writer's 
out-patient  clinic  illustrate  the  relative  frequency  at  various  ages: 

Birth  to  Months  Months  Years  Years 

3  months  3-6  6-12  1-2  2-3 


Rickets  10  10  24  38  18 

No  Rickets  31  24  22  27  20 

It  seems  probable  that  there  is  little,  if  any,  relation  to  sex.  Out  of  179 
female  children  in  the  hospital,  73,  that  is  40.8  |X:r  cent.,  showed  rickets, 
while  out  of  138  boys,  57,  that  is  41.3  per  cent,,  were  found  to  be 
rickety.  According  to  Woronichin,  out  of  equal  numberr  of  sick  chil- 
dren of  each  sex,  the  proportion  of  rachitic  boys  to  rachitic  girls  was 
13  to  10. 

Etiology. — Many  different  views  have  been  held  as  to  the  etiology  and 
no  doubt  several  factors  may  play  some  ^)art  in  its  production.  But  it 
may  be  said  at  once  that,  although  thero  may  be  several  predisposing  or 
contributing  causes,  the  one  determining  cause  is  faulty  feeding  or  faulty 


RICKETS  867 

assimilation.  Rickets  is,  in  fact,  a  food  disorder.  Recognizing  tiiis, 
however,  we  may  well  pay  attention  to  those  other  factors  to  which  more 
or  less  weight  has  been  attached  by  various  observers,  for  some  of  these 
factors  may  prove  to  be  of  importance  in  the  prophylaxis  of  the  disease. 

Overcrowding:  Defective  Hygiene. — As  already  mentioned,  rick- 
ets is  more  frequent  in  cities  than  in  country  districts  and  this  fact  has 
suggested  that  defective  hygiene  is  responsible  for  the  disease.  In  many 
of  the  cities  where  rickets  is  most  prevalent  there  is  much  overcrowding, 
and  where  a  whole  family  of  several  children  with  their  parents  live  in  one 
room,  the  vitiated  atmosphere  may  well  interfere  with  the  nutrition  of  an 
infant  who  spends  perhaps  the  greater  part  of  the  day  and  night  in  this  one 
room.  Undoubtedly,  in  London,  rickets  is  far  commoner  among  the 
poorer  classes  than  among  the  wealthy;  but  it  seems  likely  that  the  differ- 
ence lies  much  less  in  environment  than  in  feeding.  The  children  of  the 
well-to-do  become  rickety  when  fed  in  the  same  way  as  the  childern  of  the 
poor.  The  very  minor  part  played  by  environment  seems  to  be  shown 
also  by  the  fact  that,  in  London  at  any  rate,  rickets  is  usually  treated 
amongst  hospital  patients  by  simple  dietetic  measures  and  the  adminis- 
tration of  cod-liver  oil,  with  no  change  of  environment;  and  yet  the  results 
of  such  treatment  are  excellent. 

The  same  objections  might  be  urged  against  the  view  which  has  been 
held  that  deficiency  of  sunlight  is  a  large  factor  in  the  causation  of  rickets. 
It  is  pointed  out  that  in  cities,  with  their  narrow  streets  and  high  buildings, 
the  rooms  of  the  poor  are  often  ill-lighted  and  get  little  or  no  sunshine. 
But  it  is  equally  true  that  in  some  less-civilized  parts  of  the  world,  where 
rickets  is  said  to  be  extremely  rare,  it  is  customary  to  live  in  dwell- 
ings even  less  open  to  sunlight. 

If,  however,  there  is  little  evidence  that  overcrowding  and  squalor, 
with  their  attendant  defects  of  sanitation,  have  much  influence  'per  se  in 
the  production  of  rickets,  clinical  experience  seems  to  indicate  strongly 
that  certain  conditions  of  city  and  town  life  do  play  a  very  important 
part  in  determining  its  prevalence.  The  struggle  for  existence  in  these 
crowded  districts  often  makes  it  necessary  that  both  parents  should 
go  out  to  work,  and  infants  are  therefore  artificially  fed;  moreover, 
wherever  poverty  abounds,  the  cheaper  substitutes  for  cow's  milk  are 
likely  to  be  used,  especially  condensed  milk.  It  seems  probable  also  that, 
particularly  amongst  town-bred  women,  there  is  an  increasing  inability  to 
suckle  their  offspring,  which  favors  the  occurrence  of  rickets. 

Parental  Influence. — Direct  heredity  has  been  held  accountable  by 
some  (Henoch,  Pfeiffer,  Ritter  von  Rittershain) .  Ritter  found  traces  of 
rickets  in  the  mothers  of  27  out  of  71  rickety  children.  But  in  the  districts 
from  which  observations  on  this  point  have  come,  rickets  is  a  common 
disease,  and  it  is  at  least  possible  that  parent  and  child  have  both  been 
subjected  in  early  life  to  faulty  methods  of  feeding. 

The  health  of  the  mother  during  pregnancy  has  long  been  considered 
to  have  some  influence  upon  the  development  of  rickets  in  post-natal  life. 
Jenner,  discussing  this  point,  said :  "Of  this  much  I  am  sure,  that,  when 
the  mother  is  in  delicate  health,  in  a  state  of  which  anaemia  and  general 
want  of  power  form  the  prominent  features  without  being  the  subject  of 
disease,  usually  so-called,  there  the  children  are  often  in  a  very  decided 
degree  rickety,  although  the  father  is  in  robust  health  and  the  hygienic 


868  CONSTITUTIONAL  DISEASES 

conditions  in  which  the  children  are  placed,  most  favorable."  Phthisis 
during  i>regnancy  is  especially  mentioned  by  Garrod  and  Fletcher^  as  a 
cause  of  rickets  in  the  oifsi)nno',  and  the  same  writers  consider  that  want 
of  fresh  air  and  exercise  during  pregnancy  has  a  similar  result;  they 
mention,  also,  multi[)le  pregnancy,  and  pregnancy  at  an  advanced  age, 
or  at  an  unduly  early  age,  as  factors. 

It  is  commonly  stated  that  the  last  children  born  in  a  large  family 
are  more  often  affected  with  rickets  than  the  earlier  children,  especially 
if  the  pregnancies  have  been  not  only  numerous  but  in  rapid  succes- 
sion. In  such  cases  it  is  sujjposed  that  exhaustion  of  the  mother  inter- 
feres with  the  nutrition  of  the  infant  in  some  way  so  that  some  months  after 
birth  rickets  appears.  Actual  statistics  hardly  bear  out  tiiis  sup|)osition. 
Baxter  found  that  in  consecutive  cases  of  rickets,  1!)  per  cent,  were  first- 
born, 13.5  per  cent,  second-born,  19  per  cent,  third-born,  13.5  per  cent, 
fifth-born,  8  per  cent,  sixth-born,  16  per  cent,  seventh-born,  2  per  cent, 
ninth-born  or  later.  Similar  in  its  effect,  presumably,  is  lactation  during 
pregnancy,  which  some  observers  have  thought  to  be  a  cause  of  rickets 
in  the  offspring. 

Whether  any  of  these  influences  can  be  regarded  as  more  than  predis- 
posing, is  doubtful.  Rickets  at  birth  is  generally  thought  to  be  exceedingly 
rare,  and  when  the  disease  makes  its  appearance  some  months  after 
birth,  there  is  always  a  possibility  and  often  a  probability  that  post-natal 
factors,  ])articularly  the  feeding,  played  a  larger  part  in  producing  the 
disease  than  any  parental  influence  before  birth. 

Syphilis. — Parrot's  view  that  syphilis  causes  rickets  is  now  generally 
discredited;  but  some  still  hold  that  syphilis  strongly  predisposes  to 
rickets.  INIonti  states  that  he  has  never  seen  a  case  of  inherited  syphilis 
which  did  not  develop  rickets;  Cheadle,  on  the  other  hand,  says  that  many 
cases  of  congenital  syphilis  are  not  rickety.  Undoubtedly,  some  of  the 
most  severe  degrees  of  rickets  are  seen  where  this  disease  is  associated 
with  congenital  syphilis,  and  it  would  seem  that  in  such  cases  the  osseous 
and  perhaps  the  visceral  lesions  of  rickets  may  be  modified  not  only  in 
degree  but  also  in  kind.  In  the  skull,  osteophytic  change  is  more  common 
and  more  marked  when  syphilis  is  associated  with  rickets  although  it  may 
occur  with  rickets  alone.  Some  have  thought  also  that  localized  thinning 
of  the  cranial  bones,  craniotabes,  is  specially  frequent  when  these  two 
diseases  are  combined. 

Dietetic  Causes. — What  part,  if  any,  is  played  by  the  factors  already 
mentioned  is  uncertain;  but  there  are  strong  grounds  for  believing  that 
dietetic  influences  stand  in  a  much  more  direct  relation  than  any  of  the 
foregoing.  Put  briefly,  the  facts  are  these:  Rickets  is  uncommon  and 
in  its  severer  degrees  is  exceedingly  rare  in  infants  who  are  having 
the  breast  milk  only.  It  occurs  almost  invariably  where  the  feeding 
has  been  such  that  the  food  constituents  depart  widely  from  the 
standard  of  human  milk  or  include  excess  of  carbohydrate  whether  in 
the  form  of  sugar  or  starch.  Rickets  occurs  in  some  of  the  lower  ani- 
mals, and  in  these  it  has  been  shown  to  be  preventable  by  simple  dietetic 
measures.  Several  observers  claim  to  have  produced  changes  resem- 
bling rickets  in  animals  by  special  methods  of  feeding.    Rickets  in  chil- 

^  British  Medical  Journal,  September  21,  1895. 
^Pathological  Society  Transactions,  vol.  xxxii,  p.  360. 


RICKETS  869 

dren  is  successfully  treated  by  suitable  feeding  without  other  measures 
of  any  sort. 

As  to  the  particular  fault  in  the  diet,  some  indication  is  obtained  by  a 
comparison  of  the  methods  of  feeding  in  a  series  of  rachitic  children. 
These  can  be  grouped  thus  in  approximate  order  of  frequency:  (1) 
Starchy  food;  corn  flour;  potato;  bread  with  more  or  less  milk,  fresh 
or  condensed.  (2)  Condensed  milk  alone,  often  excessively  diluted. 
(3)  Proprietary  foods,  whether  containing  starch  or  not,  and  made 
with  or  without  the  addition  of  fresh  milk.  (4)  Cow's  milk  diluted,  with- 
out addition  of  cream.  (5)  Breast  milk,  with  addition  of  starchy  foods. 
(6)  Breast  milk  only. 

Great  importance  has  been  attached  to  the  early  use  or  to  excess  of 
carbohydrate  food,  especially  starch.  Baxter  found  that  92  per  cent,  of 
the  cases  of  rickets  had  had  farinaceous  food  before  the  age  of  twelve 
months,  42  per  cent,  had  had  farinaceous  food  daily  from  their  birth, 
30  per  cent,  daily  from  the  age  of  three  months,  4  per  cent,  from  the  age 
of  six  months,  and  16  per  cent,  from  the  age  of  nine  months.  He  found, 
also,  that  in  many,  though  not  in  all,  the  first  onset  of  the  disease  and 
its  degree  of  severity  appeared  to  be  distinctly  related  to  the  period  at 
which  the  administration  of  starchy  matter  was  begun  and  to  the  propor-  . 
tion  between  this  element  in  the  dietary  and  the  others  with  which  it 
was  associated. 

It  is  clear,  however,  from  the  occurrence  of  rickets  in  groups  2,  4  and 
6,  that  the  use  of  starchy  food  is  not  essential  to  its  production.  There 
is  also  some  evidence  that  excess  of  sugar  is  not  an  essential  factor,  for  in 
group  2  personal  observations  showed  that  rickets  most  often  arose  where 
excessive  dilution  of  the  condensed  milk  had  been  used  so  that  the  propor- 
tion of  sugar  was  actually  slightly  below  that  present  in  human  milk; 
and  in  group  6  it  is  very  improbable  that  any  notable  and  prolonged 
excess  of  sugar  should  occur;  for  the  average  proportion  of  sugar  in 
human  milk  is  remarkably  constant. 

From  the  occurrence  of  rickets  on  a  diet  of  condensed  milk  in  watery 
dilution,  it  may  be  conjectured  that  the  fault  is  one  of  defect  rather  than 
of  excess,  for  all  the  constituents  of  milk  in  such  feeding  are  usually  pres- 
ent in  unduly  low  proportion;  moreover,  compared  with  human  milk 
this  dilution  of  condensed  milk  will  show  a  relatively  greater  defect  of  fat 
than  of  proteid,  as  can  be  seen  from  the  following  comparison: 

Condensed  milk 
Human  as  often  given 

milk.  (.about  1  in  10). 

Proteid 2.0  ...  1.0  per  cent. 

Fat  3.5  ...  .9  per  cent. 

Sugar 7.0  ...  5.4  per  cent. 

Salts  2  ...  .2  per  cent. 

Water  . 87.3  .    .    .  92.5  per  cent. 

Analyses  of  human  milk  make  it  probable  that  deficiency  of  fat  is 
commoner  than  deficiency  of  proteid.  Where  rickets  occurs  in  an  infant 
who  has  been  fed  only  on  cow's  milk  diluted,  there  has  almost  always  been 
dilution  sufficient  to  reduce  the  fat  to  half  or  less  than  half  the  proportion 
present  in  human  milk,  and  this  low  proportion  has  been  continued 
usually  for  many  months.    Such  dilution  reduces  the  proteid  little  if  at 


870  CONSTITUTIONAL  DISEASES 

all  below  that  found  in  human  milk.  When  the  proprietary  foods  are 
used,  whether  with  fresh  milk  or  without,  analysis  shows  that  there  is 
almost  invariably  a  deficient  proportion  of  fat  in  the  diet.  All  these  facts 
suo;o;est  that  deficiency  of  fat  in  the  food  is  an  important  factor. 

Failure  of  assimilation  of  fat  may  be  as  effectual  as  deficiency  of  fat- 
supply  in  causing  fat-starvation.  It  seems  likely  that  an  infant,  even  when 
receiving  an  amj>le  quantity  of  good  breast  milk,  may  fail  to  assimilate  it 
properly  if  farinaceous  food  is  being  given  at  the  same  time.  Whether 
starchy  food  or  excess  of  sugar  has  any  special  influence  in  hindering  the 
absorption  of  fat  is  uncertain,  but  there  is  no  doubt  tiiat  by  setting  up 
dyspepsia  and  fermentation  it  can  and  does  interfere  with  the  absorption 
of  any  food-stuif,  including  fats.  Similarly,  any  cause  which  weakens  the 
infant's  digestive  ])owers,  be  it  simple  debility,  as  in  a  premature  child  or 
in  one  of  twins,  or  a  gastro-intestinal  disorder,  or  disease  such  as  syphilis 
or  tuberculosis,  may  interfere  with  the  absorption  of  food  and  so  of  the  fat. 

Strong  support  has  been  given  to  this  view  by  the  observations  of 
Bland  Sutton  upon  animals  in  the  Zoological  Gardens  in  London.  These 
have  been  described  very  fully  by  Cheadle,^  from  whose  account  the 
following  statements  are  quoted:  "Young  monkeys  deprived  of  their 
mothers'  milk  and  fed  entirely  upon  vegetable  food,  chiefly  fruits,  became 
rickety.  Two  young  bears  fed  exclusively  upon  rice,  biscuits,  and  raw 
meat,  of  which  latter  they  hardly  ate,  died  of  extreme  rickets.  For  many 
years  the  lion  whelps  were  weaned  early  and  fed  on  raw  flesh  only;  they 
invariably  became  rickety  and  died.  When  milk,  pounded  bones,  and 
cod-liver  oil,  were  added  to  the  raw  meat,  they  lost  all  signs  of  rickets  and 
were  successfully  reared."  Here  evidently  there  had  been  no  deficiency 
of  proteid.  The  addition  of  pounded  bone  to  the  diet  makes  the  experi- 
ment less  conclusive  than  it  might  have  been  if  fat  only  had  been  added; 
but  a  comparison  with  the  results  of  addition  of  cod-liver  oil  only  to  the 
regimen  of  children  makes  it  all  but  certain  that  the  fat  was  the  effective 
therapeutic  agent. 

The  value  of  cod-liver  oil  is  in  itself  suggestive  of  the  role  of  fat-starva- 
tion and  from  recent  experience  it  would  seem  that  any  fat,  animal  or 
vegetable,  jjrovided  it  is  easily  digested,  is  equally  curative  of  rickets.  It 
is  noteworthy  also  that  those  who  have  advocated  the  use  of  phosphorus 
have  almost  always  used  it  in  an  oily  solution. 

Whilst,  therefore,  it  seems  possible  that  deficiency  of  proteid,  and  per- 
haps deficiency  of  certain  salts,  in  the  food  may  contribute  in  some  degree 
to  the  j:)roduction  of  rickets,  there  is  strong  evidence  that  the  chief,  perhaps 
the  only  constant,  fault  is  deficiency  of  fat  assimilation,  whether  this 
deficiency  be  due  to  a  low  proportion  of  fat  in  the  diet,  or  to  faulty  methods 
of  feeding  interfering  with  digestion  and  so  with  the  absorption  of  fat. 
It  must  be  added,  however,  that  some  experiments  on  pigs,  by  Herter, 
of  New  York,  showed  that  prolonged  fat-starvation,  although  it  produced 
muscular  weakness  and  drowsiness,  did  not  produce  the  bone-changes  of 
rickets  (Freeman). 

Pathology. — Morbid  Anatomy. — The  most  obvious  change  is  the 
enlargement  at  the  junction  of  epiphysis  and  diaphysis  in  the  ribs  and  in 
the  long  bones,  but  to  understand  the  changes  here,  it  is  necessary  to  have 

^  Allhutfs  System  of  Medicine,  vol.  iii,  p.  131. 


RICKETS  871 

some  knowledge  of  the  normal  processes  of  growth  in  bone.  At  the  ends 
of  the  long  bones,  for  instance  of  the  radius  of  an  infant  about  nine  months 
old,  there  arc  between  the  cartilage  of  the  epiphysis  and  the  cancellous 
tissue  of  the  diaphysis,  two  distinct  zones  of  transition:  the  one  nearer 
the  cartilage  is  a  thin,  translucent,  bluish-gray  band  about  ^  to  ^  of  an 
inch  (1  to  2  mm.)  in  thickness,  and  beyond  this  is  a  much  narrower  yel- 
lowish-white opaque  zone  which,  toward  the  cartilage,  has  a  sharply 
defined  and  perfectly  regular  limit,  but  toward  the  bone  merges  irregu- 
larly into  the  cancellous  tissue:  the  former  is  the  zone  of  proliferation, 
the  latter  is  the  zone  of  calcification. 

In  rickets,  the  bluish-gray  zone  of  proliferation  is  enlarged  so  that  it  may 
be  more  than  twice  the  normal  thickness,  and  instead  of  being  an  even 
band  with  sharply  defined  edges  limiting  it  from  the  cartilage  on  the  one 
side  and  the  zone  of  calcification  on  the  other,  it  is  quite  irregular, 
especially  toward  the  zone  of  calcification,  where,  even  with  the  naked 
eye,  it  can  be  seen  that  the  two  zones  are  mixed  together,  islets  of  calcifica- 
tion are  seen  amidst  translucent  cartilage,  and  irregular  processes  of 
cartilage  extending  into  the  region  of  calcification,  and  the  whole  is 
abnormally  vascular  so  that  to  the  naked  eye,  num^erous  vessels  are  obvious, 
traversing  these  confused  zones  in  all  directions. 

Histologically,  there  is  the  same  confusion ;  the  cartilage  cells  are  more 
numerous  than  they  should  be,  the  arrangement  of  columns  has  lost  its 
regularity;  they  are  ill-formed  and  no  longer  parallel.  Between  them 
in  many  places  are  areas  of  calcification,  sometimes  even  of  fully  formed 
laminated  bone,  lying  amid  cartilage  cells  and  cartilaginous  matrix  in 
which  are  numerous  vessels  passing  inward  from  the  adjacent  perios- 
teum or  perichondrium.  The  cancellous  tissue  of  the  shaft  has  also  an 
undue  vascularity,  and  the  absorption  of  this  tissue  which  should  proceed 
but  slowly,  keeping  pace  with  the  formation  of  new  bone  from  the  perios- 
teum without,  proceeds  in  rickets  too  rapidly,  so  that  the  bone  consisting 
of  an  imperfectly  ossified  layer  without,  is  further  weakened  by  the  rare- 
faction and  looseness  of  its  cancellous  tissue  within. 

The  subperiosteal  formation  of  bone  is  also  disturbed,  the  periosteum 
itself  becomes  thickened  and  the  proliferating  layer  beneath,  in  which 
calcification  should  occur,  is  excessively  vascular,  and  contains  abundant 
cell  elements,  but  is  imperfectly  calcified,  and  the  production  of  true  lam- 
inated bone  is  deficient,  so  that  the  bone  here  also  is  softer  than  normal 
and  bending  easily  occurs.  The  bone  thus  formed  may  be  of  spongy 
character,  a  condition  specially  noticeable  in  the  thickened  areas  of  the 
parietal  and  frontal  bones,  where  also  the  vascularity  is  sometimes  so 
great  that  it  can  be  observed  clinically  as  a  bluish  discoloration  seen 
through  the  tense  scalp. 

Muscles. — It  is  stated  that  the  muscles  show  microscopically  some 
blurring  of  striation,  and  that  there  is  excess  of  fat  in  the  connective  tissue 
between  the  muscle  fibers.  In  severe  cases,  fatty  degeneration  of  the 
muscle  fibers  themselves  has  been  observed. 

Viscera. — The  liver  is  sometimes  enlarged,  and  the  cause  of  this  is  not 
yet  certain.  The  surface  is  smooth;  the  consistence  is  not  appreciably 
altered.  It  is  stated  that  the  interstitial  tissue  is  chiefly  increased,  that  in 
the  portal  areas  particularly,  there  is  some  overgrowth  of  connective 
tissue,    and   some    increase    of    the    liver    cells    (Dickinson).     Jenner 


872  CONSTITUTIONAL  DISEASES 

described  an  "albuminoid"  cliangv  whifh,  whilst  givinp;  to  the  liver 
some  of  the  translucency  of  lardaccous  disease,  dill'ers  in  not  yielding  the 
iodine  reaction.  But  the  connection  of  such  changes  with  rickets  is 
quite  uncertain.  A  much  commoner  change  is  fatty  infiltration,  but  this 
certainly  is  not  peculiar  to  rickets. 

The  Spleen. — The  s])]een  is  only  occasionally  found,  at  autopsy,  to  be 
enlarged,  and  then  only  to  a  slight  degree.  This,  like  the  enlargement 
of  the  liver,  has  been  attril)uted  by  some  to  overgrowth  of  the  fibrous 
stroma,  by  others,  to  increase  of  the  cell  elements.  According  to  recent 
observations,  the  first  change  is  hyperplasia  of  the  spleen-pulp;  then 
overgrowth  of  the  perivascular  connective  tissue  and  of  the  stroma  in 
general,  and  ultimately  in  severe  cases,  replacement  of  the  parenchyma 
by  fibrous  tissue,  so  that  the  INIalpighian  corpuscles  atrophy  (Sarcinelli, 
Sasuchin). 

The  Brain. — The  brain  has  been  described  as  hypertrophied,  and  it  is 
suggested  that  this  is  due  to  increase  of  neuroglia,  but  this  has  not  been 
established.  It  was  formerly  su])i)osed  that  hydrocephalus  was  a  result 
of  rickets.  V.  Starck  states  that  in  113  autopsies  on  rickets,  he  found 
hydroce])halus  12  times.  Such  an  experience  must  be  very  exceptional; 
probably  any  association  bet\\een  rickets  and  hydrocephalus  is  nothing 
more  than  a  coincidence;  but  Stoeltzner,  whilst  denying  any  causal  con- 
nection between  rickets  and  progressive  hydrocephalus,  states  that  a 
slight  dilatation  of  the  ventricles,  insufficient  to  produce  any  untoward 
symptoms  clinically,  is  a  characteristic  feature  in  the  morbid  anatomy 
of  rickets;  the  writer  is  unable  to  confirm  this  from  his  own  experience. 

The  lungs  show  no  characteristic  change,  but  there  is  almost  always 
much  collapse  of  alveoli,  and  more  or  less  bronchitis  and  bronchopneu- 
monia. These  may  be  regarded  as  epiphenomena;  they  show  no  peculiar- 
ities to  distinguish  their  occurrence  from  that  in  any  other  diseases. 

Pathogeny. — Chemistry  of  Rickets. — The  chemical  pathology  is  at 
present  entirely  unknown.  Of  the  several  theories  which  have  been  put 
forward,  none  rests  upon  a  satisfactory  basis;  experiments  and  observa- 
tions have  been  discordant  and  contradictory.  The  facts  which  have  to 
be  explained  are  not  merely  the  softening  and  bending  of  bone,  but  the 
overgrowth  of  cartilage,  the  perversion  of  the  whole  process  of  bone  for- 
mation, and  in  addition  more  general  disturbance,  especially  in  the  nervous 
system,  and  also  in  the  muscles  and  viscera.  There  is  evidently  some 
wide  disturbance  of  metabolism. 

One  of  the  few  points  upon  Avhich  there  is  agreement  is  deficiency  of 
lime-salts  in  the  bones:  in  the  healthy  child  the  bone  yields  about  63 
to  65  per  cent,  of  earthy  salts,  and  35  to  37  per  cent,  of  organic  matter; 
in  rickets,  according  to  Friedleben,  the  tibia  yielded  37  to  48  per  cent, 
earthy  salts  and  51  to  63  per  cent,  organic  matter:  other  observations 
showed  in  rachitic  bone,  20.89  percent,  earthy  salts,  79.1  per  cent,  organic 
matter  (Boettger),  20.6  per  cent,  earthy  salts,  79.4  per  cent,  organic  matter 
(Marchand).  Deficiency  of  lime  in  the  food  w'as  found  by  Chossat  (1842) 
to  produce  fragility  of  bones  in  pigeons,  and  recently  Stoeltzner,  by  feed- 
ing puppies  on  lime-deficient  food,  produced  softening  of  bones;  but 
mere  softening  or  fragility  of  bones  is  not  rickets,  and  it  has  been  shown 
both  by  Friedleben  and  by  Stoeltzner  that  the  changes  produced  in  these 
experiments  are  not  those  characteristic  of  rickets. 


lilCKETS  S73 

Deficient  absorption  of  lime-salts  has  also  been  suggested,  but  if  this 
were  so  the  lime-salts  eliminated  in  the  urine  might  be  expected  to  be 
increased;  some  observers  have  found  this  to  be  the  case,  others  have 
found  no  difference  from  normal  urine. 

Cow's  milk  contains  .15  per  cent,  of  lime,  whereas  human  milk  contains 
only  .02  per  cent,  of  lime  (Cautley);  it  is  evident,  therefore,  that  even  when 
cow's  milk  is  given  greatly  diluted,  much  more  lime  is  supplied  to  the 
child  than  when  breast  milk  is  used:  but  rickets  is  very  much  commoner 
in  children  fed  on  cow's  milk  than  in  children  who  are  being  fed  only  on 
breast  milk.  The  facts  that  lime-water  has  no  therapeutic  value  in 
rickets,  and  that  rickets  is  so  common  in  districts  where  the  water  contains 
much  lime,  are  also  noteworthy,  but  it  is  possible  that  for  the  absorj^tion 
of  lime,  its  administration  in  organic  combination  may  be  important. 

A  relative  deficiency  of  lime,  rather  than  an  absolute,  has  been  sug- 
gested by  Kassowitz,  who  points  out  that  prolonged  hypersemia  of  bone, 
which  he  produced  by  intermittent  constriction  of  the  limb  of  a  growing 
animal,  causes  proliferation  of  cartilage  and  some  absorption  of  bone; 
the  formation  of  bone  tissue  is  in  excess,  the  supply  of  lime  salts  necessary 
for  its  perfect  calcification  is  not  correspondingly  increased.  This  theory 
presupposes  some  irritant  chemical  or  otherwise,  which  causes  prolonged 
hypersemia  and  changes  similar  to  those  of  chronic  inflammation  in  the 
areas  of  bone-formation.  No  such  irritant  is  known  to  exist  in  rickets, 
but  the  frequent  association  of  gastro-intestinal  disturbance  with  this 
disease  has  led  some  to  suggest  that  this  may  be  primary,  while  the  rick- 
ets is  the  result  of  an  intestinal  toxaemia. 

Solution  of  lime  salts  by  lactic  acid  circulating  in  the  blood  has  also 
been  suggested;  according  to  this  view,  lime  already  deposited  in  the 
bone  is  dissolved  out  by  the  acid,  or  the  acid  in  the  blood  prevents  the 
deposit  of  lime  salts.  This  theory  is  based  on  the  fact  that  starchy  food 
is  liable  to  give  rise  to  fermentation  in  the  alimentary  canal  with  the  pro- 
duction of  lactic  acid,  and  that  starchy  food  is  known  to  be  frequently 
associated  with  the  presence  of  rickets.  Lactic  acid  has  been  found  in 
the  urine  in  rickets.  It  has  been  stated  that  lime  salts  are  found  in  excess 
in  the  urine;  and  finally  Heitzmann  claimed  to  have  produced  true  rickets 
by  administering  lactic  acid  to  animals  in  their  food.  Such  a  theory,  how- 
ever, is  untenable.  It  has  been  shown  that  the  alkalinity  of  the  blood  is 
not  diminished  in  rickets  (Stoeltzner) — injections  of  lactic  acid  into  ani- 
mals and  also  a  repetition  of  Heitzmann's  experiments,  failed  to  produce 
rickets  (Spellman).  A  diet  of  meat,  which  does  not  produce  lactic  acid, 
produced  rickets  in  animals  (Guerin).  The  addition  to  the  diet  of  certain 
nutritive  elements  in  which  it  is  deficient,  cures  rickets  without  any  diminu- 
tion of  the  farinaceous  constituents  (Cheadle).  Lactic  acid  is  often  found 
in  urine  apart  from  rickets;  in  some  cases  of  rickets  there  is  no  excess  of 
lime  in  the  urine  (Zuelzer). 

Excess  of  carbonic  acid  in  the  blood  has  been  held  accountable 
(Wachsmuth)  by  keeping  the  lime  salts  in  solution:  the  only  clinical 
evidence  adduced  in  support  of  this  theory  has  been  the  occurrence  of 
rickets  in  children  living  in  ill- ventilated  rooms;  but  rickets  occurs  both 
in  children  and  in  animals  who  spend  a  large  part  of  their  time  in  the  open 
air.  The  disease  is  successfully  treated  without  any  change  beyond 
dietetic  measures  and  the  administration  of  oils.    Moreover,  there  is  no 


874  CONSTITUTIOXAL  DISEASES 

proof  that  any  such  excess  of  carbonic  acid  as  could  interfere  with  deposit 
of  Ume  salts,  exists  in  the  blood  in  rickvts.  Rickets  has  been  attributed  to 
deficiency  of  phosphoric  acid  in  the  diet,  especially  where  calcium  is 
deficient  at  the  same  time:  on  the  other  hand  the  administration  of  phos- 
phate of  potash  to  dogs  has  been  stated  to  produce  rickets  (Delcourt)  and 
Wegner  has  stated  that  by  administering  phosphorus  to  animals,  who  at 
the  same  time  were  deprived  of  lime-containing  food,  he  produced  rachitic 
lesions.  The  same  observer  found  that  by  injections  of  phosphorus  near 
the  epiphysis  of  growing  animals,  he  produced  a  change  in  the  bone  of 
inHanunatory  type.  But  none  of  these  observations  can  be  considered  as 
established,  and  although  AYcgner's  conclusion  that  rickets  is  the  result  of 
the  combined  action  of  some  irritant  on  growing  bone  and  of  a  deficient 
supply  of  lime,  may  be  correct,  his  experiments  hardly  prove  it. 

Some  experiments  have  recently  been  made  by  Frcund  on  the  relation 
between  fat  in  the  diet  and  the  absorption  of  phosphorus  from  the  food. 
He  found  that  when  infants  were  fed  upon  a  diet  of  cream  diluted  with 
water  so  as  to  contain  more  fat  than  the  diet  of  other  infants  who  were  fed 
on  milk  diluted  with  water,  the  urine  contained  a  much  larger  proportion 
of  phosphates  and  from  this  fact  and  other  results  of  his  investigations,  he 
concludes  that  when  much  fat  is  given  in  the  food,  there  is  a  much  greater 
absorption  of  phosphorus  compounds  from  the  intestine.  Possibly  this 
observation,  taken  in  conjimction  with  an  analysis  of  the  ffeces  in  rickets 
quoted  by  Ritter,  in  which  it  appeared  that  a  very  high  proportion  of 
phosphorus  compounds,  especially  calcium  phosphate,  were  excreted  in 
the  freces,  i.  e.,  were  not  absorbed  from  the  food  in  rickets,  may  serve  to 
connect  the  clinical  facts  as  regards  the  deficiency  of  fat  in  the  ricket- 
producing  diet,  and  the  therapeutic  value  of  fat,  with  the  pathological 
fact  of  deficiency  of  calcium  phosphate  in  the  bones. 

The  problem  is  obviously  extremely  complex  and  no  mere  chemical 
formula  is  likely  to  explain  a  condition  which  is  intimately  bound  up  with 
biological  processes  of  which  at  present  we  know  but  little. 

Bacteriology. — There  is  little  to  be  said  in  favor  of  an  infective  origin. 
Mircoli,  on  grounds  of  theory  and  experiment,  has  suggested  that  the 
bony  changes  are  of  the  nature  of  an  attenuated  and  chronic  form  of 
osteomyelitis,  and  that  this  is  produced  by  streptococci  and  staphylococci, 
which  reach  the  tissues  from  the  alimentary  canal.  Morpurgo  claims  to 
have  produced  rickets  by  injecting  a  certain  diplococcus  into  young  rats. 
Spellman  inoculated  animals  with  pieces  of  bone  from  rachitic  infants 
and  also  with  the  diarrhoeal  stools  of  rachitic  infants,  but  in  127  of  these 
and  other  similar  observations,  only  once  foimd  any  rickets  (Freeman). 
Up  to  the  present  it  cannot  be  said  that  there  is  any  proof  that  rickets 
is  ever  produced  by  bacterial  infection. 

SjnnptoniS. — Rickets  is  a  disorder  of  nutrition,  and,  as  such,  affects 
the  whole  organism.  The  bone  changes  are  only  part  of  a  general  disease. 
Much  of  the  confusion  as  to  the  pathogeny  and  even  the  diagnosis  has 
resulted  horn  the  tendency  to  concentrate  attention  upon  the  osseous 
lesions  to  the  exclusion  of  other  features.  A  child  may  suffer  severely 
and  yet  show  so  slight  a  degree  of  rachitic  change  in  the  bones  that  the 
disease  might  almost  pass  unnoticed  if  only  the  osseous  system  were 
considered.    The  stress  may  fall  upon  the  nervous  system  in  one  case, 


RICKETS  875 

upon  the  muscular  in  another,  and  perhaps  even  upon  the  blood  and  blood- 
forming  tissues  in  a  third. 

Before  describing  the  symptoms  in  detail,  an  outline  of  a  typical  and 
well-marked  case  of  rickets  may  be  given.  An  infant  aged  about  eighteen 
months  is  brought  for  inability  to  walk.  He  has  been  suckled  entirely 
perhaps  for  six  or  seven  months,  and  then  has  had  condensed  milk  and 
occasionally  bread  or  potato.  For  some  months  past,  he  has  sweated 
profusely  about  the  head  and  neck  whenever  he  falls  asleep.  Dentition 
did  not  begin  until  he  was  nearly  a  year  old,  and  even  now  ho  has  but  three 
or  four  teeth.  He  has  never  walked,  and  sitting  on  the  mother's  lap  there 
is  a  marked  kyphosis  especially  in  the  upper  lumbar  region.  He  is  pale  and 
fretful;  perhaps  rather  fat,  but  flabby;  the  head  is  unduly  large,  with  a 
tendency  to  squareness;  the  anterior  fontanelle  is  much  more  widely  open 
than  it  should  be  at  this  age.  The  chest  is  ill  shaped,  the  sternum  a  little 
prominent,  and  there  is  some  transverse  constriction  below  the  level  of 
the  nipples.  A  row  of  knob-like  eminences  rfiark  the  junctions  of  the 
costal  cartilages  with  the  ribs  on  each  side  of  the  chest;  the  lower  ribs  are 
somewhat  everted  above  the  big  abdomen,  in  which  the  liver  can  easily 
be  felt,  and  the  spleen  is  also  just  palpable.  The  muscles  feel  flabby  and 
soft.  Just  above  the  ankle  and  the  wrist,  the  bones  seem  thickened. 
There  is  little  or  no  abnormal  curvature  of  the  bones. 

Such  is  a  moderate  degree  of  rickets;  but  there  are  many  more  in  which 
the  symptoms  are  altogether  less  marked,  and  perhaps  delay  of  dentition 
and  of  closure  of  the  fontanelle,with  slight  thickening  at  the  costochondral 
functions  (beading  of  the  ribs),  and  possibly,  but  not  necessarily,  some 
enlargement  of  the  radial  epiphysis,  are  the  only  evidences  of  the  disease. 
There  are  also  cases,  much  less  frequent,  in  which  the  symptoms  are 
altogether  more  severe,  the  limbs  are  deformed  by  various  bendings  and 
distortions  of  the  bones,  the  cranium  is  irregularly  thickened  or  thinned, 
and  the  child  perhaps  shows  severe  nervous  symptoms,  convulsions,  or 
laryngismus  stridulus. 

Nutrition. — The  child  is  often  unduly  fat  especially  in  slight,  or  moder- 
ate degrees  of  rickets.  This  deposit  of  fat  is  apparently  derived  from 
carbohydrate  food,  for  it  is  seen  where  the  diet  is  greatly  deficient  in  fat. 
It  would  seem  also  that  this  stored  fat  is  unable  to  replace  the  functions 
of  fat  taken  as  such  in  the  food.  In  severe  rickets  wasting  of  greater  or 
less  degree  is  common. 

Head  Sweating. — This  is  often  one  of  the  earliest  symptoms  and  may 
be  so  profuse  that  the  pillow  is  soaked.  It  usually  occurs  when  the  child 
falls  asleep;  it  is  not  present  in  all  cases.  Probably  with  this  is  associated 
a  feeling  of  heat,  for  the  infant  at  this  stage  is  very  apt  to  push  the  bed- 
clothes off  at  night  and  lies  uncovered. 

Temperature. — This  is  normal  in  most  cases  even  during  the  most  active 
stage  of  the  disease,  so  far  as  the  writer's  observations  go;  a  rise  of 
temperature  is  almost  always  due  to  some  complication. 

Teeth. — Delayed  dentition  is  one  of  the  most  constant  symptoms. 
In  32  out  of  42  consecutive  cases,  between  nine  months  and  three  years 
old,  this  was  present.  Frequently  no  teeth  have  appeared  at  the  end  of 
the  first  year.  Rarely  their  appearance  is  delayed  beyond  the  age  of 
eighteen  months.  There  is  a  striking  tendency  to  very  early  caries;  even 
before  the  tooth  is  fully  cut  the  enamel  at  the  cutting  edge  is  often  com- 


876  CONSTITUTIONAL  DISEASES 

pletely  destroyed.    If  dentition  has  begun  before  the  onset  of  rickets,  it 

is  often  arrested  for  several  months. 

Muscular  Weakness:  Laxity  of  Ligaments. — Muscular  weakness 
is  a  very  common  result  in  the  active  stage  of  the  disease,  and  in  the 
more  severe  cases  is  almost  always  well  marked.  It  may  be  quite  out  of 
proportion  to  the  osseous  changes,  and  for  this  reason  is  liable  to  be  mis- 
taken for  some  paralysis  of  nervous  origin;  it  may  be  so  great  that 
a  child  of  two  or  three  years  is  unable  to  stand  or  even  to  sit  up.  The 
late  acquirement  of  sitting,  standing,  and  walking,  is  chiefly  due  to  this 
weakness,  though  in  part,  no  doubt,  to  laxity  of  ligaments,  and  to  bone 
changes.  The  child  who  has  already  begun  to  stand  often  loses  this 
power  at  the  onset,  so  that  he  is  said  to  have  "gone  off  his  legs."  The 
stooping  of  the  back,  or  kyphosis,  which  is  common  in  rachitic  children, 
would  seem  to  depend  chiefly  upon  weakness  of  the  muscles  of  the  back. 
It  is  possible  that  muscular  weakness  of  the  respiratory  muscles  plays 
some  part  in  the  tendency  to  ])ulmonary  affections. 

The  effects  of  muscular  weakness  are  intensified  by  laxity  of  the 
ligaments,  apparently  as  the  result  of  some  structural  change  which  has 
not  yet  been  determined,  but  which  renders  them  soft  and  yielding.  The 
child  can  often  place  his  toes  behind  the  ears  without  difficulty;  and  the 
head  of  the  tibia  shows  an  undue  amount  of  lateral  mobility,  so  that  it  can 
be  loosely  knocked  against  the  condyles  of  the  femur.  Both  these  changes, 
the  muscular  and  the  ligamentous,  contribute  to  some  of  the  deformities, 
such  as  talipes  valgus  and  planus,  genu  valgum  and  varum,  and  lateral 
curvature  of  the  spine. 

Osseous  Symptoms. — These  are  the  outcome  of  the  delayed  and 
imperfect  ossification,  hyperplasia,  and  abnormal  absorption  of  bone 
tissue.  The  most  frequent  manifestation  is  the  so-called  "rickety  rosary," 
or  beading  of  the  ribs,  a  thickening  at  the  costochondral  junction  which 
in  a  thin  child  can  be  seen  and  in  others  easily  felt.  These  beads  are 
usually  largest  and  most  readily  felt  on  the  fifth,  sixth  and  seventh  ribs, 
and  in  a  mild  case  may  be  scarcely  perceptible  on  other  ribs.  They  are 
often  seen  postmortem  to  be  more  marked  on  the  internal  than  on  the 
external  surface  of  the  thorax  (Fig.  69).  The  internal  bead,  however, 
is  sometimes  exaggerated  by  a  displacement  of  the  bony  rib  backward  at 
the  costochondral  junction,  so  that,  instead  of  joining  the  cartilage  end 
to  end,  it  joins  it  at  an  angle  which  projects  on  the  inner  aspect  of  the 
thorax  (Fig.  70).  In  such  cases  the  external  beading  may  be  obscured 
altogether,  and  the  junction  of  rib  and  cartilage  forms  a  depression 
externally,  so  that,  clinically,  beading  may  not  be  detected. 

The  rickety  rosary  is  one  of  the  earliest  symptoms  and  is  often  the  only 
bone  change  to  be  found  during  life.  It  gradually  dim.inishes  after  the 
fourth  and  fifth  year  and  has  usually  disappeared  before  puberty. 

As  a  result  of  the  backward  displacement  of  the  anterior  portion  of  the 
rib,  in  some  cases  there  is  an  exaggeration  of  the  angle  of  the  rib,  poster- 
iorly, or  actually  a  greenstick  fracture  at  that  situation;  the  projections 
formed  thus  are  sometimes  described  as  "posterior  beading,"  but  are 
obviously  different  in  their  pathology  from  the  anterior  "rickety  rosary." 
Enlargement  of  epiphyses  is  a  very  common  symptom.  It  is  generally 
most  marked  at  the  lower  end  of  the  radius,  where  some  thickening  was 
present  in  64  per  cent,  of  the  writer's  cases.    At  the  lower  end  of  the  femur 


RICKETS  877 

and  tibia  it  is  also  frequent.  Other  long  bones  show  it  less  frequently. 
The  ends  of  the  phalanges  of  the  fingers  are  oeeasionally  affeeted  giving 
a  somewhat  spindle-shaped  appearance.  Some  thickening  of  the  diaphy- 
sis  of  the  phalanges  has  also  been  described  (Koplik). 

Fig.  09. 


Anterior  wall  of  thorax,  internal  surface  showing  extreme  rickety  deformity;  sternum  and 
cartilages  project  forward  in  front  of  the  internal  beading  which  is  seen  to  consist  partly  oS 
a  sharply  angular  junction  between  bony  rib  and  cartilage. 

Owing  to  the  softness  of  the  bones,  some  degree  of  curvature  in  the 
limbs  is  common :  43  per  cent,  of  the  writer's  patients  showed  curvature 
of  the  bones  either  in  the  upper  or  in  the  lower  limbs,  but  in  most  of 
these  the  bending  was  slight  in  degree.  The  commonest  deformity  of 
this  kind  is  a  bending  outward  of  the  lower  third  of  the  tibia, — sometimes 
there  is  combined  with  this,  or  alone,  a  forward  bend  which  may  be  slight 
or  may  be  sharply  angular  in  the  lower  third.    (Fig.  71.) 

The  femur  is  less  often  affected;  it  shows  a  general  outward  curve  in 
children  who  are  already  able  to  stand  or  walk  when  the  rickets  affects 
them.  In  children  who  are  being  carried  about  on  the  nurse's  arm,  the 
curve  in  the  femur  is  often  anteroposterior  with  the  convexity  forw^ard. 
A  much  rarer  result  of  rickets  is  the  condition  known  as  "coxa  vara,''  in 
which  the  head  of  the  femur  is  bent  downward  so  that  it  is  at  the  same 
level  with,  or  even  lower  than,  the  great  trochanter,  while  the  neck  of  the 
femur  is  curved  with  the  convexity  forward  and  upward.  Bending  of  the 
bones  of  the  upper  limbs  takes  place  chiefly  in  children  who  spend  much 
of  their  time  crawling  about  or  in  the  sitting  position  supporting  the  weight 
of  the  trunk  partly  upon  the  hands ;  a  favorite  position  is  that  showm  in 


878 


CONSTITUTIOXAL  DISEASES 


the  illustration  (Fig.  72),  where  the  child  sits  tailor-wise  and  uses  its 
hands  as  a  prop.    Both  the  humerus  antl  the  bones  of  the  forearm  are 
usually  curved  outward  in  such  cases. 
The  clavicle,  in  severe  cases,  often  shows  a  sharp  angular  bend  forward 


Fin.  70. 


Anteroposterior  section  of  costochon- 
dral  junction  to  show  rachitic  disi)lace- 
ment.  In  the  upper  specimen  the  dis- 
placement is  slight,  in  the  lower,  which 
was  taken  from  the  chest  shown  in  Fig. 
69,  there  is  complete  displacement. 

and  uj)ward  at  the  junction  of  the  inner  and 
middle  third;  and  sometimes  there  is  evident 
thickening  here,  the  result  of  a  greenstick 
fracture. 

All  these  deformities  are  the  result  partly  of 
pressure  from  without,  partly  of  the  weight  of 
the  body,  and  partly  of  muscular  traction  upon 
the  softened  bones. 

Similar  in  their  production  are  the  rachitic 
deformities  of  the  thorax  and  pelvis.  The  for- 
mer shows  a  lateral  contraction  so  that  the 
sternum  and  costal  cartilage  appear  to  project 
forward  in  front  of  the  ribs,  while  the  depres- 
sion at  the  junction  of  each  rib  and  cartilage 
forms  a  furrow  passing  downward  and  out- 
ward and  usually  lost  in  a  deeper  transverse 
groove  just  below  the  level  of  the  nipple,  the 
so-called  "Harrison's  sulcus."  This  sulcus, 
which  extends  from  the  ensiform  cartilage  to  the  posterior  axillary  line, 
is  commonly  associated  with  eversion  of  the  lower  ribs  over  a  dis- 
tended abdomen  which  increases  the  distorted  apjiearance  of  the  chest. 
The  pigeon  chest  (pectus  carijiatuvi)  in  which  the  ribs  appear  straightened 
as  they  pass  from  the  posterior  axilla  to  join  the  prominent  sternum  so 
that  the  cross-section  of  the  thorax  would  be  roughly  triangular  with  the 
apex  at  the  sternum,  is  often  described  among  rachitic  deformities. 
Neither  pigeon  chest,  however,  nor  "Harrison's  sulcus"  are  essentially 
rachitic.  They  are  seen  in  any  condition  in  which  there  is  obstructed 
respiration. 


Photograph  of  a  cast  at  the 
museum  'of  the  Hospital  for 
Sick  Children,  Great  Ormond 
Street,  London,  showing  a 
common  rhachitic  curvature  of 
tibia. 


RICKETS 


879 


Pelvic  deformities  hardly  enter  into  the  clinical  picture  of  rickets  in 
childhood,  for  they  attract  no  attention  at  that  age,  although  in  the  adult 
female  they  become  of  great  importance.  Rickets  here,  as  in  the  rest  of 
the  bones,  may  arrest  development  so  that  the  pelvis  remains  small  and 
generally  contracted.  Often  there  is  in  addition  flattening  of  the  pelvis 
antero-posteriorly;  it  is  shallow,  and,  occasionally,  from  traction  of  the 
muscles  and  the  pressure  transmitted  from  the  spine  and  from  the  femora, 
more  marked  distortion  takes  place. 


Fig.  72. 


Common  position  of  rickety  child  witli  bending  of  forearm,  showing  also  large  head,  large 
abdomen  and  deformed  thorax  with  Harrison's  sulcus. 

The  bones  in  rickets  become  not  only  soft  but  brittle,  so  that  fractures, 
usually  of  greenstick  character,  are  apt  to  occur  in  severe  cases  with  little 
evidence  of  traumatism,  sometimes  apparently  from  muscular  traction 
alone.  This  tendency  depends  partly  on  absorption  of  cancellous  tissue 
in  the  rickety  bone,  partly  on  deficient  calcification,  and  partly  perhaps 
upon  some  abnormal  arrangement  of  the  trabecuhe  in  the  substance. 

As  a  result  of  the  epiphyseal  affection  and  of  the  sclerosis  which  may 
occur  in  the  bones  after  the  rachitic  process  has  ceased  to  be  active,  per- 
manent stunting  of  growth  occasionally  takes  place,  so  that  the  child 
may  be  undergrown  or  actually  dwarfed  for  the  rest  of  its  life. 

Cranium. — One  of  the  most  constant  symptoms  is  d  Jay  in  the  closure 
of  the  anterior  fontanelle.  Normally  this  should  measure  about  f  t"  1 
inch  (2  to  2.5  cm.)  antero-posteriorly  and  transversely  at  the  end  of  the 


880  COXSTITVTIOXAL  DISEASES 

first  year  and  should  close  at  or  ;il)()ut  the  age  of  eighteen  months.  In 
rickets,  it  often  measures  2  inches  (5  cm.)  in  both  directions  at  twelve 
months,  and  is  frequently  open  as  late  as  two  and  a  half  or  three  years; 
the  writer  found  it  o])en  at  four  and  one-half  years.  This  delay  of  closure 
is  not  due  to  any  general  expansion  of  the  skull  such  as  occurs  in  hydro- 
cephalus, for  it  occurs  equally  where  there  is  no  enlargement  of  the  head 
and  where  the  head  is,  as  often  happens  in  rickets,  unduly  large;  it  indi- 
cates rather  the  general  backwardness  in  bone  formation  which  is  one  of 
the  features  of  the  disease  and  which  may  determine  more  extensive  fail- 
ure of  consolidation  in  the  cranium  so  that  the  interparietal  and  the 
parietooccijntal  sutures  arc  not  firmly  united  for  many  months. 

The  size  of  the  head  is  conunouly  above  the  normal;  in  17  cases  of 
rickets  with  an  average  age  of  4.72  years,  I.ucas^  found  that  the  average 
circumference  was  21.2  inches  (54  cm.),  whereas  in  17  non-rachitic  children 
with  an  average  age  of  (3.05  years,  the  average  circumference  was  19.95 
inches  (50.5  cm.).  The  cause  of  this  increase  in  size  is  uncertain;  some- 
times the  brain  has  been  found  above  the  average  weight  and  in  some 
cases  there  is  considerable  thickening  of  the  bones  of  the  skull,  though 
hardly  sufficient  to  account  for  the  large  size. ' 

The  rachitic  skull  differs  from  the  normal  not  only  in  size  but  also  in 
shape.  Two  types  may  be  recognized.  In  the  one,  the  more  frequent, 
the  skull  is  flattened  on  the  vertex  and  tending  to  squareness,  the  posterior 
segment  especially  is  enlarged;  in  the  other  the  head  is  narrow  from  side 
to  side  and  elongated  antero-posteriorly. 

The  softening  of  the  bones  is  sho^^•n  in  the  skull  by  the  deep  grooves 
which  are  hollowed  out  on  its  surface  by  the  veins  of  the  scalp  so  that 
their  course  can  easily  be  traced  by  running  one's  finger-nail  along  the 
groove. 

The  relation  of  bossing  of  the  skull  and  of  craniotabes  to  rickets  has 
been  much  disputed.  Both  have  been  attributed  to  syphilis  by  some,  and 
to  rickets  by  others.  So  far  as  personal  observations  go,  both  seem  to 
occur  in  rickets  apart  from  syphilis  but  to  be  aggravated  when  syphilis 
is  added  to  rickets.  Some  have  thought  that  the  symmetrical  bosses 
which  occur  on  the  frontal  and  parietal  bones,  giving  rise  to  the  "caput 
quacbxitum"  or  "hof-rross-bvn  head,"  can  be  distinguished  by  their  position 
from  those  of  syphilis,  which  are  said  to  be  closer  to  the  anterior  fonta- 
nelle.  However  this  may  be,  there  are  certainly  two  conditions,  very 
different  in  appearance,  which  give  rise  to  the  local  thickenings  felt  on 
the  skull.  In  the  one,  the  surface  of  the  bone  is  smooth  and  the  thickening 
is  due  to  a  very  vascular  increase  of  the  cancellous  tissue  between  the 
compact  inner  and  outer  tables;  in  the  other,  there  is  a  deposit  of  vas- 
cular spongy  bone  on  the  outer  surface  of  the  skull,  which  has  a  roughened, 
worm-eaten  appearance.  Whether  these  represent  difPerent  stages  of 
one  and  the  same  process  or  whether  they  indicate  different  processes 
is  at  present  uncertain. 

The  term  "craniotabes"  is  used  with  varying  significance.  Some  would 
apply  it  to  a  diffuse  yielding  of  bone  near  the  sutures,  especially  about  the 
parietooccipital  sutures,  which  is  not  uncommon  in  rachitic  children 
under  twelve  months  of  age  and  is  exceedingly  common  in  infants  during 

^  Pathological  Society  Transactions,  Vol.  xxxii,  p.  359. 


RICKETS 


881 


Fig.  7a. 


Posterior  view  of  rachitic  skull,  show- 
ing characteristic  areas  of  true  craniotabes. 


the  first  two  months  of  life.  In  early  infancy  this  thinness  of  the  bone  is 
often  associated  with  unusual  separation  of  sutures  and  patency  of  the 
fontanelles,  posterior  and  lateral  as  well  as  anterior.  It  is  very  doubtful 
whether  such  a  condition  should  be  taken  as  necessarily  indicating  rickets; 
certainly  it  is  quite  common  during  the  first  three  or  four  months  of  life 
in  breast-fed  infants,  particularly  those  of  small  size  and  generally  feeble 
development,  with  no  other  evidence  whatever  of  rickets. 

Much  more  significant  are  localized  patches  of  thinning  of  the  bone 
situated  generally  in  the  occipital  or  in  the  parietal  bone  (more  commonly 
the  latter)  near  to,  but  not  actually  adjoining,  the  parietooccipital  suture, 
from  which  they  are  separated  by  an  area  of  firm  bone  (Fig.  73).  The 
patches  are  usually  about  J  to  1  inch 
(1.5  to  2.5  cm.)  in  diameter,  round  or 
oval,  and  can  be  detected  by  taking  the 
head  between  the  palms  of  the  hands  so 
that  the  fingers  rest  on  the  posterior 
parietal  and  occipital  region.  On  press- 
ing firmly  with  the  fingers,  the  affected 
areas  are  felt  to  yield,  bulging  inward 
like  a  piece  of  thick  parchment  and 
rebounding  when  pressure  is  removed. 
In  severe  cases  these  areas  run  together, 
but  even  then  the  irregular  and  patchy 
distribution  distinguishes  them  usually 
from  the  diffuse  thinness  mentioned 
above. 

This  condition,  unlike  the  diffuse  thinness  of  the  edge  of  the  bone,  is 
often  found  when  the  sutures  are  well  closed  and  only  the  anterior  fon- 
tanelle  remains  patent.  It  occurs  often  in  the  second  year  of  life  in  chil- 
dren who  have  only  developed  rickets  after  the  skull  bones  are  already 
well  ossified.  It  is  an  absorption  of  already  formed  bone,  not  a  mere 
delay  of  development  as  the  diffuse  thinness  with  patent  sutures  prob- 
ably is  in  some  cases. 

According  to  the  meaning  attached  to  craniotabes,  its  frequency  has 
varied  in  statistics.  According  to  some  recent  observations  made  by  S. 
Fraser  upon  children  under  three  years  of  age  at  the  Children's  Hospital, 
Great  Ormond  street,  London,  29  per  cent,  of  the  rickety  children  showed 
craniotabes,  but  this  series  included  many  cases  in  which  there  was  only 
yielding  of  the  bones  near  the  sutures. 

There  can  be  no  doubt  that  craniotabes  occurs  with  rickets  without 
syphilis.  In  the  form  of  isolated  patches  it  is  associated  particularly  with 
laryngismus  stridulus  and  tetany,  the  former  of  which,  if  not  also  the 
latter,  when  it  occurs  in  childhood,  occurs  almost  exclusively  in  the 
rachitic  and  has  no  connection  with  syphilis.  Out  of  21  cases  of  larjmgis- 
mus  stridulus  in  which  the  writer  noted  this  point,  craniotabes  was  present 
in  7.  According  to  Barlow  and  Lees,  47  per  cent,  of  cases  of  cranio- 
tabes show  evidence  of  syphilis;  but  many  of  their  cases  with  sypliiUs 
had  rickets. 

Nervous    Symptoms. — Mental. — The  rickety  infant  is  often  fretful 
and  peevish,  but  perhaps  more  from  the  discomfort  of  prolonged  ill-feed- 
ing than  from  any  direct  effect  of  the  disease.    In  later  childhood,  rickets 
56 


882  CONSTITUNIONAL  DISEASES 

has  been  described  as  a  cause  of  precocity,  and  the  large  head  has  been 
supposed  to  allow  a  larger  capacity  for  mental  development.  Thackeray 
has  been  quoted  as  an  instance.  The  accuracy  of  these  observations  is 
very  questionable;  the  child  who  is  invalided  by  any  chronic  disease  is 
likely  to  be  much  with  its  elders  and  to  accpiire  a  precocious  manner 
in  consequence.  The  writer  is  quite  unable  from  his  own  observation  to 
afHrm  any  intellectual  superiority  in  rachitic  children.  There  is  no  evi- 
dence that  they  are  inferior,  although  it  was  stated  by  Sir  W.  Jenner*  that 
"Children,  the  subjects  of  extreme  rickets,  are  almost  always  deficient  in 
intellectual  capacity  and  power." 

Convulsive  conditions  are  the  chief  evidence  of  rickets  affecting  the 
nervous  system:  from  about  the  sixth  to  the  twenty-fourth  month  con- 
vulsions in  infancy  are  most  often  due  to  it.  The  cortex  is  in  some  way 
rendered  so  unstable  that  trivial  exciting  causes,  such  as  constipation 
or  dentition,  are  sufficient  to  induce  an  attack.  As  part  of  this  convulsive 
tendency  must  be  reckoned  laryngismus  stridulus  and  tetany  Avith  their 
almost  constant  accompaniment — the  so-called  "facial  irritability." 

In  laryngismus  stridulus,  a  spasm  of  the  larynx  suddenly  closes  the 
glottis  so  that  the  infant  is  for  a  few  seconds  unable  to  draw  air  into  the 
chest:  the  face  becomes  livid,  the  infant  looks  terrified,  and  makes  violent 
eft'orts  to  inspire.  After  a  few  seconds  the  spasm  relaxes  and  a  deep  in- 
spiration is  taken  with  a  loud  crowing  noise.  These  attacks  come  on 
usually  when  the  infant  begins  to  cry  or  just  as  it  wakes,  or  a  sudden 
draught  of  cold  air  may  start  the  attack.  There  may  be  many  in  the  day, 
or  only  two  or  three  in  a  week.  If  the  spasm  is  prolonged  many  seconds, 
the  infant  becomes  cyanosed  and  may  pass  into  a  general  convulsion,  or 
may  die  silently  of  asphyxia.  These  attacks  occur  most  often  between 
the  ages  of  six  and  eighteen  months ;  they  are  rare  after  the  age  of  two 
years.  Of  35  cases,  32  showed  definite  rickets,  2  probable  rickets;  only 
1  showed  no  bone  manifestations  of  rickets. 

Tetany,  a  tonic  spasm  affecting  chiefly  the  muscles  of  the  forearm  and 
hand,  and  leg  and  foot,  is  in  young  children  almost  always  associated 
with  rickets.  The  hand  is  generally  slightly  flexed  at  the  wrist,  the  thumb 
is  adducted  so  that  its  tip  points  to  the  interval  between  the  ring-  and  the 
mid-finger,  the  rest  of  the  fingers  are  semi-flexed  at  the  metacarpopha- 
langeal and  extended  at  the  phalangeal  joints,  often  with  some  tendency 
to  overextension  at  these  latter.  The  toes  are  crowded  together  in  a 
position  as  far  as  possible  resembling  that  of  the  fingers;  the  foot  is  some- 
times extended  at  the  ankle.  Apparently  from  some  pressure  on  veins 
by  the  contracting  muscles,  oedema  of  the  hands  and  feet  is  often  seen 
with  the  tetany.  The  spasm  of  tetany  is  in  some  cases  persistent  for 
several  hours  or  even  for  days;  in  others  it  is  intermittent,  lasting  only 
a  few  minutes  at  a  time  and  causing  some  cramp-like  pain  each  time  it 
recurs.  It  is  most  frequent  at  the  age  at  which  laryngismus  stridulus  is 
common,  and  is  usually  associated  therewith. 

A  latent  form  of  tetany  is  not  uncommon  in  rickety  children;  it  is  dem- 
onstrated by  the  method  described  by  Trousseau :  the  upper  arm  is  firmly 
grasped  in  such  a  way  as  to  compress  the  vessels  and  nerves  on  the  inner 
side  of  the  arm,  and  after  a  period  varying  from  thirty  seconds  to  about 
two  minutes,  the  hand  assumes  the  characteristic  position  of  tetany. 
^Lectures  on  Rickets,  Vol.  iii,  p.  416. 


RICKETS  883 

Of  24  cases  of  tetany  in  young  children,  22  showed  definite  rickets, 
1  doubtful  rickets,  and  1  no  bone  manifestations  of  rickets.  Twenty- 
three  of  these  cases  were  associated  with  laryngismus  stridulus. 

Facial  irritability,  Chvostek's  sign,  is  also  closely  related  and  par- 
ticularly to  the  convulsive  manifestations.  On  gentle  tapping  over 
superficial  branches  of  motor  nerves,  a  contraction  of  the  corres[)onding 
muscles  occurs.  This  was  first  described  with  regard  to  the  face,  but  is 
to  be  seen  in  the  limbs  also.  Of  35  cases  of  laryngismus  stridulus,  33 
showed  this  nerve  irritability;  and  it  is  almost  always  present  with 
tetany  whether  this  is  associated  with  laryngismus  stridulus  or  not. 
Facial  irritability  is  found  in  rickets  also  apart  from  laryngismus 
stridulus  and  tetany,  and  is  then  probably  always  an  indication  of  a  con- 
vulsive tendency.  In  some  of  these  cases  there  is  a  history  of  preceding 
convulsions;  in  others,  after  the  facial  irritability  has  been  observed, 
coiivulsions  occur.  It  is  therefore  of  practical  value  as  indicating  the 
need  for  such  drugs  as  bromides,  by  which  convulsions  may  be  averted. 
This  nerve  irritability  is  probably  most  common  in  the  face,  but  as  the 
writer  has  notes  of  cases  in  which  it  was  in  the  limbs  only,  the  term  facial 
irritability  is  not  sufficiently  conclusive. 

Head  nodding  with  nystagmus  (spasmus  nutans)  needs  only  to  be 
mentioned  here,  for,  although  it  is  generally  associated  (Hadden,  J. 
Thomson),  the  rickets  ic  regarded  only  as  a  predisposing  cause. 

The  pronounced  nervous  instability  may  show  itself  in  other  ways, — 
a  rhythmic  head-rolling  upon  the  pillow  so  that  the  back  of  the  head  is 
rubbed  almost  bald,  or  a  head-banging  in  which  the  child  beats  its  head 
with  its  hands  or  against  any  object  near,  are  both  seen  most  often  in 
rickety  children,  although  the  determining  cause  may  be  some  peripheral 
irritation,  dentition,  or  middle-ear  catarrh. 

Hydrocephalus  was  regarded  by  Jenner  as  sometimes  produced  by 
rickets  but  this  view  is  now  generally  discarded.  The  large  head  of 
rickets,  especially  when  the  square  shape  is  less  pronounced  than  usual, 
may  simulate  hydrocephalus,  but  is  probably  rarely,  if  ever,  due  to  dis- 
tension of  the  ventricles. 

The  association  of  zonular  or  lamellar  cataract  with  rickets,  and  espe- 
cially with  convulsions,  has  been  noticed  by  several  observers  since  David- 
son and  Horner  of  Zurich  first  drew  attention  to  it  in  1865. 

Tenderness. — It  is  generally  stated  that  there  is  some  tenderness 
present  not  only  in  the  bones  but  also  in  the  muscles  (Gee).  Hilton 
Fagge  described  this  as  one  of  the  characteristic  features.  If  such  a 
condition  occurs  at  all,  it  must  be  quite  exceptional.  The  rickety  child 
is  often  fretful  and  nervous,  resents,  or  is  frightened  by,  any  examination; 
but  if  there  is  definite  tenderness,  the  presence  of  scurvy  with  the  rickets 
should  be  suspected. 

Gastro-intestinal  Symptoms.— The  abdomen  is  usually  distended  so 
that  the  rachitic  "pot-belly"  has  become  a  recognized  term.  The  dis- 
tension is  due  to  three  causes, — flatulence  arising  from  improper  feed- 
ing; displacement  downward  of  the  liver  and  spleen  by  eversion  of  the 
lower  ribs;  diminished  space  in  the  small  pelvis;  probably  to  these 
may  be  added  relaxation  of  the  abdorninal  muscles  so  that  they  afford 
less  support  than  normal. 


884  CONSTITUTIONAL  DISEASES 

As  a  result  of  this  distension,  the  recti  muscles  arc  often  separated  so 
that  there  may  be  a  gap  of  1  inch  (2.5  cm.)  between  them,  where  the 
abdominal  wall  is  jmtt'ed  out  in  a  bulging  ridge  when  the  child  lies  on  its 
back  putting  the  abdominal  wall  on  the  stretch;  but  this  is  not  peculiar 
to  rickets;  it  occurs  in  young  childern  with  chronic  distension  of  the 
abdomen  from  any  cause 

In  the  gastro-intestinal,  as  in  the  pulmonary  mucosa,  there  is  a  special 
tendency  to  catarrh. 

The  liver  is  often  to  be  felt  1  inch  (2.5  cm.)  or  more  below  the  costal 
margin,  but  this  is  due  in  many  cases,  partly  at  least,  to  disi)lacement 
downward  by  eversion  of  the  ribs.  The  si)leen,  for  the  same  reason,  is 
often  felt  \  to  1  inch  (1.5  to  2.5  cm.)  below  the  costal  margin;  it  is  probably 
but  seldom  enlarged  to  any  considerable  extent,  unless  the  condition 
known  as  splenic  anicmia  is  to  be  regarded  as  a  manifestation  of  rickets. 
Kiittner  found  the  spleen  enlarged  in  44  out  of  GO  cases;  in  33  it  was  just 
palpable;  in  9  it  was  two  finger-breadths  below  the  costal  margin  and  in 
2  there  was  great  hypertrophy. 

Respiratory  System. — The  laryngeal  spasm  has  already  been  de- 
scribed. Bronchitis  is  very  frequent  in  rachitic  children,  and  this  ten- 
dency is  favored,  in  severe  cases,  by  the  softness  of  the  ribs  and  the  weak- 
ness of  the  resj)iratory  muscles.  There  is,  in  fact,  a  vicious  circle.  For 
the  mechanical  reasons  mentioned,  the  lung  is  very  imperfectly  filled  with 
air  and  the  collapse  thus  induced  favors  the  occurrence  of  bronchitis  and 
hence  further  collapse.  The  movements  of  the  diaphragm  also  must  be 
rendered  less  extensive  by  the  eversion  of  the  lower  ribs,  and  at  the  same 
time  hampered  by  the  abdominal  distension. 

Circulatory  Symptoms. — Antemia  is  common  and  sometimes  very  pro- 
found. In  severe  cases,  the  child  may  have  a  waxy  complexion  not  unlike 
that  of  chlorosis  and  Hutchison  has  referred  to  cases  in  which  the  blood 
changes  corresponded.  In  a  rickety  infant  aged  one  year  and  seven 
months,  the  blood  showed  four  million  red  corpuscles  and  only  20  per  cent, 
haemoglobin;  in  another  child,  aged  three  years,  with  rickets,  the  red  cells 
numbered  five  million,  the  hremoglobin  was  only  31  per  cent.  The  leuko- 
cyte count  shows  nothing  characteristic;  some  observations  by  Thursfield 
and  Drysdnle^  gave  the  following  results:  Haemoglobin,  44  per  cent.; 
red  corpuscles,  4,364,000;  white  corpuscles,  11,000;  polymorphonuclears, 
49.2  per  cent.;  lymphocytes,  46.8  per  cent„;  large  mononuclears,  3.3  per 
cent.;  eosinophiles,  .5  per  cent.;  myelocytes,  0;  occasional  nucleated  red 
corpuscles.  This  would  agree  very  nearly  with  the  average  proportions 
of  the  differential  count  for  a  healthy  infant  of  about  twelve  months, 
except  perhaps  for  a  very  slight  increase  of  polymorphonuclear  cells. 

A  systolic  bruit  is  frequently  heard  over  the  open  anterior  fontanelle, 
and  was  formerly  thought  to  be  of  value  in  the  diagnosis  between  a 
rachitic  and  a  hydrocephalic  head  (Rilliet  and  Barthez).  It  is,  however, 
as  Osler^  has  shown,  frequent  in  infants  and  young  children  who  are  free 
from  rickets;  it  is  heard  most  commonly  in  the  second  year  of  life  but 
may  be  heard  as  late  as  the  sixth  year. 

Complications. — Bronchitis  has  already  been  mentioned  as  extremely 
frequent.     Bronchopneumonia  is  also  common  and  is  one  of  the  chief 

^Med-Chir.  Society  Transactions,  1904. 

^Boston  Medical  and  Surgical  Journal,  CIII,  No.  2,  p.  29. 


RICKETS  885 

sources  of  danger  to  life,  especially  where  there  is  much  rachitic  deformity 
of  the  chest. 

Gastro-intestinal  catarrh  and  diarrhoea  are  common  accompaniments 
and  considerable  dilatation  of  the  stomach  is  sometimes  evident  both 
clinically  and  postmortem. 

Infantile  scurvy  is  an  occasional  complication,  but  the  association  is 
to  be  regarded  as  a  coincidence;  there  is  no  essential  connection. 

Diagnosis. — ^The  clinical  picture  of  severe  rickets  is  so  striking  that  it 
can  hardly  be  mistaken.  The  projecting  rickety  rosary,  the  large  epiphy- 
ses, the  large  square  head,  the  bent  limbs,  are  characteristic  enough;  but 
in  slight  cases  the  difficulty  is  greater  and  it  is  clear  from  a  comparison  of 
various  observers'  statistics  that  there  is  no  general  agreement  as  to  what 
constitutes  evidence  of  rickets.  For  instance  in  Munich,  at  the  same  insti- 
tution, one  observer  found  about  70  per  cent,  of  the  childern  under  two 
years  to  be  rickety;  another  observer  found  that  less  than  5  per  cent,  of 
the  children  were  rachitic. 

Beading  of  the  ribs  has  often  been  accepted  as  evidence  of  rickets,  but 
this  is  not  necessarily  so*  it  is  common  to  find  beading  of  the  ribs  in 
healthy  infants  just  after  birth,  and  Escher  found  on  microscopic  exami- 
nation that  these  showed  none  of  the  characteristic  changes  of  rickets. 
Yielding  of  the  skull  bones  on  pressure,  a  diffuse  thinness  along  the  edge 
of  the  bones  with  some  separation  of  sutures,  has  been  taken  as  a  proof  of 
rickets,  but  this  also  is  incorrect.  A  simple  delay  of  development  occurs 
quite  apart  from  rickets  and  Fede  and  Finizzio  concluded  from  a  micro- 
scopic examination  of  the  skull  bones  that  the  yielding  of  the  skull  in  new- 
born infants  was  not  necessarily  due  to  rachitic  change. 

It  seems  probable  that  there  are  other  bone  diseases  which  may 
cause  softening  of  bones  or  deficiency  of  calcification,  so  that  bending 
or  fracture  of  bones  results.  Osteomalacia,  or  mollities  ossium,  in 
which  at  an  age  usually  beyond  puberty  the  bones  show  progressive 
softening  so  that  they  bend  in  all  directions,  is  probably  quite  distinct 
in  its  pathology  as  it  usually  is  in  its  course.  Occasionally  cases  are  seen 
in  childhood  with  extreme  softening  and  bending  of  bones  and  lacking 
the  usual  characteristics  of  rickets,  such  as  the  enlarged  epiphyses  and  the 
large  square  head.  Some  of  these  cases  are  probably  much  nearer  allied 
to  the  so-called  osteomalacia  of  adults.  It  may  be  that  in  some  cases  a 
condition  like  the  osteoporosis  produced  experimentally  in  puppies  occurs 
in  children  also. 

The  weakness  of  the  limbs  may  be  mistaken  for  infantile  paralysis; 
the  general  distribution,  the  gradual  onset,  the  retention  of  reflexes  and 
the  changes  in  the  bones  will  usually  suffice  for  the  distinction. 

The  kyphosis  may  be  so  marked  as  to  suggest  spinal  caries;  it  is 
generally  taught  that  the  curve  of  rickets  disappears  when  the  child  is 
held  up  supported  under  the  armpits,  whereas  that  of  spinal  caries  re- 
mains. In  long-standing  cases,  however,  the  kyphosis  may  not  disappear 
thus,  nor  even  when  the  child  is  made  to  lie  on  its  face,  and  the  diagnosis 
has  to  be  made  from  the  more  general  curving  of  the  spine  and  from  the 
association  of  the  kyphosis  with  marked  rickets  elsewhere. 

The  enlargement  of  the  head  is  sometimes  difficult  to  distinguish  from 
that  due  to  hydrocephalus.  As  a  rule  the  flattening  of  the  vertex  and  the 
square  shape  distinguish  the  rachitic  head  from  the  more  globular  hydro- 


886  CONSTITUTIONAL  DISEASES 

cephalic  head;  but  there  are  cases  in  whieh,  if  the  chihl  is  first  seen  after 
the  fontanehe  and  sutures  have  closed,  the  diaynosis  may  be  impossible; 
and  it  is  only  when  symj)toms  result  from  increasing  tension  in  the  ventri- 
cles that  the  (juestion  may  be  settled. 

Course  and  Prognosis. — Rickets  is  readily  amenable  to  treatment, 
and  when  once  the  disease  has  stopped,  any  recrudescence  is  very  excep- 
tional. Probably,  some  of  the  cases  described  as  late  rickets  are  of  this 
nature.  The  intensity  and  duration  of  the  symjitoms  vary  chiefly  accord- 
ing to  the  feeding;  no  doubt,  in  some  cases  as  the  child  grows  older  and 
takes  a  more  varied  diet,  which  happens  to  include  a  sufficient  proportion 
of  the  requisite  constituents,  the  disease  comes  to  a  stand-still  without 
special  treatment.  In  others  it  progresses  so  rapidly  that  within  a  few 
months  consiilerable  softening  and  bending  of  bones  occurs,  nervous 
and  respiratory  symptoms  become  pronounced,  and  the  child  dies.  When 
death  results  from  rickets,  the  immediate  cause  is  usually  bronchitis  or 
bronchopneumonia,  convulsions,  or  laryngismus  stridulus. 

Rickets  is  seldom  seen  in  active  progress  after  the  age  of  three  years, 
but  the  deformities  produced  may  last  for  life.  In  their  slighter  degree 
however,  some  of  these  may  disappear:  the  beading  of  the  ribs  is  gradually 
lost  in  many  cases  and  even  considerable  deformity  of  the  chest  may 
diminish  greatly  as  the  child  becomes  stronger  and  expands  his  lungs 
more  thoroughly.  Slight  curvature  of  the  legs  may  right  itself  if  the 
child  is  kept  off  his  feet  for  several  months  while  suitable  treatment 
is  used. 

Treatment. — Prophylaxis. — Rickets  is  in  large  measure  a  preventable 
disease,  and  as  it  is  due  chiefly  to  faults  of  diet  so  its  prevention  depends 
almost  entirely  upon  dietetic  measures.  The  surest  safeguard  is  the 
continuance  of  breast  feeding  alone  for  nine  or  ten  months,  and  the 
use  of  fresh  milk  as  the  chief  article  of  diet  until  the  end  of  the  second 
year.  It  is  important  to  realize  that  breast  feeding  does  not  protect  from 
rickets  ^vhen  other  food  is  given  at  the  same  time.  An  infant  suckled, 
and  at  the  same  time  receiving  farinaceous  food,  often  develops  a  marked 
degree  of  rickets.  Even  when  an  infant  has  been  suckled  entirely  for  the 
first  nine  or  ten  months,  this  does  not  prevent  the  onset  subsequently  if 
the  feeding  is  then  unsuitable.  It  is  probable  that  the  liability  becomes 
gradually  less  after  the  end  of  the  first  year;  in  other  words,  of  the  large 
number  of  cases  seen  in  the  second  year,  most  have  had  their  onset 
at  some  period  within  the  first  twelve  months;  but  there  are  certainly 
some  in  which  the  disease  began  in  the  second  year.  For  this  reason  the 
diet  in  the  second  year  requires  care  as  well  as  in  the  first.  A  common 
fault  is  to  allow  the  child  much  farinaceous  food  to  the  neglect  of  milk. 
Milk  should  certainly  be  the  staple  diet  until  the  child  is  two  years  old. 

There  is  no  doubt  that  the  early  use  of  farinaceous  food  plays  a  large 
part,  and  it  is  the  writer's  belief  that  even  the  small  proportion  of  starch 
present  in  barley-water  has  this  tendency  and  should,  therefore,  be  avoided 
during  the  earlier  half  of  the  first  year.  Few  infants  are  the  better  for 
any  starch  addition  to  the  diet  before  the  age  of  nine  months,  and  even 
then  its  introduction  should  be  very  gradual.  It  should  be  added  first  only 
to  one  meal  daily,  and  when  the  infant  is  twelve  months  old  should  not 
be  given  in  more  than  two  meals.  The  rest  should  consist  of  milk  to 
which  raw  meat  juice  may  be  added.    The  yolk  of  an  egg,  lightly  boiled, 


RICKETS  887 

may  also  be  allowed  at  this  age.  Potatoes  are  to  be  avoided  altogether 
until  the  age  of  eighteen  months,  and  even  then  only  very  little,  thoroughly 
mashed  with  milk,  should  be  allowed.  During  the  second  year  the  child 
should  not  take  less  than  one  and  one-half  pints  (about  one  liter)  of  milk 
daily. 

Where  hand-feeding  is  inevitable,  careful  modification  of  fresh  milk  is 
necessary.  It  is  not  sufficient  to  order  cow's  milk  diluted  with  water; 
the  proportions  must  be  properly  adjusted.  It  is  not  uncommon  to  find 
marked  degrees  of  rickets  in  children  who  have  had  no  starch  whatever 
but  have  been  given  equal  parts  of  milk  and  water  up  to  the  age  of  nine 
or  ten  months,  with  no  addition  of  cream.  The  fault  in  such  cases  is 
probably  the  deficiency  of  fat,  and  for  this  same  reason  rickets  is  a  common 
result  of  many  of  the  proprietary  foods  whether  mixed  with  fresh  milk  or 
not  and  whether  containing  starch  or  not.  It  would  seem  that  a  propor- 
tion of  fat  under  2  per  cent,  for  infants  over  the  age  of  six  months  involves 
some  risk,  and  that  a  proportion  of  fat  under  1.5  per  cent,  given  for 
several  months  at  any  period  of  infancy  involves  a  high  probability  of 
rickets.  The  addition  of  cream  to  the  diluted  milk  is  an  important  pre- 
ventive measure,  and  if  circumstances  make  this  impracticable,  the  milk 
should  be  given  as  little  diluted  as  possible.  Where  deficiency  of  fat  is 
combined  with  the  too  early  use  of  starch  or  with  excess  of  carbohydrate, 
as  in  many  of  the  proprietary  foods,  the  risk  is  greatly  increased. 

Other  possible  factors  should  also  be  considered:  the  child  should  be 
out  in  the  open  air  three  hours  daily  or  more  if  possible,  and  the  rooms  in 
which  he  lives  should  be  well  ventilated  and  get  plenty  of  sunlight. 

If  rickets  has  already  appeared,  much  may  be  done  to  prevent  bending 
of  the  bones  by  adopting  such  measures  as  will  avoid  the  pressure  of  the 
body  or  other  weight  upon  the  Hmbs.  Standing  and  walking  especially, 
should  be  forbidden  until  the  remedies,  dietetic  or  otherwise,  which  are 
employed  have  had  time  to  diminish  the  softness  of  the  bones  and  the 
laxity  of  the  ligaments  and  muscles.  This  may  take  several  weeks. 
The  greater  vigor  of  the  child's  movements,  the  disappearance  of  sweating, 
and  the  increased  activity  of  dentition,  afford  some  indication  of  the 
improvement;  but  in  a  general  way  it  may  be  said  that  with  a  marked 
degree  of  rickets,  if  the  child  has  already  begun  to  stand  before  the  symp- 
toms attract  attention,  he  should  be  kept  off  his  feet  altogether  for  at  least 
three  months  from  the  time  when  treatment  is  begun,  and  if  standing  has 
not  yet  been  acquired  the  parents  should  be  instructed  not  to  encourage 
the  child  to  attempt  to  stand. 

In  severe  rickets  in  the  active  stage  of  the  disease  even  sitting  should  be 
discouraged,  for  apart  from  the  kyphosis  and  lateral  curvature  of  rickets, 
which  are  usually  transitory,  the  occurrence  of  pelvic  deformities  is 
favored  by  the  pressure  from  above  and  below  incurred  by  the  sitting 
position.  In  cases  where  much  deformity  of  the  chest  has  occurred,  with 
sinking  in  of  the  ribs  in  the  axillary  region  and  prominence  of  the  sternum 
and  cartilages,  the  danger  of  bronchitis  and  bronchopneumonia  is  to  be 
remembered,  and  every  precaution  taken  to  avoid  these  complications. 

Therapeutics. — The  most  important  factor  is  the  diet.  In  almost  all 
cases  this  requires  modification,  generally  in  the  diminution  or  discontin- 
uance of  farinaceous  food  according  to  the  age,  and  in  increase  of  the  fat. 
The  latter  presents  difficulties  chiefly  amongst  the  poor  who  are  unable  to 


8SS  COXSTITUTIOXAL  DISEASES  1 

afford  cream  or  who  live  under  such  contlitions  that  milk  and  cream 
undergo  much  bacterial  contamination.  Under  such  circumstances,  the 
deficiency  may  be  supplied  by  any  oil  or  fat  which  is  easily  assimilated. 
Cod-liver  oil  is  most  conmionly  used  in  England  but  other  oils,  such  as 
cotton-seed  oil  and  olive  oil,  have  been  used;  and  apparently  it  makes 
little  difference  how  the  fat  is  sup]:)lic(l  provided  it  can  be  digested. 

There  are  many  i)alatable  emulsions  of  cod-liver  oil,  and  any  of  these 
may  be  used,  but  it  may  be  more  convenient  to  use  the  plain  oil.  In 
either  case  the  amount  of  oil  given  at  each  dose  should  not  exceed  15 
minims  (.75  cc.)  for  an  infant  six  months  old;  20  minims  (1.25  cc.)  for  an 
infant  twelve  months  old;  and  25  to  30  minims  (1.5  to  2  cc.)  for  an  infant 
of  eighteen  to  twenty-four  months;  these  doses  should  be  given  three 
times  daily  just  after  food.  In  some  cases,  one  of  the  combinations  of 
malt  extract  with  cod-liver  oil  is  taken  better  and  may  be  more  valuable, 
especially  where  some  farinaceous  food  is  being  allowed,  as  the  diastasic 
power  of  the  malt  assists  the  digestion  of  starch.  A  valuable  method  of 
administering  fat  is  to  add  to  the  diet  daily  the  yolk  of  one  egg.  This 
contains  20  to  30  per  cent,  of  fat.  It  must  be  given  very  lightly  boiled, 
otherwise  it  becomes  indigestible.  An  infant  of  nine  months  can  have 
half  the  yolk  of  1  egg  daily,  at  ten  or  eleven  months  the  whole  of  the 
yolk  can  be  given.  After  the  age  of  twelve  months,  the  egg  can  also  be 
given  in  the  form  of  custard. 

In  some  parts  of  Europe,  especially  in  Vienna,  but  also  in  America  by 
Jacobi,  phosphorus  has  been  strongly  advocated.  Opinions  are,  how- 
ever, much  divided  as  to  its  value;  some  writers  state  that  it  is  not  only 
entirely  without  effect  but  that  it  produces  gastro-intestinal  disturbance 
and  occasionally  serious  toxic  symptoms.  It  seems  probable  that  some, 
at  least,  of  the  benefit  which  has  been  attributed  to  phosphorus,  may  have 
been  due  to  the  oil  in  which  it  has  almost  invariably  been  given.  It  is 
usually  dissolved  in  cod-liver  oil  or  given  in  an  emulsion  with  almond 
oil;  aJo  to  iJo  grain  (.3  to  .6  mg.)  of  phosphorus  may  be  dissolved 
in  1  dram  of  cod-liver  oil  (3.5  cc),  and  half  this  quantity  may  be  given  two 
or  three  times  a  day.  Jacobi  recommends  the  elixir  phosphori  of  the 
U.  S.  pharmacopoeia;  of  this,  6  to  15  minims  (about  0.4  to  1  cc.)  should 
be  given  three  times  daily. 

Various  organic  and  other  compounds  of  phosphorus  have  been  used 
in  rickets,  particularly  lecithin,  preparations  of  hypophosphites  in  syrup, 
wheat  phosphates,  the  soluble  part  of  bran,  and  many  patent  prepara- 
tions containing  phosphorus.  The  syrupus  ferri  phosphatis  of  the  British 
pharmacopceia  is  used  by  many  for  rickety  children  over  the  age  of 
twelve  months;  it  is  given  in  doses  of  |  to  1  dram  (1.75  to  3.5  cc). 
Glycerin  extract  of  bone-marrow  has  given  good  results  in  some  cases. 
Various  organic  remedies  have  been  tried,  but,  in  most  observers'  hands, 
have  proved  useless.  Stoeltzner  advocated  the  use  of  suprarenal  extract; 
but  subsequent  observations  by  Honigsberger  gave  entirely  negative 
results;  the  thymus  and  thyroid  have  also  been  tried,  but  the  successes 
claimed  for  them  have  not  been  justified. 

The  value  of  baths  is  perhaps  hardly  sufficiently  recognized;  the  child 
should  have  a  warm  bath  at  about  85°  F.  every  morning,  and  while  sitting 
in  the  bath  should  be  douched  with  w^ater  at  a  slightly  lower  temperature, 
75°  to  80°  F.  If  this  is  done  with  tact  and  the  child  gradually  accustomed 


RICKETS  889 

to  It,  there  should  be  no  dislike  to  it,  and  it  seems  to  have  an  invigorating 
and  tonic  effect  which  may  be  of  value  especially  in  reducing  the  nervous 
instability. 

If  convulsions  have  already  occurred,  or  if  a  tendency  to  them  is  shown 
by  the  presence  of  laryngismus  stridulus,  tetany,  or  facial  irritability, 
bromide  should  be  given  with  cod-liver  oil.  Two  to  4  grains  (.13  to  .26 
gm.)  of  potassium  bromide  in  1  dram  (3.5  cc.)  of  cod-liver  oil  emulsion, 
are  given  three  times  daily.  Sometimes  chloral  |  to  2  grains  (.032  to 
.13  gm.)  is  more  effectual  than  bromide,  and  may  be  given  every  four 
or  six  hours. 

Massage  has  also  been  advocated  and  is  likely  to  be  useful  in  maintain- 
ing the  nutrition  of  the  muscles  while  it  is  necessary  to  keep  the  child  off 
his  feet;  but  the  massage  must  be  extremely  gentle  and  is  less  applicable 
to  the  infants  under  twelve  months  than  to  those  who  are  older. 

The  child  must  be  kept  off  its  feet  during  the  active  stage  of  rickets, 
and  if  fat  and  heavy  and  especially  if  the  bones  of  the  legs  already  show 
bending,  this  measure  may  be  necessary  for  several  months.  Often  the 
only  way  to  ensure  this  is  to  apply  long  splints  to  the  outer  side  of  the 
legs,  the  splints  being  sufficiently  long  to  project  well  beyond  the  sole  of 
the  foot.  They  should  be  removed  when  the  child  goes  to  bed  so  that  it 
may  kick  its  legs  about  freely  and  exercise  its  muscles  as  much  as 
possible. 

CONGENITAL  RICKETS. 

It  seems  certain  that  rickets  may  be  present  at  birth,  but  until  recently 
cases  of  achondroplasia  were  described  as  foetal  or  congenital  rickets, 
and,  as  Ballantyne  has  shown,  there  are  several  types  of  bone  disease  which 
occur  in  utero,  all  of  which  have  probably  been  described  as  rickets  in 
the  past.  The  relation  of  these  to  rickets  is  uncertain  but  they  bear  so 
little  resemblance  to  postnatal  rickets,  that  it  seems  wise  at  present  to 
consider  them  as  something  altogether  distinct,  although,  as  Ballantyne 
suggests,  it  may  be  that  rickets  occurring  during  intra-uterine  life, 
would  be  modified  according  to  the  period  of  development  at  which  it 
occurred. 

As  to  the  frequency  of  congenital  rickets,  there  is  a  wide  discrepancy  in 
statistics.  Feyerabend  at  Konigsberg,  among  180  new-born  infants, 
found  68.9  per  cent,  rickety.  Schwarz  in  Vienna  found  that  among  500 
new-born  infants,  80.6  per  cent,  showed  rickets.  Fede  and  Cacace,  at 
Naples,  among  500  new-born  infants,  found  only  1  with  clinical  evi- 
dence of  rickets,  and  in  another  series  of  475  new-born  infants,  Fede  and 
Finizzio  found  only  3  with  rickets.  Personal  experience  at  the  Children's 
Hospital,  Great  Ormond  Street,  suggests  that  within  the  first  two  months 
after  birth  rickets  is  excessively  rare. 

The  symptoms  are  those  which  have  already  been  described  as  char< 
acteristic  of  postnatal  rickets,  but  the  frequency  of  fractures  in  the  long 
bones  is  a  notable  feature  of  the  congenital  disease.  Often  4  or  5  of 
the  bones  are  broken  and  the  fracture  is  often  complete,  not  green- 
stick.  Monti  quotes  Chaussier  as  having  found  in  1  case  42,  in  another 
112  fractures.  These  are  certainly  not  always  produced  during  parturi- 
tion for  they  have  been  found  already  united  or  in  process  of  uniting  at 


890  CONSTITUTIONAL  DISEASES 

the  time  of  birth  (Notta).  All  degrees  of  curvature  of  bones  are  also 
found.  It  has  been  stated  that  the  rachitic  distortions  of  the  thorax  are 
lacking  in  this  form,  but  this  is  ])erhaps  doubtful,  for  H.  Ashby  has 
recorded  a  case  in  which  the  ty[)ical  deformity  of  the  rachitic  chest  was 
present  at  the  age  of  fourteen  days  in  association  with  several  fractures  in 
the  limbs. 

There  has  been  extensive  failure  of  ossification  of  the  skull  in  several  of 
the  recorded  cases,  a  defect  which  some  have  described  as  craniotabes. 
It  is  very  doubtful,  however,  whether  such  a  condition  bears  any  relation 
to  the  localized  patches  of  craniotabes  mentioned  as  characteristic  of  ordi- 
nary rickets  where  the  thinning  of  the  skull  is  probably  due  to  absorption 
rather  than  to  defect  of  formation  of  bone. 

Infants  with  congenital  rickets  are  often  of  premature  birth  and  apart 
from  this  are  commonly  feeble,  so  that  the  prognosis  must  be  guarded. 
But  so* far  as  the  fractures  are  concerned,  the  outlook  is  good;  they  unite 
rapidly  after  birth.  With  suitable  feeding  the  rickets  rapidly  improves 
and  may  even  disappear  entirely  in  a  few  months. 

Congenital  rickets  is  no  doubt  dependent  upon  some  deficiency  in  the 
mother's  blood  of  the  constituents  requisite  for  bone  formation,  and  it  is 
an  observed  fact  that  in  a  considerable  proportion  of  the  cases  the  mother 
has  been  ill  during  pregnancy.  That  the  mother's  health  may  exercise 
some  effect,  especially  upon  bone  formation,  in  the  foetus,  is  suggested  by 
some  experiments  on  rabbits  in  which  the  inoculation  of  the  parents  with 
the  toxins  of  diphtheria  or  tuberculosis  resulted  in  deformities  of  the 
hind  limbs  in  the  offspring  (Charrin  and  Gley). 

Treatment. — The  treatment,  apart  from  suitable  fixation  for  the  frac- 
tured bones,  consists  chiefly  in  careful  feeding,  at  the  breast  if  possible, 
otherwise  with  milk  which  has  been  carefully  modified  so  as  to  contain  a 
proper  proportion  of  fat. 

LATE  RICKETS. 

Rickets  is  occasionally  seen  as  an  active  disease  in  the  later  period  of 
childhood  and  in  adolescence,  and  has  then  been  described  as  late 
rickets,  recrudescent  rickets,  or  rachitis  tarda. 

Probably  the  term  recrudescent  rickets  most  accurately  describes  the 
majority,  for  usually  the  patient  has  shown  evidence  of  rickets  within  the 
first  two  years  of  life  and  then  after  years  of  quiescence  the  disease  has 
again  started  into  activity.  ]\Iuch  more  rarely  rickets  makes  its  first 
appearance  at  this  later  period. 

Whether  recrudescent  or  not,  this  late  rickets  is  very  rare;  but  it  is 
said  by  some  surgeons  that  adolescents  at  the  period  of  rapid  growth  not 
infrequently  show  slight  bending  of  bones,  and  this  has  by  some  been 
described  as  rickets.  Apart  however  from  the  curvature  of  bones,  such 
cases  usually  show  no  other  evidence  of  rickets  and  it  seems  very  doubtful 
whether  a  mere  failure  of  the  hardening  process  in  bone  to  keep  pace  with 
the  rapid  growth  of  bone  at  this  age  should  be  considered  evidence  of 
rickets.  There  is  no  doubt  that  bending  of  bones  resembling  that  seen  in 
rickets  may  occur  quite  apart  from  the  histological  characters  of  rickets. 
Stoeltzner's  experiments  have  already  been  mentioned.  He  produced 
bending  of  limbs  in  puppies  by  a  special  diet  but  microscopic  examination 
showed  that  the  changes  were  not  those  of  rickets. 


RICKETS 


891 


Fia.  'J?. 


Late  rickets  has  occurred  most  often  between  the  age  of  nine  and  ff)ni- 
teen  years,  but  it  has  begun  as  late  as  seventeen  yeilrs.  At  what  age; 
rickets  should  be  described  as  late,  has  not  been  s(!ttled.  Probably 
the  disease  beginning  or  recrudescing  after  the  age  of  four  years,  might 
properly  be  described  thus. 

Symptoms. — The  symptoms  are 
similar  to  those  already  described,  but 
the  onset  has  usually  been  with  some 
pain  in  the  limbs,  more  or  less  severe, 
especially  in  the  legs.  At  the  same 
time  there  has  been  weakness  so  that 
in  some  cases  the  patient  has  been 
unable  to  walk  without  assistance. 

The  ribs  become  beaded  and  the 
epiphyses  enlarged,  as  may  be  seen  in 
the  accompanying  Fig.  74  of  a  boy 
aged  nine  and  three-fourths  years,  in 
whom  the  symptoms  of  rickets,  after 
remaining  almost  quiescent  since  his 
earUest  years,  became  a(."tive  again  at 
the  age  of  nine  and  one-half  years. 
He  was  under  the  care  of  my  colleagues, 
R.  Hutchison  and  A.  E.  Garrod,  at  the 
Children's  Hospital,  Great  Ormond 
Street.  There  was  no  enlargement  of 
the  head  in  this  case,  and  this  appears 
to  be  the  rule;  only  1  case  has  been 
recorded  in  which  the  head  became 
enlarged  during  late  rickets  (James). 

The  thorax  has  become  distorted  in 
some  cases  with  deformity  described  as 
typically  rachitic.  The  bending  of  the 
lower  limbs  is  sufficient  generally  to 
cause  a  waddling  awkward  gait.  With 
the  ic-rays,  the  bones  give  a  less  marked 
shadow  than  normal,  presumably  from 
deficiency  of  calcification. 

Examination  of  the  urine  in  one 
case  (James)  showed  excessive  excre- 
tion of  lime  (more  than  twice  the  nor- 
mal). The  amount  of  phosphoric  acid  was  fully  up  to  the  normal  but 
hardly  excessive.  Irregular  pyrexia  was  noted  in  one  case  (Cautley) 
during  the  progressive  stage  of  the  disease. 

Like  rickets  at  an  earlier  age,  the  late  form  of  the  disease  hinders 
growth  and  development,  the  establishment  of  puberty  may  be  delayed, 
and  the  child  remain  undergrown.  Hitherto  no  explanation  of  these 
cases  of  late  rickets  has  been  found.  It  has  been  stated  in  some  cases 
that  there  was  no  obvious  fault  in  the  diet;  in  some  cases  a  severe  illness 
has  preceded  the  onset  of  the  symptoms. 

Prognosis. — Prognosis  must  be  guarded,  for  the  deformity  is  often 
considerable;  the  disease  is,  however,  rarely  fatal.    There  seems  to  be  less 


892  CONSTITUTIONAL  DISEASES 

tendency  to  respiratory  complications  than  in  rickets  during  the  first  two 
years  of  life. 

Treatment.— The  treatment  which  has  been  found  most  effectual  is 
similar  to  that  used  in  ordinary  rickets,  namely,  the  administration  of 
cod-liver  oil,  to  which  some  have  added  phos])horus.  After  the  disease 
has  become  quiescent,  operative  measures  may  be  required  for  the 
correction  of  deformities. 


CHAPTER  XXXIV. 

SCURVY  (SCORBUTUS). 
By  ROBERT  HUTCHISON,  M.  D.,  F.  R.  C.  P.  (Lond.) 

Scurvy  may  be  defined  as  a  general  disorder  of  nutrition  characterized 
by  debility,  mental  apathy  and  anaemia,  with  sponginess  of  the  gums, 
ulceration  of  the  mouth,  and  a  tendency  to  hemorrhages  into  the  sub- 
cutaneous tissues  and  from  mucous  surfaces. 

History. — Good  historical  accounts  of  the  disease  have  been  given  by 
Budd^  and  by  Hirsch.^  Scurvy  does  not  seem  to  have  been  clearly 
recognized  in  Greek  and  Roman  times  though  some  passages  in  the 
writings  of  Hippocrates  may  perhaps  refer  to  it,  especially  where  he 
speaks  of  "a  condition  marked  by  foul  breath,  gums  receding  from  the 
teeth,  bleeding  from  the  nose,  and  ulcers  of  the  legs."  The  earliest 
description  of  the  disease  as  we  now  know  it  does  not  occur  until  the  year 
1260,  when  a  severe  outbreak  occurred  amongst  the  troops  of  the  Christian 
Army  fighting  in  Egypt  under  Louis  IX. ^  The  historian  of  that  campaign, 
himself  a  sufferer  from  the  disease,  describes  clearly  all  the  chief  symp- 
toms— bleedings  from  the  gums,  black  spots  on  the  legs,  epistaxis, 
debility,  and  a  tendency  to  syncope.  In  later  periods  good  descriptions 
of  land  scurvy  are  found  in  various  writings  of  the  sixteenth  and  seven- 
teenth centuries,  notably  in  the  history  of  the  northern  nations,  by  Olaus 
Magnus,  and  in  the  writings  of  the  three  physicians,  Roussens,  Ecthius 
and  Wierus.  It  is  noteworthy  that  these  writers  recommend  the  same 
remedies  as  are  at  present  in  use  against  the  disease.  From  that  time 
down  to  the  present  day  accounts  of  scurvy  are  constantly  met  with, 
especially  as  occurring  in  besieged  garrisons  and  among  troops  exposed 
to  the  privations  of  war,  conditions  in  which,  outbreaks  still  most  fre- 
quently occur. 

The  earliest  report  of  the  occurrence  of  scurvy  on  board  ship  is  con- 
tained in  the  Narrative  of  the  Voyage  of  Vasco  de  Gama  Round  the  Cape 
in  the  Year  1497,  in  which  about  100  of  his  men,  out  of  a  total  of  160, 
died  of  the  disorder.  About  this  period,  when  long  voyages  became 
frequent  and  fresh  food  was  unobtainable  on  board  ship,  scurvy  developed 
into  a  terrible  scourge  of  the  sailor  and  the  accounts  of  the  voyages  of 
most  explorers  abound  with  references  to  it. 

It  prevailed,  indeed,  down  to  the  year  1795  when,  on  the  initiative  of 
Sir  Gilbert  Blane,  lime  juice  was  introduced  into  the  Navy,  after  which 
scurvy  rapidly  declined  in  that  service  though  it  is  still  met  with  occa- 

*  Tweedie's  System  of  Practical  Medicine,  1840,  v,  p.  58. 

^Handbuchder  historisch-geographischen  Pathologic,  StuttgSiTt,  1883.  26  Aufl. 
Abth.  ii,  p.  354. 

^Histoire  de  Louis  IX  par  le  Sieur  Joinville,  Trans.,  vol.  i,  p.  162. 

893 


894  '   CONSTITUTIONAL  DISEASES 

sionally  even  now  in  ships  of  the  Mercantile  Marine.  The  rarity  of  the 
disease,  however,  is  shown  by  the  fact  that  in  the  last  ten  years  only 
22  cases  have  been  treated  in  the  Seamen's  Hospital  at  Greenwich 

Etiology. — The  true  causation  of  scurvy  is  still  rather  obscure.  It  will 
be  convenient  to  consider  in  order  the  different  views  which  have  been 
entertained. 

1.  That  Scurvy  is  Due  to  a  Deficiency  of  Potassium  in  the  Blood. — 
This  hypothesis  was  first  put  forward  by  Alfred  Garrod.^  Guided 
presumably  by  the  Ilippocratic  axiom  " curat ioncs  naiuravi  morhorum  os 
tend  lint"  lie  analyzed  diets  known  to  have  antiscorbutic  properties  and 
found  that  they  differ  from  those  which  tend  to  produce  scurvy  chiefly  in 
containing  larger  (luantities  of  potassium.  Proceeding  further  he  found 
that  potassium  salts  were  diminished  in  amount  in  the  blood  and  urine 
of  patients  suffering  from  scurvy,  and  putting  the  two  facts  together  he 
formulated  the  above-stated  hypothesis  as  to  the  causation  of  the  disease. 
It  was  soon  shown,  however,  that  his  view,  in  this  simple  form  at  least, 
was  untenable,  for,  as  Ralfe  jiointcd  out,  beef-tea,  though  it  contains  a 
large  quantity  of  salts  of  potash,  has  no  antiscorbutic  power  and,  further, 
the  crucial  test  of  administering  nitrate  of  potassium  to  patients  suffering 
from  scurvy  failed  to  show  that  it  was  possessed  of  any  curative  influence. 

Buzzard^  modified  Garrod's  hypothesis  by  suggesting  that  it  is  not 
potash  as  such  but  the  form  in  which  it  is  combined  which  is  of  impor- 
tance, and  it  was  to  the  organic  salts  of  potash  that  he  attributed  the  anti- 
scorbutic power  of  fresh  vigetables.  "AH  antiscorbutic  juices,"  he  says, 
"contain  salts  of  citric,  tartaric  or  malic  acids,  and  we  have  no  evidence  of 
any  substances  which  contain  these  materials  in  considerable  quantity, 
and  are  yet  deficient  in  the  power  of  preventing  scurvy.  The  mode  by 
which  they  act  is  still  involved  in  obscurity."  Subsequent  investigations 
have  been  directed  to  the  clearing  up  of  this  obscurity  and  have  led  to 
the  adoption  of  the  following  view: 

2.  That  scurvy  is  caused  by  a  diminution  in  the  alkalinity  of  the 
blood,  or,  in  other  words,  that  it  is  to  be  regarded  as  an  acid  intoxication. 

This  hypothesis  was  first  put  forward  by  Ralfe,^  who  concluded  from 
his  analyses  of  the  urine  of  patients  with  scurvy  and  that  of  healthy 
persons  after  the  withdrawal  of  fresh  vegetables  from  the  diet : 

1.  That  the  primary  change  that  occurs  in  scurvy  is  a  chemical  altera- 
tion in  the  quality  of  the  blood. 

2.  That  this  chemical  alteration  as  far  as  can  be  judged  from  inferences 
drawn  from  the  analysis  of  urine  in  patients  suffering  from  scurvy,  and 
analysis  of  scorbutic  and  antiscorbutic  diets,  points  to  a  diminution  of  the 
alkalinity  of  the  blood. 

3.  That  this  diminution  of  alkalinity  is  produced  in  the  first  instance 
(physiologically)  by  an  increase  of  acid  salts  (chiefly  urates)  in  the  blood, 
and  finally  (pathologically)  by  the  withdrawal  of  salts  having  an  alkaline 
reaction  (chiefly  alkaline  carbonates). 

4.  That  this  diminution  of  the  alkalinity  of  the  blood  finally  produces 
the  same  results  in  scurvy  patients  as  happens  in  animals  when  attempts 
are  made  to  reduce  the  alkalinity  of  the  body  (either  by  injecting  acid 

1  Edinburgh  Monthly  Journal  of  Medicine,  1848,  New  Series,  ii,  p.  457. 

2  Reynolds's  System  of  Medicine,  1866,  vol.  i,  p.  731. 

s  "An  Inquiry  into  the  General  Pathology  of  Scur\'y,"  Lanpet,  1877,  ii,  p.  81. 


SCURVY  895 

into  the  blood  or  feeding  with  acid  salts) ;  namely,  dissolution  of  the  blood 
corpuscles,  ecchymoses  and  blood  stains  on  mucous  surfaces,  and  fatty 
degeneration  of  the  muscle  of  the  heart,  the  muscles  generally,  and  the 
secreting  cells  of  the  liver  and  kidney. 

This  conception  of  the  disease  has  been  independently  advocated  by 
A.  E.  Wright,  whose  line  of  argument  is  as  follows:^  "The  scorbutic 
condition  is  a  pathological  condition  which  is  induced  by  a  dietary  con- 
sisting of  meat  and  cereals  to  the  exclusion  of  green  veg(;tables,  tubers 
and  fruits.  Inasmuch  as  the  foodstuffs  which  are  excluded  from  the 
dietary  in  question  are  foodstuffs  which  contain  an  excess  of  bases  over 
mineral  acids,  while  the  foodstuffs  (meat  and  cereals)  which  remain  are 
foodstuffs  which  contain  a  large  excess  of  mineral  acids  over  bases,  it  is 
obvious  that  the  scorbutic  condition  is  one  which  supervenes  upon  the 
ingestion  of  a  considerable  excess  of  mineral  acids  over  bases.  It  would, 
in  view  of  this  consideration,  seem  probable  that  scurvy  is  a  condition  of 
acid  intoxication  very  similar  to  the  acid  intoxication  which  can  be 
experimentally  produced  in  herbivora  by  the  ingestion  of  a  surplus  of 
mineral  acids.  The  theory  that  scurvy  is  essentially  a  condition  of  acid 
intoxication  would  appear  to  be  in  harmony  with  the  circumstance  that 
the  rapidity  with  which  the  scorbutic  condition  supervenes  depends 
apparently  upon  the  degree  to  which  the  mineral  acids  are  in  excess  in 
the  dietary.  The  condition  is  apparently  more  rapidly  superinduced  by  a 
dietary  of  corned  meat  (i.  e.,  meat  which  has  been  rendered  hyperacid  by 
the  removal,  in  the  process  of  corning,  of  the  alkaline  salts  of  the  blood 
and  lymph)  than  by  a  dietary  of  fresh  meat  (z.  e.,  meat  which  still  contains 

these  alkaline  salts) Justification  for  the  identification  of 

scurvy  with  a  condition  of  acid  intoxication  would  appear  to  be  afforded 
also  by  the  consideration  that  the  scorbutic  condition  is  remedied  or 
alleviated  by  the  addition  to  the  scorbutic  dietary  of  any  one  of  a  whole 
series  of  different  substances — tubers,  green  vegetables,  decoctions  of 
leaves  and  growing  shoots,  blood  (used  for  this  purpose  by  the  Laps), 
fruits  and  fruit  juices — substances  which  have  apparently  in  common 
only  the  circumstance  that  they  all  contain  an  excess  of  bases  over  mineral 
acids."  In  confirmation  of  this  view  Wright  found  that  there  was  a 
striking  reduction  in  the  alkalinity  of  the  blood  in  a  series  of  scurvy  cases 
which  he  examined  and  that  as  the  condition  passed  off  the  alkalinity 
rose  again  to  normal. 

3.  The  view  that  scurvy  is  caused  by  poisoning  with  ptomaines  was 
first  put  forward  by  Torup,  of  Christiania,  and  has  been  investigated 
experimentally  by  Jackson  and  Vaughan  Harley.^  They  argue  from  the 
experience  of  Nansen  in  the  Arctic  regions  that  scurvy  cannot  be  due 
to  a  diet  devoid  of  fresh  vegetable  constituents  and  exposure  to  insani- 
tary surroundings,  for  Nansen  was  subjected  to  both  these  conditions  and 
yet  escaped  the  disease.  They  also  advance  evidence  to  show  that  the 
disease  is  not  prevented  by  the  consumption  of  lime  juice  but  that  it  is 
associated  with  the  eating  of  tinned  or  salted  meat.  They  then  describe 
experiments  upon  monkeys  fed  upon  a  diet  of  boiled  rice  or  maize  to 
which  was  added  a  proportion  of  tinned  meat  given  either  fresh  or  after 
being  kept  until  it  was  slightly  tainted.    The  monkeys  which  were  fed  on 

*"0n  the  Pathology  and  Therapeutics  of  Scurvy,"  Lancet,  1900,  ii,  p.  565. 
^Lancet,  1900,  i,  p.  1184. 


896  CONSTITUTIONAL  DISEASES 

the  tainted  meat  developed  sponginess  of  the  gums,  and  diarrhoea  with 
blood  and  mucus  in  the  stools.  Interesting  as  these  experiments  are  it 
would  be  rash  to  conclude  that  we  have  here  an  exact  reproduction  of  the 
disease  as  it  occurs  in  the  human  subject.  It  is  to  be  noted,  for  instance, 
that  in  none  of  the  animals  was  there  any  swelling  or  tenderness  of  the 
fimbs  or  appearance  of  puv})uric  spots,  and  in  any  case  the  diet  above 
described  must  be  regarded  as  so  abnormal  for  monkeys  that  it  would  be 
unwise  to  draw  conclusions  from  its  effects  upon  them  as  to  the  results 
which  it  might  be  expected  to  produce  in  the  human  subject. 

4.  The  view  has  recently  been  gaining  ground  that  scurvy  is  the  result 
of  a  specific  infection  which  takes  place  through  the  mouth. 

The  earliest  attempts  to  cultivate  a  microorganism  from  the  cases  of  the 
disease  were  made  by  ^Nlurri,^  Contu,^  and  Wieruszkij,^  but  yielded  no 
definite  results.  Babes, ^  however,  was  more  successful  and  succeeded 
in  reproducing  some,  at  least,  of  the  features  of  the  disease  in  rabbits  by 
injecting  them  with  cultures  taken  from  the  gums  of  patients  suffering 
from  scurvy.  He  demonstrated,  also,  in  the  blood  of  his  cases,  a  bacillus 
which  he  believed  to  be  the  cause  of  the  disease.  He  describes  it  as  being 
narrower,  and  considerably  longer  than  the  cholera  bacillus,  pointed  at 
the  ends,  and  not  staining  by  Gram's  method.  It  is  probably  always 
present  in  the  mouth. 

Myer  Coplans^  strongly  supports  the  infective  view  of  the  origin  of 
scurvy  as  the  result  of  his  experience  of  the  disease  in  the  Concentration 
Camps  during  the  Boer  War.  He  found  that  the  disease  prevailed 
directly  as  the  habits  of  the  occupants  of  the  camps  were  filthy,  and  could 
trace  no  relation  between  its  prevalence  and  the  character  of  the  diet;  the 
disease  might  be  present  in  one  camp  and  not  in  another  although  the 
rations  of  the  two  were  identical. 

Summing  up  all  the  evidence,  it  seems  probable  that  whilst  a  deficiency 
of  fresh  vegetables,  i.  e.,  of  organic  salts  of  potash,  plays  a  part  in  the 
production  of  the  disease  by  reducing  the  alkalinity  of  the  blood,  yet 
this  does  not  afford  a  complete  explanation  of  the  occurrence  of  all  the 
symptoms,  and  it  is  not  unlikely  that  upon  the  soil  so  prepared  there 
is  grafted  some  specific  infection  which  finds  access  to  the  body  by 
the  mouth.  Insanitary  surroundings,  overwork,  mental  depression,  and 
exposure  to  cold  and  damp,  facilitate  the  development  of  the  disease  by 
lowering  the  resistance  of  the  patient. 

Morbid  Anatomy. — The  bodies  of  patients  who  have  died  of  scurvy 
usually  exhibit  only  a  slight  degree  of  rigor  mortis,  and  putrefaction  occurs 
early.  The  only  constant  morbid  change  found,  however,  is  effusion  of 
blood  in  various  situations.  These  effusions,  which  may  be  diffuse  or 
circumscribed,  are  met  with  both  in  the  skin  and  subcutaneous  tissues 
and  under  the  periosteum  of  the  bones  and  consist  of  altered  blood  which 
may  have  undergone  partial  clotting  or  even  organization  into  fibrous 
tissue.  Hemorrhages  are  also  met  with  in  the  pleura  and  pericardium 
and  though  more  rarely,  in  the  peritoneum  as  well.    There  may  also  be 

^Riv.  Clin,  di  Bologna,  1881,  3s.  i,  p.  215. 
^Raccoglitore  Medico,  1881,  xvi,  p.  188. 
^Wratsch,  1890,  pp.  208  and  303. 
*Deut.  Med.  Wochensch,  1893,  xix,  p.  1035. 
^Lancet,  1904,  i,  p.  1714. 


SCURVY  897 

hemorrhagic  effusion  into  the  joints.  The  internal  organs  show  no  con- 
stant change  but  the  heart  muscle  is  soft  and  often  degenerated.  The 
lungs  are  oedematous,  and  may  contain  infarctions.  The  kidneys  and 
liver  rarely  exhibit  any  signs  of  disease.  The  spleen  is  large,  soft,  and 
congested,  and  may  also  show  infarcts  on  its  surface.  It  is  important  to 
note  that  all  accurate  observations  agree  in  showing  that  the  bloodvessels 
exhibit  no  gross  or  microscopic  changes. 

In  the  altered  gums,  Babes  distinguishes  five  layers:  (1)  A  surface 
layer,  for  the  most  part  free  from  epithelium,  moderately  thick,  pale, 
resembling  a  diphtheritic  membrane  with  a  few  fragments  of  nuclei,  and 
containing  various  bacteria,  especially  streptococci.  (2)  A  structureless 
layer,  about  one  millimeter  thick,  consisting  of  a  felt-work  of  long  fine 
bacteria.  (3)  Uni-  and  multi-nucleated  round  cells.  (4)  A  layer  of 
oedematous  mucous  membrane  containing  many  bacilli  resembling  those 
in  the  second  layer.  In  the  walls  of  the  vessels  are  numerous  swollen 
spindle-cells.  (5)  Large  and  much  dilated  vessels  with  large  spindle- 
cells  in  their  walls.  In  the  blood  which  fills  the  vessels  are  various  cell 
masses,  numerous  multi-nucleated  leukocytes,  endothelial  and  mast  cells 
but  no  bacteria. 

Symptoms. — Prodromal  Symptoms. — Scurvy  is  usually  a  disease  of 
insidious  onset.  The  patient  begins  to  suffer  from  loss  of  bodily  vigor, 
and  from  an  even  more  marked  mental  apathy  and  lassitude  so  that  the 
slightest  task  becomes  a  burden.  At  the  same  time  he  looks  ill.  The 
face  becomes  pale,  or  sallow  and  drawn,  the  eyes  sunken,  lusterless  and 
encircled  by  dark  rings.  At  this  period  too,  there  may  be  some  pitting 
of  the  ankles  on  pressure,  and  a  tendency  to  diarrhoea  whilst  it  may  be 
observed  that  the  least  knock  or  injury  tends  to  be  followed  by  a  bruise. 
He  suffers  also  from  pains  of  a  rheumatic  sort  in  the  limbs  and  joints. 
To  these  symptoms  there  are  soon  added  those  characteristic  of  anaemia — • 
shortness  of  breath  on  exertion,  palpitation,  and  a  tendency  to  syncope. 

Such  symptoms  may  precede  by  a  few  days  or  even  weeks,  the  more 
characteristic  signs  of  the  disease.  Amongst  these  the  most  striking 
though  not  necessarily  always  present,  are  the  changes  in  the  mouth. 
The  gums  begin  to  swell,  especially  around  stumps  or  carious  teeth,  and 
as  the  process  goes  on  the  swelling  may  become  so  great  as  to  amount  to  a 
veritable  hypertrophy  so  that  the  teeth  become  buried  in  a  mass  of  soft, 
fungous  tissue  of  a  bluish  or  purplish  tint.  Ulceration  quickly  follows 
along  the  margins,  the  process  being  accompanied  by  the  discharge  of 
a  sanious  fluid  which  imparts  an  odor  of  great  foetor  to  the  breath. 
Finally  the  teeth  become  loosened  in  their  sockets  and  may  fall  out 
whilst  necrosis  of  the  alveolar  edges  ensues. 

Equally  characteristic  and  constant  are  hemorrhages  inio  the  skin  and 
subcutaneous  tissue  which  assume  the  form  either  of  petechise  or  of  ecchy- 
moses.  The  former  occur  as  small  red  or  purple  spots  resembling  flea 
bites  which  appear  first  around  the  hair  follicles  of  the  lower  extremities 
and  impart,  by  the  elevations  which  they  produce,  a  slight  feeling  of 
roughness  to  the  skin.  They  remain  for  about  a  week,  and  then  gradu- 
ally fade  into  greenish  spots  which  soon  disappear;  their  disappearance 
being  followed  by  a  slight  degree  of  desquamation.  The  production  of 
the  petechise  is  determined  by  the  slight  irritation  caused  by  the  friction 
of  the  clothes,  and  hence  they  are  always  to  be  found  first  on  the  outer 
67 


898  CONSTITUTIONAL  DISEASES 

surface  of  the  leg,  and  the  outer  and  anterior  aspects  of  the  thigh.  Here 
and  there  the  petechia?  may  coalesce  into  Uirger  areas  or  maculae.  In 
severe  cases  the  slightest  pressure  on  the  skin  is  sufficient  to  cause  ulcera- 
tion, the  ulcers  having  thick  edges  and  bleeding  surfaces  from  which  a 
very  offensive  discharge  is  given  off.  Such  ulcers  may  spread  rapidly, 
and  invade  surrounding  tissues,  giving  rise  in  some  cases  to  dangerous, 
and  even  fatal  hemorrhage.  Ecchymoses,  the  other  characteristic  sur- 
face lesion  of  scurvy,  are  produced  by  hemorrhage  into  the  subcutaneous 
or  intermuscular  tissue.  They  may  occur  spontaneously  or  as  the  result 
of  injury,  and  vary  greatly  both  in  size  and  extent,  being  commonest  in 
the  lower  extremities  where  they  may  form  quite  large  swellings.  The 
part  affected  by  them  is  brawny,  tender  and  pits  on  pressure,  the  indenta- 
tion persisting  longer  than  it  does  in  ordinary  cedcma.  The  skin  over 
them  is  red,  shiny,  and  hot.  Such  effusions  are  common,  also,  in  the 
popliteal  space  and  in  the  bend  of  the  elbow  as  well  as  in  the  loose  tissue 
around  the  malleoli,  and  beneath  the  muscles  of  the  jaw.  In  these  situa- 
tions they  form  indurated  swellings  which  fill  up  the  natural  hollows  of 
the  part,  and  greatly  interfere  with  the  movements  of  the  adjacent  joint. 
Where  such  effusions  occur,  as  they  sometimes  do,  over  the  shins,  they 
are  apt  to  be  mistaken  for  syphilitic  nodes. 

There  is  no  marked  tendency  to  bleeding  from  the  internal  organs  in 
scurvy,  but  hemorrhages  may  take  place  from  the  mucous  surfaces.  Of 
such  hemorrhages,  epistaxis  and  bleeding  from  the  mucous  membrane  of 
the  mouth  are  commonest.  Bleeding  may  also  occur  from  the  mucous 
membrane  of  the  intestine  when  there  is  a  co-existing  diarrhoea.  Hae- 
moptysis, haematemesis  and  haematuria  are  rare.  Hemorrhagic  effusion 
into  the  pleura  and  pericardium  have  also  been  described.  Not  uncom- 
monly hemorrhage  occurs  under  the  conjunctiva  and  may  be  so  extensive 
as  appreciably  to  raise  the  ocular  layer,  leaving  the  cornea  at  the  bottom 
of  a  pit  surrounded  by  swollen  and  red  conjunctival  membrane. 

As  the  disease  progresses  anaemia  becomes  a  marked  feature.  The 
blood  itself  presents  simply  the  characters  of  a  secondary  anaemia,  and 
there  is  no  leukocytosis  unless  secondary  inflammatory  complications 
exist.  Special  interest  attaches  to  the  chemical  condition  of  the  blood  on 
which,  however,  but  few  observations  have  been  made.  If  the  views  of 
Ralfe  and  of  Wright  as  to  the  etiology  of  the  disease  are  correct  one  would 
expect  to  find  a  diminution  of  alkalinity  and  of  coagulability  and  Wright 
in  a  few  cases  has  shown  that  diminution  of  coagulability  is  actually 
present.  Barnardo,  who  had  the  opportunity  of  investigating  this  point 
during  the  Somaliland  Campaign,  found  no  constant  relation  between 
the  degree  of  reduced  alkalinity  and  the  severity  of  the  symptoms. 
Although  he  states  that  in  all  cases  where  the  alkalinity  is  much  reduced 
profound  constitutional  disturbance  will  soon  manifest  itself  if  it  be  not 
already  present. 

Alimentary  symptoms  are  often  absent.  Appetite  is  not  necessarily 
impaired  but  dyspeptic  symptoms  may  be  present  as  the  result  of  the 
imperfect  diet  which  produces  the  disease.  Constipation  is  the  rule  but 
the  conditions  under  which  scurvy  is  developed  frequently  favor  the 
production  of  diarrhoea  of  a  dysenteric  t}qDe  and  when  such  a  complication 
exists  it  may  be  attended  by  bloody  discharges  from  the  bowel. 


SCURVY  899 

The  urine  at  the  outset  is  scanty,  high-colored,  turbid  and  occasionally 
albuminous  but  as  improvement  sets  in  it  becomes  more  abundant  and 
pale.  The  amount  of  free  acid  in  it  is  diminished  and  so,  it  is  alleged,  are 
the  potash  salts. 

Of  the  complications  of  scurvy,  gangrene  of  the  lung  is  one  of  the  most 
frequent  and  dangerous.  It  is  marked  by  the  usual  expectoration  of  dark 
foetid  matter,  by  rapid  and  difficult  breathing  with  great  depression,  and 
usually  ends  fatally. 

Buzzard  describes  an  affection  of  the  chest  in  scurvy  which  may  be 
mistaken  for  pneumonia.  Faint  rigors,  followed  by  a  certain  amount  of 
feverishness  and  accompanied  by  lancinating  pain  in  one  or  both  sides, 
usher  in  this  condition.  The  pain  is  felt  only  in  coughing  and  a  very 
viscid  mucus  is  expectorated.  The  dyspnoea  increases,  and  a  constric- 
tion as  though  from  a  cord  bound  tightly  round  the  chest  is  described. 
Although  it  occasionally  happens  that  these  pulmonary  symptoms  are 
dependent  upon  true  inflammation,  they  are  much  more  commonly 
associated  with  the  effusion  of  sanguineous  fluid  into  the  cavity  of  the 
pleura  or  into  the  substance  of  the  lung  itself,  these  structures  sharing 
with  every  other  organ  that  tendency  to  effusion  which  is  the  dominant 
feature  of  scurvy.  When  the  lung  is  thus  invaded  the  expectoration  after 
a  short  time  becomes  dark  and  sanious,  with  all  the  horrible  foetor  which 
is  ordinarily  associated  with  gangrene  of  the  lung,  but  which  is  here 
dependent  upon  decomposition  of  the  bloody  fluid  poured  into  the  lung 
substance.  There  are  now  cold  sweats,  increasing  dyspnoea  and  anxiety, 
a  small  and  frequent  pulse,  and  death.  In  other  cases  there  is  no  pain  or 
cough  but  the  breathing  rapidly  becomes  short  and  labored  and  death 
occurs  suddenly.  Auscultatory  signs  in  the  lungs  are  usually  wanting, 
but  now  and  then  there  is  localized  dulness  on  percussion  with  bronchial 
breathing,  or  mucous  rales  are  heard,  sometimes  also  with  gurgling 
sounds  at  certain  parts  of  the  chest. 

Night  blindness  is  a  condition  sometimes  met  with  in  patients  suffering 
from  scurvy  who  have  also  been  much  exposed  to  bright  light,  and  may 
occur  quite  early  in  the  disease.  It  would  appear  to  be  merely  the  result 
of  the  ansemia  and  exhaustion  which  scurvy  produces  and  is  in  no  sense 
an  essential  part  of  the  scorbutic  process. 

Diagnosis.—If  all  the  characteristic  symptoms  are  present  and  if  the 
disease  arises  simultaneously  in  a  number  of  subjects  in  circumstances 
known  to  favor  its  development,  the  diagnosis  of  scurvy  is  easy.  Diffi- 
culty only  occurs  when  one  has  to  deal  with  sporadic  cases,  such,  for 
example,  as  the  cases  of  land  scurvy  occasionally  met  with  in  badly  fed 
individuals. 

The  disease  which  perhaps  most  closely  resembles  it  is  purpura  haemor- 
rhagica  (morbus  maculosus  of  Werlhof)  but  in  this  the  affection  of  the 
gums  is  absent  and  the  hemorrhages  have  not,  as  they  have  in  scurvy,  an 
inflammatory  character. 

Mercurial  cachexia,  which  in  many  points- closely  simulates  scurvy,  is 
now  but  rarely  seen  and  an  inquiry  into  the  history  will  usually  lead  to  a 
correct  conclusion. 

Acute  lymphatic  leukcemia,  which  is  often  marked  like  scurvy  by  ulcera- 
tion in  the  mouth,  can  be  at  once  distinguished  by  an  examination  of  the 
blood. 


900  CONSTITUTIOXAL  DISEASES 

Prognosis. — The  prognosis  of  scurvy,  exccjit  in  tlie  severest  cases,  is 
favorable,  provided  suitable  treatment  can  be  adopted.  It  has  often  been 
noted  that  the  outlook  in  this  tlisease  is  by  no  means  dependent  upon  the 
severity  of  the  lesions  in  the  skin,  mouth,  and  muscles,  but  is  in  far  closer 
relation  to  the  state  of  the  internal  organs  such  as  the  lungs  and  heart. 
The  supervention  of  complications  and  of  intercurrent  disease  also  exerts 
powerful  influence  upon  the  prognosis  whilst  a  speedy  and  often  un- 
expected fatal  result  may  be  brought  about  by  severe  hemorrhage  or 
lieart  failure. 

Even  in  eases  which  run  a  favorable  course  it  may  be  weeks  or  even 
months  before  the  patient  is  restored  to  his  original  vigor,  and  when 
recovery  is  comj)lete  there  may  still  be  some  results  of  the  disease  shown 
in  cicatrices  in  the  skin  or  })artial  ankylosis  of  joints. 

Treatment. — The  first  point  is  to  remove  the  patient  if  possible  from 
the  place  in  which  the  disease  has  developed  and  to  bring  him  under 
more  hygienic  conditions.  Cold  and  damp  should  especially  be  avoided 
and  he  should  be  placed  in  warm  and  dry  surroundings.  Of  even  greater 
imj)ortance  is  it  to  make  a  radical  alteration  in  his  diet.  Whatever  view 
may  be  held  as  to  the  causation  of  the  disease  all  experience  goes  to  show 
that  the  introduction  into  the  diet  of  a  sufficient  quantity  of  fresh  vegetable 
food  has  a  powerfully  curative  effect. 

It  would  appear  that  there  is  no  particular  form  of  vegetable  food 
which  has  a  specific  influence  over  the  disease  but  that  all  are  equally 
efficacious.  The  antiscorbutic  power  of  fresh  limes  and  lemons  has  been 
known  since  the  seventeenth  century  and  these  fruits  still  constitute  a 
favorite  remedy.  It  is  important  that  they  should  be  fresh;  lime  juice 
which  has  been  bottled  for  some  time  is  apt  to  decompose  into  free  citric 
acid  and  carbonates  and  loses  much  of  its  value.  An  objection  to  lime 
juice  IS  its  rather  acrid  taste,  on  account  of  which  it  is  sometimes  found  to 
be  difficult  to  induce  those  who  are  exposed  to  the  disease  to  take  it  regu- 
larly as  a  preventive.  Lemonade  made  from  fresh  lemons  is  not  open  to 
this  objection. 

Preserved  vegetables,  though  useful,  seem  to  have  a  feebler  antiscor- 
butic power  than  fresh;  sauerkraut  appears  to  be  more  serviceable  in 
preventing  the  disease  than  any  other  form  of  preserved  vegetable  and 
Captain  Cook  employed  it  successfully  in  some  of  his  voyages.  Infusions 
of  malt  are  also  powerfully  antiscorbutic.  Forster,^  who  accompanied 
Cook  in  his  second  voyage,  describes  a  severe  outbreak  of  scurvy  and  its 
cure  of  infusion  of  malt  without  any  other  change  in  the  diet;  he  adds, 
"The  encomivuns  on  the  efficacy  of  malt  cannot  be  exaggerated."  In 
some  of  the  worst  cases  that  he  saw  the  patient  took  as  much  as  5  pints  of 
the  infusion  in  a  day.  The  infusion  should  be  fresh,  for  its  good  qualities 
are  impaired  if  it  is  allowed  to  become  damp  and  mouldy. 

Fresh  meat  juice  has  been  found  to  be  of  value  as  an  antiscorbutic 
owing,  it  is  alleged,  to  the  lactates  which  it  contains.  Milk  is  also  service- 
able, 3  pints  of  it  containing  as  much  citric  acid  as  1  ounce  of  lime  juice 
and  instances  are  on  record  of  outbreaks  of  scurvy  which  have  been 
checked  by  its  administration.  Of  beverages,  French  and  Italian  wines 
are  stated  to  be  antiscorbutic  but  opinions  as  to  the  power  of  cider  in  this 
resj)ect  vary  considerably. 

^Notes  from  a  Voyage  Round  the  World,  by  George  Forstcr,  vol.  i,  1777. 


SCURVY  901 

Drugs  are  of  far  less  use  in  scurvy  than  the  measures  above  indicated. 
Wright,  on  hypothetical  grounds,  has  recommended  the  administration  of 
Rochelle  salt  in  doses  of  30  to  60  grains  (gm.  2  to  4)  thrice  daily  until  the 
urine  is  alkaline,  along  with  20  grain  (gm.  1.3)  doses  of  crystallized 
calcium  chloride  to  increase  the  coagulability  of  the  blood.  Barnardo 
speaks  favorably  of  this  treatment  as  the  result  of  his  experience  in 
Somaliland. 

The  administration  of  bitters — especially  of  quinine — and  of  iron  to 
combat  the  anaemia  is  of  help  in  restoring  health,  and  special  complica- 
tions may  require  the  administration  of  appropriate  remedies.  In  the 
treatment  of  diarrhoea,  bael  fruit  is  stated  to  be  specially  useful. 

Locally  the  conditions  of  the  mouth  will  demand  most  attention.  Anti- 
septic washes  of  permanganate  or  chlorate  of  potash  or  peroxide  of 
hydrogen  help  to  remove  the  foetor,  whilst  the  spongy  and  ulcerated  gums 
may  be  painted  with  a  strong  solution  of  nitrate  of  silver.  Absorption  of 
local  effusions  of  blood  may  be  promoted  by  gentle  massage. 

The  prophylactic  treatment  consists  in  attention  to  general  hygienic 
conditions  and  in  the  provision  of  an  abundant  and  varied  dietary  con- 
taining an  adequate  proportion  of  vegetables.  In  Nansen's  Arctic  ex- 
pedition, which  lasted  three  years  and  during  which  scurvy  was  entirely 
avoided,  the  diet  consisted  of  meat  of  various  sorts  in  hermetically  sealed 
tins,  dried  fish,  potatoes  both  dried  and  tinned,  all  sorts  of  dried  and  pre- 
served vegetables  and  fruits,  jam,  marmalade,  condensed  milk,  preserved 
butter  and  desiccated  soups.  Flour  was  carried  to  make  fresh  bread. 
Drinks  consisted  of  tea,  coffee  and  cocoa,  beer  and  lemonade. 

Lime  juice  has  long  been  used  as  a  prophylactic  but  is  apt  to  undergo 
decomposition  when  kept  long  in  a  barrel.  Two  ounces  twice  a  week  is 
recommended  as  a  preventive  dose. 


INFANTILE  SCURVY. 

-  That  infantile  scurvy  is  closely  related  to  the  adult  form  of  the  disease 
there  can  be  little  doubt,  and  as  in  the  latter  there  is  reason  to  believe  that 
a  deficiency  of  vegetable  salts  in  the  food  plays  an  important  part  in 
its  development.  None  the  less  the  clinical  manifestations  of  the  two 
forms  are  very  different,  but  the  differences  are  probably  to  be  explained 
by  differences  of  diet  and  by  the  anatomical  and  physiological  peculiari- 
ties of  the  infantile  period  of  life. 

Historical. — As  far  back  as  the  middle  of  the  seventeenth  century 
Glisson,  in  his  Treatise  on  the  Rickets,^  had  already  given  a  clear  descrip- 
tion of  scurvy  occurring  as  a  complication  of  rickets  but  the  disease 
seems  to  have  been  lost  sight  of  until  two  centuries  later  when  Lloller^ 
described  some  cases  under  the  title  of  "acute  rickets"  a  term  which  was 
adopted  by  other  continental  writers  on  the  subject,  such  as  Bohn,  and 
Hirschsprung.  In  1873  Jalland^  described  a  case  in  a  child  of  ten  months 
and  considered  it  as  identical  with  the  scurvy  of  adults. 

^English  Trans.,  1651,  p.  249. 

^Konigsb.  Med.  Jahrhucher,  1859,  i,  p.  377. 

^Med.  Times  and  Gazette,  1873,  i,  p.  248. 


902  COXSTITUTIOXAL  DISEASES 

Anothei'  case  was  published  in  1870  by  Thomas  Smith  wlio  described 
it  as  one  of  "Hemorrhagic  periostitis  of  several  of  the  long  bones  with 
separation  of  the  epiphyses,"^  but  failed  to  recognize  its  scorbutic  nature. 
To  Cheadle  belongs  the  credit  of  first  clearly  emphasizing  the  identity 
of  such  cases  with  the  scurvy  of  adults,  which  he  did  in  a  paper  on 
"Three  Cases  of  Scurvy  Supervening  on  Rickets  in  Young  Children,"^ 
published  in  1878.  In  1881,  Gee^  published  a  series  of  cases  under  the 
name  of  osteal  or  periosteal  cachexia,  but  in  1882  Cheadle'*  again  insisted 
upon  the  identity  of  such  cases  with  scurvy.  A  year  later  Barlow  secured 
general  recognition  of  the  truth  of  Cheadle 's  views  by  a  paper  entitled, 
"On  Cases  Described  as  'Acute  Rickets'  Which  are  Probably  a  Combina- 
tion of  Scurvy  and  Rickets,  the  Scurvy  Being  an  Essential  and  the  Rickets 
a  Variable  Element."^  This  paper  contained  an  exhaustive  clinical  and 
pathological  account  of  the  disease  and  has  become  a  classical  publication 
of  the  subject  which  on  the  Continent  has  secured  for  infantile  scurvy  the 
title  of  Barlow's  Disease.  The  terms  "acute  rickets"  and  "scurvy 
rickets"  are  still  sometimes  used  but  all  later  observations  tend  to  show 
that  the  rickety  element  is  a  mere  complication  and  not  an  essential  part 
of  the  process.  The  latest  and  most  exhaustive  account  of  infantile 
scurvy  was  written  by  Cheadle,^  but  almost  every  day  adds  to  the  literature 
of  the  disease. 

Etiology. — Clinical  observation  shows  that  the  vast  majority  of  cases 
of  scurvy  arise  in  infants  who  are  being  fed  on  a  diet  which  is  deficient  in 
fresh  constituents.  The  diet  which  most  commonly  produces  the  disease 
seems  to  be  one  consisting  of  condensed  milk  with  the  addition  of  a  tinned 
food,  but  a  diet  of  sterilized  milk  alone  is  undoubtedly  capable  of  giving 
rise  to  it,  and  so  even  may  milk  which  has  merely  been  boiled.  Griffith,^ 
in  summarizing  the  results  of  an  investigation  of  356  cases  collected  by  a 
committee  of  the  American  Pediatric  Society,  with  the  addition  of  18 
cases  of  his  own,  concludes  that  in  60  per  cent,  a  proprietary  food  had  been 
used  but  often  with  the  addition  of  sterilized  milk.  Nine  per  cent,  had 
been  fed  on  condensed  milk  and  19  per  cent,  on  sterilized  milk  only.* 
Pasteurized  milk  seems  much  less  apt  to  produce  the  disease.  That 
the  want  of  freshness  in  the  food  is  not  the  only  cause  of  the  disease,  how- 
ever, seems  to  be  shown  by  the  fact  that  10  of  the  cases  had  been  fed  on 
the  breast  only  and  several  of  them  on  raw  milk. 

It  may  be  asked,  What  is  it,  in  a  diet  deficient  in  fresh  constituents, 
which  tends  to  produce  infantile  scurvy  ?  That  the  fault  is  a  negative  and 
not  a  positive  one,  that  is  to  say,  due  to  the  absence  from  the  food  of  some 
constituent  which  it  should  contain  rather  than  to  the  presence  of  some 
abnormal  element,  is  shown  by  the  fact  elicited  by  some  observations  made 

*  Transactions  of  the  Pathological  Soceity  of  London,  xxvii,  1876,  p.  219. 
2  The  Lancet,  1878,  ii,  p.  685. 

^  St.  Bartholomew's  Hospital  Reports,  vol.  xvii,  p.  9. 

*  The  Lancet,  1882,  ii,  p.  48. 

^  Trans.  Royal  Medical  and  Chirurgical  Society,  1883,  Ixvi,  p.  159. 

'  AUbutt's  System  of  Medicine. 

'  New  York  Medical  Journal,  1901,  Ixxiii,  p.  317. 

*  For  additional  evidence  for  the  production  of  scurvy  by  sterilized  milk,  see 
Netter  (Scorbut  infantile  et  lait  sterilis)  Rev.  des  Maladies  de  VEnfance,  xx,  p.  543, 
1902;  Neumann,  Deut.  Med.  Woch.,  1902,  xxviii,  pp.  628,  647;  and  Ashby,  Brit. 
Med.  Journ.,  1904,  i,  p.  479. 


SCURVY  903 

by  the  writer^  that  the  mere  addition  of  sterilized  fruit  juice  to  the  diet 
without  any  other  alteration,  exercises  an  undoubtedly  curative  influence. 
The  same  was  found  to  be  true,  though  in  a  lesser  degree,  of  the  vegetable 
salts  of  potash  when  administered  artifically.  It  would  seem  probable 
that  a  deficient  supply  of  vegetable  salts  plays  at  least  a  large  part  in  the 
causation  of  infantile  scurvy  just  as  it  does  in  that  of  the  adult  form  of  the 
disease.  Milk  contains  a  considerable  quantity  of  citrate  of  lime;  and 
Corlette^  has  pointed  out  that  this  salt  is  present  in  fresh  milk  in  the 
amorphous  and  more  soluble  form,  its  solution  being  aided  by  the  presence 
of  phosphates,  but  that  when  milk  is  boiled  the  amorphous  is  converted 
into  the  crystallizable  form  of  the  salt,  which  is  less  soluble  and  separates 
out.  The  mere  boiling  and,  a  fortiori,  the  sterilization  of  milk  causes 
it  to  become  poorer  in  citrates  than  it  ought  to  be,  and  to  this  he 
attributes  the  tendency  for  scurvy  to  develop  when  such  milk  is  exclu- 
sively used. 

How  it  is  that  a  deficiency  of  vegetable  salts  in  the  food  leads  to  the 
hemorrhagic  tendency  characteristic  of  scurvy  we  do  not  know.  It  is  not, 
apparently,  by  reducing  the  coagulability  of  the  blood,  for  (as  already 
pointed  out)  the  coagulation  time  in  cases  of  scurvy  is  not  longer  than  the 
normal.  It  is  more  likely  that  the  hemorrhages  are  in  some  way  induced 
by  a  lowering  of  the  alkalinity  of  the  blood  (according  to  the  views  of 
Ralfe  and  Wright  as  already  stated  in  the  section  on  Scurvy  in  the 
Adult),  although  no  actual  proof  of  the  existence  of  a  diminished  alka- 
linity in  cases  of  infantile  scurvy  has  yet  been  obtained.  In  favor,  too,  of 
this  hypothesis  is  the  fact  that  the  mere  withdrawal  from  the  diet  of  a 
tinned  cereal  food,  where  such  is  being  given  and  which  yields  an  acid 
ash,  is  often  sufficient  of  itself  to  lead  to  a  cure  of  the  disease. 

There  is  therefore  considerable  reason  to  believe  that  a  reduction  of 
the  alkalinity  of  the  blood  from  a  deficient  supply  of  vegetable  salts  plays 
at  least  a  large  part  in  the  production  of  infantile  scurvy  just  as  it  does  in 
the  scurvy  of  adults.  On  the  other  hand  there  is  much  less  reason  to 
assume  the  existence  of  an  infective  element  in  the  infantile  form,  for  the 
infants  who  exhibit  it  are  but  rarely  drawn  from  the  poorer  classes  but, 
on  the  contrary,  are  more  commonly  the  children  of  well-to-do  parents 
and  enjoy  clean  and  comfortable  surroundings. 

Morbid  Anatomy. — ^The  chief  changes  found  after  death,  in  infants 
who  have  died  of  infantile  scurvy,  are  present  in  the  neighborhood  of  the 
bones.  If  a  section  be  made  across  a  limb  which  has  been  the  seat  of 
swelling  during  life  it  will  be  found  that  the  periosteum  is  thickened, 
highly  vascular  and  separated  from  the  subjacent  bone  by  a  layer  of  blood 
clot  which  may  show  various  degrees  of  organization.  There  is,  however, 
no  sign  of  inflammation  and  as  a  rule  no  hard  bone  is  formed  in  the  perios- 
teum except  in  very  old-standing  cases.  The  muscles  surrounding  the 
bone  may  be  infiltrated  with  blood  or  serum,  which  gives  them  a  sodden 
appearance. 

The  bone  itself  exhibits  a  considerable  degree  of  rarefaction,  the  can- 
cellous tissue  being  unusually  porous  and  the  normal  marrow  replaced  by 
a  highly  vascular  connective  tissue  into  which  hemorrhages  may  have 

^Goulstonian  Lectures  for  1904  on  Some  Disorders  of  the  Blood  and  Blood-form.' 
ing  Organs  in  Early  Life. 

"^British  Medical  Journal,  1900,  ii,  p.  573. 


904  COXSTITUTIOXAL  DISEASES 

occurred.  The  changes  characteristic  of  rickets  may  also  be  present  in 
the  bones. 

The  rarefaction  of  the  bone  is  apparently  the  result  of  delayed  ossifica- 
tion and  is  the  cause  of  the  fractures  which  are  not  uncommonly  met 
with  in  severe  cases  and  which  are  usually  situated  a  little  above  the 
epiphyseal  line,  although  there  may  sometimes  be  separation  at  the  line 
of  the  epij)hvseal  cartilage  itself. 

Hemorrhagic  efl"usions  may  be  met  with  elsewhere  in  addition  to  those 
around  the  bones,  such  as  in  the  joints  or  in  the  serous  cavities  or  sub- 
dural space.  None  of  these,  however,  is  characteristic  of  the  disease. 
The  internal  organs  exhibit  no  constant  change. 

Symptoms. — Scurvy  is  commonest  in  infants  of  about  eight  to  ten 
months  old.  In  an  analysis  of  04  cases  by  Bovaird^  the  youngest  was  six 
months  old,  the  oldest  two  and  a  half  years,  the  average  age  being  twelve 
months.  Fifty-four  per  cent,  of  the  cases  occurred  between  the  ninth  and 
thirteenth  months.  The  children  affected  are  usually  well-nourished  but 
often  exhibit  some  degree  of  pallor.  The  invasion  of  the  disease  may  be 
either  gradual  or  abrupt.  After  a  few  days  of  fretfulness  or  after  having 
exhibited  for  some  time  great  tenderness  Avhen  handled,  the  more  prom- 
inent symptoms  appear.  The  most  striking  of  these  is  tenderness  of 
the  legs,  which  causes  the  child  to  scream  out  when  touched  or  even  at  the 
approach  of  the  doctor.  It  can  be  observed  that  the  child  lies  very  still, 
usually  on  his  back  with  one  or  both  legs  everted  and  motionless.  Ex- 
amination in  a  well-marked  case  reveals  some  swelling  of  the  bones,  most 
commonly  of  the  lower  end  of  the  femur  or  upper  end  of  the  tibia.  The 
long  bones  of  the  upper  extremities  are  much  more  rarely  affected,  the 
collective  investigation  in  America  yielding  only  14  cases  with  swelling 
in  the  arms  to  131  in  which  the  legs  Avere  affected.  At  the  site  of  these 
swellings  the  tenderness  is  extremely  acute  and  the  skin  over  them  is  often 
tense  and  glossy  and  may  be  slightly  oedematous  but  there  is  no  local  heat. 
On  gently  handling  the  limb  soft  crepitus  may  be  elicited,  from  fracture, 
or  separation  of  the  epiphysis.  In  some  cases  hemorrhage  takes  place 
into  the  orbit,  giving  rise  to  proptosis  and  ecchymosis  of  the  eyelids. 
This  symptom  occurred  in  49  out  of  379  of  the  American  cases.  The 
proptosis  may  appear  suddenly,  often  during  a  fit  of  crying,  and  in  severe 
cases  may  even  lead  to  ulceration  of  the  cornea. 

Rarer  sites  of  hemorrhage  are  round  the  ribs,  clavicles,  or  bones  of  the 
skull.  Sir  Thomas  Barlow  has  described  a  peculiar  depression  of  the 
sternum  en  hloc  which  is  present  in  severe  cases  and  is  apparently  due  to  a 
loosening  of  the  articulations  between  the  sternum  and  ribs. 

Changes  in  the  Gums. — These  are  not  usually  present  unless  some 
teeth  have  been  cut,  but  even  in  the  absence  of  the  latter  there  may  be  a 
slight  degree  of  injection  and  ecchymosis,  especially  over  the  sites  of  the 
incisors.  Should  any  teeth  have  erupted,  the  gum  around  them  is  usually 
swollen  and  of  a  purplish  color,  but  the  change  is  rarely  if  ever  so  marked 
as  in  the  scurvy  of  adults  and  does  not  often  go  on  to  ulceration.  It  is 
rare  for  the  gums  to  appear  normal  after  any  teeth  have  appeared,  but  a 
few  such  cases  have  been  observed. 

Other  Symptoms. — Petechise  and  subcutaneous  ecchymoses  are  rarely 
met  with  in  infantile  scurvy  and  hemorrhages  from  mucous  surfaces, 

^  Philadelphia  Medical  Journal,  1898,  ii,  p.  375. 


BCURVY  905 

with  the  exception  of  the  gums,  are  not  common.  Hsematuria,  however, 
is  met  with  not  infrctjuently  and  a  slight  degree  of  it,  at  least,  is  probably 
much  commoner  than  is  generally  believed.  Sometimes  indeed  it  is  the 
only  symptom  present  and  in  a  few  cases  it  apjiears  to  lead  to  nephritis^ 
or  pyelitis.  Fever  is  not  a  conspicuous  feature  of  infantile  scurvy,  but 
where  extensive  hemorrhages  have  taken  place  there  may  be  a  rise  of 
temperature  which,  however,  rarely  exceeds  101°  or  102°  F. 

Changes  in  the  Blood. — There  is  usually  a  greater  or  less  degree  of 
anaemia  present,  especially  in  cases  in  which  extensive  subperiosteal 
hemorrhages  have  (occurred.  The  anaemia  is  usually  of  the  chlorotic 
type,  the  haemoglobin  being  reduced  out  of  proportion  to  the  red  cells, 
but  where  the  hemorrhages  have  been  specially  severe  the  characters  of 
a  secondary  anaemia  may  be  exhibited  as  well,  and  the  red  cells  are  re- 
duced in  number  and  some  nucleated  forms  present.  In  the  absence  of 
complications  no  leukocytosis  occurs.  The  chemical  changes  in  the  blood 
have  not  been  fully  investigated  but  in  a  series  of  cases  examined  by  the 
writer  no  alteration  in  the  coagulability  could  be  discovered.  Whether 
or  not  there  is  any  reduction  of  alkalinity  has  not  been  determined. 

Association  with  Rickets. — ^The  relation  of  scurvy  to  rickets  has  been 
much  disputed.  That  the  two  conditions  are  not  invariably  associated  is 
shown  by  an  analysis  of  40  fatal  cases  by  Schoedel  and  Nauwerk^  in  18 
of  which  the  presence  of  rickets  had  been  recognized  during  life,  whilst 
it  was  found  in  3  others  after  death.  The  frequent  co-existence  of  rickets 
in  cases  of  scurvy  would  seem  indeed  to  be  due  merely  to  the  fact  that  the 
kind  of  diet  which  produces  the  one  disease  is  also  that  which  tends  to 
give  rise  to  the  other. 

Diagnosis. — The  diagnosis  of  scurvy  in  a  well-marked  case  is  easy, 
provided  the  leading  features  of  the  disease  are  known  to  the  observer. 
The  screaming  of  the  child  on  examination,  the  swelling  and  tenderness 
of  the  legs,  and  the  condition  of  the  gums  leave  no  doubt  as  to  the  nature 
of  the  affection  with  which  one  has  to  deal.  All  cases,  however,  are  not  so 
pronounced  in  type.  Not  infrequently  one  encounters  mild  or  incipient 
forms  which  it  is  easy  to  overlook.  In  these,  tenderness  when  the  child  is 
handled  or  when  he  is  put  in  his  bath  may  be  the  only  symptom.  In  other 
cases  again,  slight  sponginess  round  the  incisor  teeth  may  alone  be  present 
or  one  may  have  to  deal  with  an  apparently  causeless  haematuria.  In  any 
case  in  which  there  is  doubt  two  points  will  help.  One  is  the  nature  of  the 
feeding.  If  this  has  been  of  such  a  nature  as  is  known  to  favor  the 
development  of  the  disease  the  diagnosis  will  be  greatly  strengthened 
The  other  point  is  the  application  of  the  therapeutic  test.  If  the  symp- 
toms present  are  really  due  to  incipient  scurvy  then  they  will  certainly 
disappear  rapidly  so  soon  as  appropriate  treatment  is  begun;  if  they  fail 
to  do  this  then  one  has  to  do  with  some  other  condition. 

The  affections  for  which  scurvy  is  most  often  mistaken  are  these: 

1.  Rheumatism. — ^Time  and  again  the  writer  has  had  well-marked 
cases  of  infantile  scurvy  sent  to  him  with  a  diagnosis  of  rheumatism  and 
in  one  such  case  he  has  known  the  affected  limb  to  be  painted  with  iodine 
with  the  result  of  greatly  aggravating  the  sufferings  of  the  unfortunate 
child.    The  mistake  should  really  never  be  made  if  it  be  remembered 

^See  Still,  Lancet,  1904,  ii,  p.  441. 

'''Rev.  des  Maladies  de  VEnfance,  1902,  xx,  p.  543. 


906  CONSTITUTIONAL  DISEASES 

that  below  the  age  of  one  year  rheumatism  is  practically  never  met  with. 
An  inquiry  into  the  mode  of  feeding  and  a  careful  search  for  the  other 
signs  of  scurvy  will  confirm  the  diagnosis, 

2.  Periostitis. — The  distinction  between  scurvy  and  periostitis  is  often 
a  matter  of  great  difficulty,  especially  when  the  gum  changes  are  absent. 
The  presence  of  a  marked  degree  of  pyrexia  is  in  favor  of  a  diagnosis  of 
periostitis,  for  in, scurvy,  fever  is  usually  absent  or  but  trivial  in  amount. 
If  the  other  signs  of  scurvy  are  present  as  well,  the  diagnosis  will  of  course 
be  clear  but  sometimes  one  may  be  obliged  to  fall  back  on  the  therapeutic 
test. 

3.  Infantile  Paralysis. — When  infantile  paralysis  sets  in,  as  it  some- 
times does,  with  a  marked  degree  of  hypersesthesia,  it  may  simulate 
scurvy.  It  will  be  noted,  however,  that  there  is  no  swelling  of  the  affected 
limb  and  that  the  other  signs  of  scurvy  are  absent. 

4.  Epiphysitis. — Epiphysitis  may  simulate  scurvy  but  the  swelling 
in  the  latter  extends  along  the  shaft  of  the  bone  and  is  not  confined  to  the 
neighborhood  of  the  epiphysis. 

5.  The  changes  in  the  mouth  may  be  mistaken  for  those  of  ordinary 
ulcerative  siomaiiiis.  In  scurvy,  however,  the  changes  are  confined  to  the 
gums  whilst  in  stomatitis  they  extend  to  the  lips  and  cheeks  as  well.  The 
ulceration  in  the  mouth  which  often  occurs  in  acute  leukaemia  may  also 
lead  to  a  suspicion  of  scurvy.  Here  the  examination  of  the  blood  will  at 
once  settle  the  diagnosis. 

6.  Cases  which  are  characterized  by  hemorrhage  into  the  orbit  may 
be  mistaken  for  sarcoma  of  the  skull  or  for  chloroma.  In  the  former  case 
there  are  usually  signs  of  sarcoma  elsewhere  and  in  the  latter  the  blood 
shows  an  excess  of  lymphocytes  whilst  in  both  the  positive  signs  of  scurvy 
are  absent. 

7.  The  hcematuria  of  scurvy  is  apt  to  be  mistaken  for  renal  hemorrhage 
from  other  causes,  such  as  renal  sarcoma.  In  a  doubtful  case  of  bleeding 
from  the  kidney  it  is  therefore  always  well  to  try  the  effect  of  an  antiscor- 
butic diet  before  proceeding  to  other  measures. 

Prognosis, — The  prognosis  in  infantile  scurvy  is  quite  favorable,  pro- 
vided the  disease  be  recognized  in  time  and  suitable  treatment  adopted. 
Nothing  in  therapeutics,  indeed,  is  more  striking  than  the  rapidity  with 
which  such  patients  improve  under  a  change  of  diet  although  some  degree 
of  thickening  of  the  bones  may  persist  for  a  long  time.  Death,  when  it 
occurs  in  the  more  severe  cases,  is  usually  the  result  of  intercurrent 
diseases,  of  which  bronchopneumonia  and  chronic  liarrhoea  are  the  most 
frequent,  although  sudden  hemorrhage,  cardiac  failure,  or  exhaustion, 
may  occasionally  lead  to  a  fatal  issue. 

Treatment, ^ — This  consists  solely  in  altering  the  diet.  Tinned  foods 
and  sterilized  milk  must  at  once  be  stopped  and  the  child  put  upon  a  due 
allowance  of  unboiled  milk.  Fruit  juice  should  be  added,  a  few  teaspoon- 
fuls  of  grape  or  orange  juice  sweetened  with  a  little  sug::.r  being  given 
daily.  Baked  potato  is  also  useful,  a  little  of  the  floury  part  under  th:;  skin 
being  rubbed  up  v^ith  the  milk  into  a  thin  cream  which  is  either  added 
to  the  bottle  or  given  separately  (two  teaspoonfuls  three  or  four  times  a 
day).  Raw  meat  juice  is  certainly  of  value.  It  may  be  gi\on  in  quantities 
of  half  an  ounce  daily.    Drugs  are  of  little  service  though  the  vegetable 


BCURVY  907 

salts  of  potash  certainly  exert  a  certain  curative  influence.     During  the 
period  of  convalescence  cod-liver  oil  and  iron  are  helpful. 

Scorbutic  infants  should  be  handled  carefully  and  the  clothing  should 
be  so  constructed  that  it  can  be  easily  taken  off  and  on.  If  it  is  necessary 
to  move  the  child  about  he  should  be  placed  on  a  pillow.  The  affected 
limb  should  be  steadied  by  light  splints  or  wrapped  in  wet  towels,  which, 
if  allowed  to  dry  in  position,  afford  considerable  support.  In  mild  cases 
a  casing  of  cotton  wool  secured  by  a  light  bandage  will  be  sufficient  pro- 
tection. 


INDEX. 


Abdomen,  actinomycosis  of,  333 
Abscess,  filarial,-  616 

hepatic,  diagnosis  of,  from  mala- 
rial levers,  437 
of  liver  in  amoebic  dysentery,  513 
of  lung  in  amoebic  dysentery,  516 
of  spleen  in  amoebic  dysentery,  516 
Abnormalities  in  processes  of  oxidation, 

280 
Absinthism,  195 
chronic,  196 
Acanthocephah,  531,  582,  604 
Acanthrotrias,  575 
Acariasis,  533,  626,  631 
demodectic,  630 

parasite  of,  630 
symptoms  of,  630 
sarcoptic,  627 

diagnosis  of,  629 
frequency  of,  628 
parasites  of,  627 
symptoms  of,  628 
treatment  of,  629 
Acarina,  531,  626 
Acarus  folliculorum,  630 
Acephalocystis,  576,  578 
"Acetone  bodies,"  700 
complex,  322 

action  of  intoxication  in,  325 
associated    with    low    carbo- 
hydrate combustion,  323 
in  cachexia,  323 
and  carbohydrate  metabolism, 
322 
not  deranged,  323 
with  disturbances   of  protein 

metabolism,  324 
in  febrile  diseases,  323 
with  normal  qualitati^'e  carbo- 
hydrate   metabol- 
ism, 323 
■protein    metabolism, 
323 
without    quantitative    altera- 
tions in  metabolism,  323 
in  starvation,  323 
in  urine  in  diabetes  mellitus,  778 
Acid  intoxication,  in  scurvy,  894 


Acidosis,  294,  716 

in  childliood,  295 

in  diabetes  mellitus,  786 
treatment  of,  796 

explanation  of,  295,  325 

and  lactic  acid,  295 
Acquired  immunity,  44 
Acromegaly,  diabetes  mellitus  and,  752 
Actinium  rays,  63 
Actinomyces  bovis,  327,  330 
Actinomycosis,  327 

of  abdomen,  333 

of  brain,  332 

clubs  in,  328,  336 

cutaneous,  334 

diagnosis  of,  335 

etiology  of,  328 

filaments  in,  328 

of  head,  332 

of  lungs,  333 

metastasis  in,  332 

of  neck,  332 

pathology  of,  331 

prognosis  of,  337 

recurrence  of,  339 

symptoms  of,  334 

of  thorax,  333 

treatment  of,  338 
Adiposity,  845.     See  Obesit3^ 
Adrenalin  diabetes,  758 
^stivo-autumnal     fever,     392.     See 
Malarial  fevers, 
parasites,  quotidian  form,  398 
tertian  form,  399 
Agamodistomum  ophthalmobium,  556 
Agamofilaria,  582 

georgiana,  623 

oculi,  623 
Agchylostoma,  582,  583 

duodenale,  582 
Ague,  392.     See  Malarial  fevers. 
Air,  69 

hunger  in  diabetic  coma,  784 

pathological  effects  of,  69 

physiological  effects  of,   69 
Albuminuria  in  diabetes  mellitus,  779 

gastro-intestinal,     due     to     auto- 
intoxications, 279 

in  gout,  831 

in  malarial  fe^er,  431 

(909) 


910 


INDEX 


Albuminuria  in  obesity,  854 
Alcohol  in  metabolism,  675 
Alcoliolic  trance,  194 
Alcoholism,  157 

ajje  at  death  from,  109 
arteriosclerosis  in,   170 
cardiac  lesions  in,  170 
chronic,  192 

symptoms  of,  193 
treatment  of,  200 
etiology  of,  157 
lieredity  in,  159,  177 
infantilism  and,  178 
infectious  diseases  and,  176 
kidneys  in,  172 
liyer  in,  171 
neryous  system  in,  173 
neuritis  in,  175 
pathological  effects  of,   168 
pathology  of,  100,  169 
relation  of  age  to,  159 
of  occupation  to,  158 
of  season  to,  160 
stomach  in,  173 
tuberculosis  and,  170 
Algid  form  of  malarial  feyer,  424 
Alimentary  glycosuria.  762 

tract,  substances  formed  by  bac- 
teria from  normal  food  \vithin, 
272 
Alkaptonuria,  metabolism  in,  713 

excess  of  protein,  305 
Allantiasis,  232 
Alloxuric  bodies,  812 

in  urine  in  diabetes  mellitus, 
779 
Alopecia  from  x-rays,  60 
Amblyomma  americanum,  627 

dissimile,  627 
Amentia  in  chronic  alcoholism,   199 
Amino-acids,  metabolism  of,  712 
Ammonia,  elimination  of,  709 
in  acidosis,  716 
relation  of,  to  ursemia,  305 
in  urine  in  diabetes  mellitus,  779 
intoxications  due  to,  298 
Amnesia  in  alcoholic  trance,  194 

in  morphinism,  212 
Amoeba  coli,  495,  532 

discoyery  of,  488 
forms  of,  496 
dysenteria;,  495,  532 
AmoebEe  of  human  intestine,  491 

behayior  of,  toward  chem- 
ical substance, 
492 
physical     condi- 
tions, 492 
biological    properties    of, 

491 
classification  of,  494 
cultiyation  of,  491 
distribution  in  body,  494 


AmoebfB  of  human  intestine,  physio- 
logical processes  of,  493 
yarieties  of,  494 
inoculation  experiments  with,  500 
methoil  of  reaching  the  liyer,  514 
mode  of  infection  with,  501 
non-recurrence    of,     in    stools    of 

dysenteric  patients,  500 
recurrence  of,  in  healthy  persons, 
498 
in  stools  of  patients  with  other 
diseases  than  dysentery,  500 
recognition  of,  519 
source  of,  501 
Amoebiasis,  488.     See  Dysentery,  amoe- 
bic. 
Amoebic  colitis,    488.     See  Dysentery, 
ama?bic. 
dysentery.     See  Dysentery,  amoe- 
bic, 
enteritis,      488.      See     Dysentery, 
amoebic. 
Amphimixis  in  inheritance,  45,  46 
Amphinuclei,  355 
Amphistoma  hominis,  549 
Amyl  alcohol,  162 
Anabolism,  639 

Anaemia  in   amoebic  dysentery,   512 
brick-makers',  582 
due  to  auto-intoxication,  279 
in  infantile  scuryy,  905 
in  malarial  feyers,"  408,  431,  582 
miners',  582 
in  rickets,  884 
tunnel,  582 
AnaBmias,    essential,  excess   of  protein 
metabolism  in,  302 
suboxidation  in,  284 
Anchilostoma  duodenale,  584 
Anchylostoma  duodenale,  584 
Anchylostomiasis,  584 
Anders'   dietary  treatment  of  obesity, 

860 
Aneurism  of  abdominal  aorta,  diabetes 
insipidus  and,  802 
of  carotid  artery,  diabetes  insipidus 

and,  802 
in  gout,  832 
Angina  pectoris  in  gout,  832 

in  obesity,  855 
Anguillula,  582 

aceti,  024 
Anguilluliasis,  595 
Anguillulina,  582 

putrefaciens,  002 
Animal  parasites,  525 
age  and,  527 
bil)liography  of,  533 
classes  of,  520 
classification  of,  530 
definition  of,  525 
diagnosis  of,  529 
fertility  of,  527 


INDEX 


911 


Animal  parasites  in  fish,  228 
frequency  of,  520 
heredity  and,  528 
identification  of,  533 
infection  with,  f!;cncric,  529 

specific,  529 
influence  on  host,  528 
origin  of,  528 
periodicity  of,  527 
prevention  of,  530 
resistance  of,  527 
sex  and,  527 
terminology  of,  533 
Ankylostoma  duodenalc,  584 
Ankylostomasis,  582 
Ankylotoinum  americanum,  583 
Anomalies,  gross,  inheritance  of,  26 
probably  of  defect,  inheritance  of, 
26 
Anopheles,  albipes,  386 
argyritarsis,  386 
barberi,  386 
bifurcatus,  378 
crucians,  378,  385 
ferruginosus,  383 
franciscanus,  386 
heimalis,  383 
life  history  of,  379 
maculipennis,  378,  383 
nigripes,  383 
pictus,  383 

punctipennis,  378,  385 
quadrimaculatus,  383 
species  of,  383 
walkeri,  383 
Anthomyia  canicularis,  637 
Antivenin,  263 

Anuria  without  intoxication,  292 
Apoplexy,  diagnosis  of,  from  malarial 
fevers,  437 
in  gout,  832,  833  _ 
Appendicitis  in  amoebic  dysentery,  517 
diagnosis  of,  from  malarial  fever, 
428 
Appetite,  loss  of,  in  amoebic  dysentery, 

512 
Argas  miniatus,  627 
persicus,  627 
reflexus,  627 
Argasidse,  626 
Argopsylla  gallinacea,  633 
Argyria,  136 

diagnosis  of,  137 
patiiology  of,  136 
prognosis  of,  137 
prophylaxis  of,  138 
symptoms  of,  137 
treatment  of,  138 
Arsenic,  detection  of,  in  urine,  122 
eating,  117 
immunity  to,  118 
poisoning,  114 
ataxia  in,  121 


Arsenic  poisoning,  diagnosis  of,  121 
erythromelaigia  in,  119 
etiology  of,  1 14 
eye  manifestations  in,  120 
from  l)(;(!r,  1 16 
clotiiing,  115 
foods,  115 
occupation,  116 
wall  paper,  114,  115 
herpes  in,    119 
keratosis  in,  119 
medicinal,  114,  116 
mode  of  entrance  of,   118 
nervous  lesions  in,  1 17 
pain  in,  120 
paralysis  in,  120 

diagnosis  of,   122 
pathogenesis  of,  118 
pathology  of,  117 
pigmentation  in,  119 
prognosis  of,  122 
prophylaxis  of,  122 
sensory  disturbances  in,  120 
skin  lesions  in,  119,   120 
symptoms  of,  119 
treatment  of,  123 
susceptibility  to,  118 
Arteriosclerosis,  diabetes  mellitus  and 
757 
in  gout,  828,  832 
in  obesity,  852 
Artificial  nutrition,  745 
Ascariasis,  596 

diagnosis  of,  599 
distribution  of,  596 
frequency  of,  597 
infection  in,  597 
parasites  in,  597 
symptoms  of,  598 
treatment  of,  599 
Ascaris,  532,  582 
capularia,  526 
lumbricoides,  597 
maritima,  597 
texana,  597,  598 
trichuria,  603 
vermicularis,  600 
Aspergillosis,  pulmonary,  350 
definition  of,  350 
diagnosis  of,  352 
etiology  of,  350 
pathology  of,  351 
prognosis  of,  352 
symptoms  of,  352 
treatment  of,  352 
Aspergillus,  350 

Asphyxia,  diabetes  mellitus  and,  752 
Asthma,  cardiac,  in  obesity,  854 

dyspepticum   due  to    auto-intoxi- 
cations, 279 
in  gout,  832 
Atavism,  31 
Atrophy  of  skin  from  x-rays,  59 


912 


IXDEX 


Auto-intoxications,  206 

associated  with  carbohydrate 
metal)olisin,  815 
with  I'at  metabolism,  321 
with  i>rotein  metabolism, 
297 
-    with    purin    metabolism, 
30,S 
asthma  dyspepticum,  279 
chissilication  of,  267 
definition  of,  26() 
diseases  of  the  nervous  system, 

279 
due  to  constipation,  27S 

to  ner\ous  dyspepsia,  278 
from  bacterial   products,   273 
cytolysis,  2GS 
excessiA-e    protein    inges- 
tion, 300 
gastro-intestinal,  270 
albuminuria,  279 
ana-mias,  279 
metabolisin  and,  268 
tetany,  277 
Autolysis,  715 
Automatism,  194 
Autotyphization,  308 


B 


Bacillus  botulinus,  232,  233,  244 

breslaviensis,  238 

enteritidis,  227,  237,  240,  242 
agglutination  of,  239 

friedebergensis,  236 

morbificans  bovis,  236 

paratyphosus,  232,  240 

piscicidus,  224 
agilis,  225 
Bacteria  in  milk,  241 

in  shell-fish,  229 
Bacterial  fish  poisons,  224,  228 
Bacteriology  of  rickets,  874 
Banting's  dietary  treatment  of  obesity, 

857 
Basedow's    diseases,    diabetes   mellitus 

and,  752 
Bed-bugs,  635 

extermination  of,  636 
Benzol  deri\-atives,  274 
Bernard's  diabetic  centre,  752 
Big  jaw,  327 
Bile,  toxicity  of,  287 
Billiarzia  capensis,  550 

disease,  550 

ha-matobia,  550 
Bilharziosis,  550 
Bilious  malarial  fe^•er,  425 
Biopliores   in   inheritance,   37,   38,   42, 

43,  46 
Black-water  fever,  449 
blood  in,  456 


15hick-water  fe\-or.  bone-marrow  in,  455 
lirain  in,  455 
(lelinition  of,  449 
tliagnosis  of,  457 
tlistribution  of,  449 
etiology  of,  455 
jauntlice  in,  456 
leukocytes  in,  457 
malarial  fe\'er  and,  450 

origin  of.  454 
morl)id  anatomy  of,  455 
prognosis  of,  458 
quinine  anil,  454,  458 
symptoms  of,  456 
treatment  of,  458 
urine  in,  456 
Blastomycetcs  and  malignant  tumors, 

327 
Hlastomvcetic  dermatitis,  346 
r>lastomycosis,  346,  350 
lilendi'd  inlieritance,  29,  34 
Hlepharoplast,  356 
Blood  in   black-water  fe\-er,  456 

clotting  components  of  venom,  255 
deficiency  of  potassium  in  scurvy, 

894 
in  diabetes  mellitus,  769 
dimiruition     in     alkalinit)^    of,    in 

scurvy,  894 
examination  of,  in  malarial  fe\ers, 

433 
fluke  infection  of,  550 
African,  550 
Asiatic,  550 
in  gout,  825 

alkalinity  of,  820,  822 
in  human  trypanosomiasis,  480 
in  uncinariasis.  590 
uric  acid  in,  817 

in  gout,  819 

origin    of   excess   of, 
820 
Blue  line  in  lead  poisoning,  99 
Body,  mechanical  efficiency  of,  662 
Boils  in  diabetes  mellitus,  780 
Bone-marrow  in  black-water  fever,  455 

in  malarial  feAers,  413 
Bones,  curvature  of,  in  rickets,  877 

in  lead  poisonmg,  102 
Boophilus  annulatus,  626,  627 
Bothriocephalus  cordatus,  569 
cristatus,  567 
latus,  533 
Botulismus,  233 

symptoms  of,  234 
toxin  in,  234 
/?-oxybutyric  acid  in  urine  in  diabetes 
mellitus,  777 
amount  of,  786 
source  of,  787 
liradycardia  in  obesity,  852 
Brain,  actinomycosis  of,  332 
in  black-water  fever,  455 


INDJ'JX 


913 


Brain,  changes  in,  in  rickets,  (S72 
in  diabetes  mellitus,  770 
in  malarial  fevers  410 
traumatism  of,  diabetes  insipidus 
and,  801 
Brass  poisoning,  138 

worker's  ague,  139 
Breads,  composition  of,  738 

digestion  of,  738 
Broad  tapeworm,  567 

description  of,  567 
diagnosis  of,  568 
distribution  of,  567 
frequency  of,  568 
infection  by,  568 

features  of,  568 
prevention  of,  568 
Bronchitis,  chronic,  in  gout,  828,  832 

in  rickets,  884 
Bronchopneumonia  in    diabetes   melli- 
tus, 770 
in  rickets,  885 
Bronze  diabetes,  756 
Budding  of  protozoa,  356 
Bunostumom,    type    trigonocephalum, 

583 
Burns,  77 

conditions  with,  291 
electrical,  67 
pathogenesis  of,  78 
pathology  of,  78 
treatment  of,  78 
x-ray,  59 


Cachexia  of  malignant  diseases,  excess 
of  protein  metabolism  in,  302 
miners',  582 

strumipriva,  suboxidation  in,  283 
suboxidation  in,  284 
Caisson  disease,  72 

pathogenesis  of,  73 
pathology  of,  73 
prevention  of,  75 
prognosis  of,  73 
symptoms  of,  73 
treatment  of,  74 
Calabar  swellings,  621 
Cameroon     fever,     392.     See    Malarial 

fevers. 
Cancer  of  liver,  associated  with  flukes, 
543 
diabetes  insipidus  and,  802 
from  x-rays,  60 
Caput  quadratum,  880 
Carbohydrate   assimilation,   316 

combustion,  low  acetone  complex 

associated  with,  323 
influence  of,  on  proteid  metabolism, 

673 
metabolism,  315,  689 
58 


Carbohydrate      metabolism,      acetone 
complex    not  deranged  in, 
323 
auto-Intoxication      associated 

with,  315 
normal     ciualitative,     acetone 
complex  with,  323 
starvation,  316 
Carbon  bisulphide;  poisoning,  149 
diagnosis  of,  154 
etiology  of,  149 
hysteria  and,  154 
industrial,  149 
mode  of  entrance  of,  151 
motor  disturbances  in,  153 
pathogenesis  of,  151 
pathology  of,   150 
prognosis  of,  155 
prophylaxis  of,  155 
psychoses  in,  153 
sensory    disturbances   in, 

152 
symptoms  of,  151 
treatment  of,  155 
tremor  in,  152 
dioxide,   excretion   of,   680,   682 

retention  of,  288 
monoxide  poisoning,  141 
accidental,   143 
acute  coma  in,  145 
diagnosis  of,  147 
I  by     blood     changes, 

147 
etiology  of,  141 
from  furnaces,  142 
house   epidemics  of,  145 
industrial,  142 
metabolism  in,  693 
mode  of  entrance  of,   144 
pathogenesis  of,  144 
pathology  of,  144 
polycytha?mia  in,  147 
prognosis  of,  148 
sequelae  of,  145 

in  nervous  system,  146 
symptoms  of,  145,  146 
treatment  of,  148 
Carbuncles  in  diabetes  mellitus,  780 

treatment  of,  798 
Cardiac  asthma  in  gout,  832, 

in  obesity,  854 
Cardiovascular  lesions  in  gout,  828 
system  in  lead  poisoning,  100 
Caries  of  spine,  diagnosis  of,  from  rick- 
ets, 886 
Catabolism,  exaggerations  of,  266 
Cataract  in  diabetes  mellitus,  783 
Catarrh,    gastro-intestinal,    in    rickets, 

885 
Cayor  worm,  637^ 
Cellular    exudates,    excess   of    protein 

metabolism  in,  303 
Centronuclei,  355 


914 


IXDEX 


Cerebellum,  tumors  of,  (li;\l)etcs  mcllitus 

antl,  752 
Cerebral  heniorrluige,  dial)ctc's  mollitus 
and,  752 
symptoms  of  Icail  poisoning;,  106 
tumors,  dialictos  insipidus  and,  SOI 
Cerebrospinal  fluiil,  trypanosoma  Gam- 

I)iensc  in,  471 
C(-stoda,  531.  557" 
Cestode  infection,  557 
Chalk-sfonos,  S27,  829 
Choose,  poisonous,  242 
Chemical  ajionts,  diseases  due  to,  S3 

properties  of  venoms,  252 
Chemistry  of  rickets,  S72 
Che\iie-Stokes   respiration   in   obesity, 

S54 
Chicken  mites,  G31 
CliigGier,  G33 
Chigol,  (533 
Chloroma,  diagnosis  of,  from  infantile 

scurvy,  900 
Cholorosis,  Egvptian,  582 

tropical,  582 
Choleraic  malarial  fe\'er,  424 
Chromitlien,  364 

Chromosomes  in  inheritance,  37 
Chvostok's  sign  in  rickets,  883 
Chvloccle  in  filariasis,  618 
Chyluria,  fihxrial,  618 

malarial,  618 
Cimex  lectularius,  635 
Circumscriljod  obesity,  855 
Cladorchis  watsoni,  549 
Cladothrix,  342 
Climatic    fever,     392.     See    Malarial 

fevers. 
Clonorchis  Looss,  1907,  new  name  based 
on  opit>iltorchis  .sinensis 
endcnricus,  for  Japanese  species 
sine7isis,  for  Chinese  species 
Coast  fever,  392.     See  Malarial  fevers. 
Cocaine,  effects  of,  220 
history  of,  217 
poisoning,  217 
acute,  218 
diagnosis  of,  221 
etiology  of,  218 
prognosis  of,  222 
treatment  of,  222 
psychosis,  221 
Coccidioidal  granuloma,  346 
Coccidium  Schubergi,  life-cycle  of,  365 
Co-efficients  of  a^ailaljilitv  of  nutrients, 

653 
Coenurus,  559 
Cold,  effects  of,  79,  80,  81 
patliogenesis  of,  SO 
pathology  of,  80 
prognosis  of,  80 
treatment  of,  80 
Colic  in  lead  poisoning,  101 

treatment  of,  112 


Colica  pictonum,  84 
Coma,  diabetic,  784 

in  gout,  833 
Comatose  malarial  fever,  423 
Combustion  products,  poisoning  by,  141 
diagnosis  of,  147 
etiology  of,  141 
mode  of  entrance  of,  ,144 
jiathogenesis  of,  144 
jiathology  of,  144 
prognosis  of,  148 
symjitoms  of,  1 15 
treatment  of,  148 
Commensalism,  525 
Compsomyia  macellaria,  637 
Conditions  truly  inherited,  25 
ex-specie,  25 
familial,  25,  26 
racial,  25,  26 
Congenital  rickets,  SS9 

symptoms  of,  890 
treatment  of,  890 
syphilis,  23 
Conjugal  diabetes,  749 
Conjuncti^■itis  in  gout,  831 
Conorhinus  sanguisuga,  635 
Conservation  of  energy,  656,  658 
Constipation     and     auto-intoxication, 
278 
in  diabetes  mellitus,  781 
in  gout,  831 
in  obesity,  853,  854 
in  scur\-y,  898 
Constitutional  diseases,  747 
Consumption,  negro,  582 
Convulsions  in  riclcets,  882 
Copper  poisoning,  138 

pigmentation  in,  139 
(brpulence,  metaljolism  of,  700 
Corpulency,  845.     See  Obesity. 
Coxa  vara,  877 
Oaniotabes  in  rickets,  881 
Cranium  in  riclcets,  879 
Creatinin,  metabolism  of,  709 
Crenocephalus  canis,  634 
Cross-breeding,  30 
Ctenoccphalus  canis,  634 
Culex,  discolor,  377 
dupreei,  377 
fasciatus,  388 
fatigans,  373 
life  history  of,  373 
perturbans,  376 
pipiens,  373 
sollicitans,  375 
squamiger,  376 
sjdvestris,  376 
ta?niatus,  388 
ta?niorhynchus,  376 
territans,  377 
triseriatus,  377 
Cutaneous  eruj)tions  in  gout,  831 
Cysticercosis,  560,  562,  574 


INDEX 


915 


Cysticercosis,  parasite  in,  575 

symptoms  of,  575 
Cysticercus  acanthotrias,  575 

bovis,  559,  560,  5()3,  575 

cellulossc,  527,  530,  5G1,  503,  574, 
575 

fasciolaris,  532,  563 

pisiformis,  563 

racemosus,  575 

tiBiiise  mediocancllattc,  560 
saginata;,  560 

tenuicollis,  575 
Cystinuria,  metaljolism  in,  304,  713 
Cystitis  in  diabetes  mellitus,  770 
Cytolysis,  acceleration  of,  267 


Davainea  asiatica,  557,  566 

madagascariensis,  557,  566 
Degeneration  and  degenerates,  32 
Delirium  in  gout,  833 
tremens,  178 

etiology  of,  178 
hallucinations  in,  182 
influence  of  season  on,  179 

trauma  on,  ISO 
mental  processes  in,  182 
mortality  in,  186,  187 
nervous  system  in,  175 
orientation  in,  184 
prognosis  of,  187 
symptoms  of,  180 

meningeal,  186 
treatment  of,  187 
tremor  in,  184 
Demodex  folliculorum,  630 

hominis,  630 
Dentition,  delayed,  in  rickets,  875 
Dermacentor  electus,  627 
occidentalis,  626,  627 
reticulatus,  627 
Dermanyssus  gallinaj,  631 

horundinis,  632 
Dermatitis  blastomycetic,  346 
coccidioides,  346 
protozoic,  346 
a;-ray,  59 
Dermatobia  hominis,  637 
Determinants  in  inheritance,  37 
Diabetes  in  gout,  833 
hunger,  759 
insipidus,  799 
age  in,  799 
classification  of,  803 
definition  of,  799 
diabetes  mellitus  and,   803 
diagnosis  of,  805 
etiology  of,  799 
hemianopsia  and,  802 
heredity  in,  799 


Diabetes  insipiflus,  incidence  of,  799 
morbid  anatomy  of,  805 
[prognosis  o\,  805 
symptoms  of,  803 
appetite,  804 
polyuria,  803 
thirst,  801 
syphilis  and,  802 
theories  as  to  cause  of,  805 
thirst  in,  804 
trauma  and,  801 
treatment  of,  800 
urine  in,  803 
mellitus,  747 

acute,  771,  787 

adrenalin,  758 

age  in,  750 

albuminuria  in,  779 

alcohol  in,  794 

appetite  in,  772 

arteriosclerosis  and,  757 

blood  in,  769 

boils  in,  780 

bread  in,  substitute  for,  793 

carbuncle  in,  treatment  of,  798 

cataract  in,  783 

chronic,  771,  778 

pancreatitis  and,  755 
complications  of,  780 
constipation  in,  781 
conjugal,  749 
course  of,  787 
definition  of,  747 
diabetes  insipidus  and,  803 
diagnosis  of,  788 

from  alkaptonuria,  788 
from  glj'cosuria,  788 
from  pentosuria,  788 
diet  in,  790 

potatoes  in,  793 
diseases  of  liver  and,  757 
of  pancreas  and,  754 
disturbances  of  metabolism  in, 

760 
emaciated,  771 
endogenous,  771 
etiology  of,  748 

predisposing  factors,   748 
exogenous,  771 
experimental  pancreatic,  753 
fat,  771 
gangrene  in,  781 

treatment  of,  798 
gastro-intestinal  tract  in,  769 
glycolytic  ferment  and,  767 
heart  "in,  770 
hemiplegia  in,  783 
hepatic  lesions  and,  757 
hereditv  and,  749 
historj^'of,  747 
incidence  of,  748 
islands  of  Langerhans  in,  754 
kidneys  in,  770 


916 


IXDEX 


Diabetes  mellitus,  liprrmia  in,  7G9 
liver  in,  770 
nieiitiil  changes  in,  783 
mild,  771 

nervous  system  and,  752,  770 
neurotic,  771,  782 
nutrition  in,  772 
obesity  an,d,  750 
pancreatic  lesions  and,  754 
paraplegia  in,  783 
pathology  of,  769 
phlebitis'in,  781 
phloridzin,  758 
posterior  sclerosis  in,  770 
pregnancy  in,  78-1 
prognosis  of,  787 
pruritus  in,  781 

treatment  of,  798 
pseudo-tabes  in,  782 
pulmonary  lesions  in,  770 

tulicrculosis  in,  782 
race  and,  748 
reflexes  in,  783 
renal,  758 
retinitis  in,  783 
severe,  771 
sex  in,  750 
symptoms  of,  771 

increased  appetites,  772 
polyuria,  771 
thirst,  772 
urine,  773 
syphilis  and,  751 
theories  of,  766 

over-production,  766 
under-consumption     and 
deficient  oxidation,  766 
toxins  and,  759 
traumatic,  752,  788 
treatment  of,  789 
dietetic,  790 
hygienic,  790 
medicinal,  794 
milk  in,  797 
prophylactic,  789 
urinary  casts  in,  780 
urine  in,  773 
xanthoma  in,  781 
metabolism  in,  318 
phosphatic,  779 
Diabetic  coma,  784 

alcoholic  form,  785 
collapse  from,  785 
dyspncric,  784 
explanation  of,  785 
frequency  of,  785 
sugar  excretion  in,  787 
treatment  of,  796 
alkalies  in,  796 
Diacanthos  polycephalus,  526 
Diacetic  acid  in  urine  in  diabetes  melli- 
tus, 778 
Diarrhoea  in  diabetes  mellitus,  781 


Diarrhoen  in  gout,  833 
in  obesity,  853 
in  rickets,  885 
in  scurvy,  898 
Diatheses,   inheritance  of,  27,  49 
Dibothriocephalus   cordatus,   557,  558 
569 
latus,  557,  558,  560,  562.  567,  570 
Dibothrium  latum,  567 
I)icroC(eIium,  540 

lanceolatum,  545 
sinense,  541 
Diet,  721 

amount   of,   723 

of  carliohydrate  in,  731 
of  fat  in,  731 
of  proteitl  in,  724 
animal,  objections  to,  741 
characteristics  and,  741 
cures,  743 

in  dial)ctes  mellitus,  790 
fads,  743 
fruitarian,  743 
hypernutrition,  744 
inorganic  salts  in,  734 
proteid-fat,  744 

required  in,  723 
in  rickets,  886 
in  scurvy,  900,  902 
statistics  of,  722 
systems  of,  740 
vegetal  )les  in,  739 
vegetarian,  743 
Dietetics,  721 

Digestion,  abnormal,  products  of,  271, 
275 
energy  required  for,  682 
normal,  products  of,  271 
Digestive     tract,     lead    poisoning     in, 
100 
juices,  intoxication  by  absorption 
of,  270 
Dilepis,  566 
Dioctophyme,  582 

renale,  624 
Diplogonoporus  grandis,  557,  569 
Dipsomania,  194 
Dipterous  infection,  637 
Dipylidium     caninum,    529,    557,   567, 

574,  634 
Dirt  eating,  582 
Disintoxication,  286 
Distoma  (or  distomum),  535 
haematobium,  550 
hepaticum,  546 
japonicum,  541 
pulmonale,  536 
pulmonis,  536 
pulmonum,  536 
ringeri,  536 
sinense,  541 
spathulatum,  541 
spatulatum,   541 


INDEX 


917 


Distoma  westermanii,  536 
Distomatosis,  535 
Distomiasis,  533,  535 
cerebral,  538 
hepatic,  535,  538,  540 
intestinal,  535,  548 

parasites  in,  549 
ophthalmic,  535,  556 
pulmonary,  53G,  537,  538,  539 
renal,  535,  550 
blood  in,  555 
diagnosis  of,  554 
distribution  of,  550 
frequency  of,  551 
hajmaturia  in,  551 
infection  in,  551 
parasites  of,  550 
pathology  of,  554 
prevention  of,  555 
prognosis  of,  553 
symptoms  of,  551 
treatment  of,  555 
varieties  of,  535 
Diver's     paralysis,     72.     See     Caisson 

disease. 
Dochmiosis,  582 
Dochmius  duodenalis,  584 
Dominant  inheritance,  35 
Dracontiasis,  611 
Dracunculosis,  611 

distribution  of,  611 
frequency  of,  612 
infection  in,  611 
parasite  of,  611 
prevention  of,  613 
symptoms  of,  612 
treatment  of,  612 
Dracunculus,  582 
loa,  620 

medinensis,  611,  624 
oculi,  620 
Drunkenness,  pathological,  194 
Dwarf  tapeworm,  564 

description  of,  564 
distribution  of,  564 
frequency  of,  564 
infection  by,  564 

features  of,  565 
prevention  of,  565 
treatment  of,  565 
Dynamic  replacement  of  nutrients,  662 
Dysenteric  malarial  fever,  425 
Dysentery,  amoebic,  488 

abscess  of  liver  in,  alcohol  and, 

513 

appendicitis  and,  514 

bacteriology    of,   514 

brain     abscess    and, 

516 
diagnosis  of,  515,  519 
intestinal    haemor- 
rhage and,  518 
leukocytosis  in,   516 


Dysentery,  amoebic,  abscess  of  liver  in, 
pathology  of,  515 
j)rognosis  of,  520 
rupture  of,  516 
symptoms  of,  515 
thrombosis  and,  516 
time  of  onset,  513 
treatment  of,  524 
of  lung  in,  diagnosis  of, 
520 
occurrence  'of,  517 
pathology  of,  516 
symptoms  of,  516 
amojbaj  in  f:cces  of,  511 
bacteriology  of,  502 
blood  in  stools  of,  511 
complications  of,  513 
course  of,  509 
definition  of,  488 
diagnosis  of,  518 
distribution  of,  489 
early  lesions  in,  503 
etiology  of,  489 
gangrene  in,  505 
healing  of  ulcers  in,  505 
histological  changes  in,  506 
immunity  from,  520 
intestinal  adhesions  in,  506 
mild  form  of,  508 
onset,  acute,  in,  509 
organisms  other  than  amoeba 

in,  502 
pathology  of,  503 

intestines  in,  large,  503 

small,  507 
kidneys  in,  507 
lymphatic  glands  in,  507 
peritonitis  in,  506 
prognosis  of,  520 
season  and,  490 
sequelae  of,  518 
sex  and  age  in,  490 
spontaneous  recovery  in,  508 
symptoms  of,  507 

abdominal  pain  in,  511 
anaemia  in,  512 
faeces  in,  510 
fever  in,  512 
gastro-intestinal,  510 
hiccough,  512 
loss  of  appetite,  512 
nausea  and  vomiting,  512 
pulse  in,  513 
respiration  in,  513 
skin  in,  512 
urine  in,  513 
synonyms  of,  488 
tenesmus  in,  512 
treatment  of,  521 

of  complications,  524 
curative,  523 
dietetic,  521 
general,  521 


918 


INDEX 


Dysentery,  amoeliic,  Iroatinont  of,  by 
irrifiatioiis,  523 
prophvlactic,  521 
results  of,  520 
symptomatic,  521 
ulcers  in,  504 
Dyspepsia,  nervous,  auto-intoxical  ions 

"and,  278 
Dyspna\a  in  pout,  833 
Dyszooamylie,  705 


E 


Ebstein's  dietary  treatment  of  obesity, 

858 
Ecchymoses  in  scurvy,  898 
Echinococcosis,  576 

diapinosis  of,  580 

distril>ution  of,  576 

duration  of,  579 

frcriuency  of,  578 

parasite  in,  576 

prevention  of,  580 

symptoms  of,  579 

treatment  of,  5S0 
Echinococcus,  576 

altricipariens,  571 

alveolaris,  577 

cysticus,  576 

disease,  576 

endogena,  578 

exogena,  578 

granulosus,  574,  576,  578 
multilocularis,  577 

hominus,  578 

hydatidosus,  578 

multilocularis,  577,  578 
exulcerans,  577 

osteoklastes,  577 

polymorphus,  576 

scolecipariens,  578 

unilocularis,  576 

veterinorum,  578 
Echinococcifer  echinococcus,  576 
Echinorhj'nchus  gigas,  601 

hominis,  604 

moniliiormis,  604 
Ectoparasites,  526 
Eczema  in  gout,  831 
Eehvorm  infection,  596 
Electrical  shock,  consequences  of,  65 
Electricity,  64 

accidents  from,  treatment  of,  68 

burns  from,  67 

death  from,  65 

eye  lesions  from,  66 

injury  from,  64 
Elephantiasis  in  filariasis,  618 
Elephantoid  fever,  616 
Emphysen:a  in  gout,  828,  832 
Encephalomalacia,     chronic,     diabetes 
mellitus  and,  753 


Encephalopathy  in  load  poisoning,  106 

treatment  of,  113 
Endocarditis,   ulcerative,   diagnosis  of, 

from  malarial  fe\ers,  437 
Eiuloparasitt's,  526 
Energy,  l)alance  of,  657 

conservation  of,  656,  658 
metaljolism  of,  650 

methods  of  study  of,  652 
([ualitative  relations  of,  651 
quantitative       relations       of, 
651 
muscular,  source  of,  683 

relation    of   carbohydrate    to, 
683 
of  fat  to,  686 
output  of,  657 
patns  of  discharge  of,  660 
psychical      functions      and,     050, 

663 
transformation  of,  650 
Entamceba  coli,  525,  526 
dysenteria*,  497 
histolytica,  525,  526 
Entozoa,  526 

Enzjrmes,  in  carbohydrate  metabolism, 
692,  763 
fat  metaljolism  and,  096 
intracellular,  715 
pathological  processes  and,  715 
purin  mctaliolism  and,  711 
uric  acid  and,  SI 6 
xanthin  bases  and,  814 
Epilepsy,  diabetes  mellitus  and,  752 
Epiphysitis,  diagnosis  of,  from  infantile 

scurvy,  906 
Epistaxis  in  scurvy,  898 
Ergot  poisoning,  243 
Ergotismus,  243 
Ethyl  alcohol,  effects  of,  163 

influence  of,  on  body  tempera- 
ture, 164 
meta]:)olisni  of,  166 
poisoning,  163 

death  from,  168 
pathology  of,  168 
subnormal  temperature 
in,  164 
Eustrongylus  gigas,  624 
Exclusive  inheritance,  35 
Excreta,  origin  of,  689 
Exophthalmic  goitre,  excess  of  protein 

metaljolism  in,  302 
Eye  lesions  from  electricity,  06 
from  .T-rays,  00 
symptoms  of  lead  poisoning,  107 


Facial  irritability  in  rickets,  883 
F;eces  in  amoabic  dj^sentery,  510 
Fasciola,  540 


INDEX 


919 


Fasciola  gigantiea,  .539 

hepatica  510,  542,  54G,  547 
huniana,  54 (J 
Fascioliasis,  535,  540,  54G 
symptoms  of,  547 
treatment  of,  548 
Fasciolopsis  buskii,  549 

complications  in,  548 
diagnosis  of,  548 
forms  of,  548 
frequency  of,  546 
infection  in,  54G 
parasite  of,  540 
rathouisi,  549 
Fat,  absorption  of,  695 

changes  of,  in  cells,  698 
formation  of,  in  boily,  G97 
from  carbohydrate,  697 
from  proteid,  698 
influence  of,  on  proteid  metabolism, 

673 
metabolism,  321,  695 

auto-intoxication   associated 
with,  321 
suboxidation  of,  322 
superoxidation  of,  322 
tapeworm,  558 
Fatness,  845.     See  Obesity. 
Feeding,  metabolism  during,  671 
Fever,  elephantoid,  616 
of  digestion,  271 

excess    of  protein   metabolism   in, 
303 
Filaria,  582,  624 

bancrofti,  613,   615,  616,  619,   620, 

621,  624 
bourgii,  620 
conjunctivae,  614,  623 
cystica,  600 
demarquayi,  614,  622 
dermathemica,  615 
diurna,  614.  615,  620,  621 
equina,  614,  623 
faniguchi,  622 
gigas,  614,  624 
hominis  oris,  614,  623 
immitis,  614,  623 
kilimariB,  614,  623 
labialis,  614,  623 
larvae  of,  613 
lentis,  614,  623 
loa,  614,  615,  620,  621 
magalhaesi,  614,  622 
nocturna,  614,  615 
oculi,  620 
ozzardi,  614,  622 
perstans,  614,  622 
philippinensis,  613,  614,  624 
powelli,  614,  624 
restiformis,  614,  623 
romanorum  orientalis,  614,  624 
sanguinis  diurna,  620 
hominis,  613,  615 


Filaria  sanguinis  major,  620 

subcoiijunctivalis,  G20 

tanigucliii,  614,  620 

traclicalis,  610 

varieties  of,  613 

volvulus,  622 

wuchcreria,  615 
Filariasis,  613 

abscess  in,  616 

chylocele  in,  6bS 

chyluria  in,  G18 

diagnosis  f>r,  619 

distribution  of,  615 

elephantiasis  in,  618 

frequency  of,  616 

infection  in,  616 

loa  infection,  620 

distril)ution  of,  620 
parasite  in,  620 
symptoms  of,  621 
treatment  of,  621 

h^mpli  scrotum  in,  617 

lymphangitis  in,  616 

orchitis  in,  618 

prevention  of,  620 

symptoms  of,  616 

treatment  of,  620 

varices  in,  617 

varicose  glands  in,  617 
Fish,  poisonous,  223 
Fit  of  the  gout,  829 
Flagellate   tetramitus  rostratus  Perty, 

stages  of,  357 
Fluke-worm  infections,  535 
Fleas,  burrowing,  633 

infection  with,  633 

jigger,  633 

jumping,  633 
Food  accessories,  733 

artificially  prepared,  745 

cellulose  in,  740 

cereal,  composition  of,  736 
proteid  content  of,  736 

changes  in,  by  cooking,  732 

composition  of,  in  relation  to  nutri- 
tion, 735 

normal,  substances  formed  by  bac- 
teria within  alimentary  tract, 
272 

poisons,  223 

preparation  of,  732 

purin  content  of,  735 

suspected,  examination  of,  245 
Foodstuffs,  available,  653 

energy,  potential,  of,  679 
Frost-bite,  pathologj-  and  pathogenesis 
of,  80 
prognosis  of,  80 
treatment  of,  SO 
Fruitarian,  diet  of,  743 
Furia  infenialis,  526 
Fuscaria,  532 
Fusel  oil,  162 


920 


INDEX 


Gallstone  colic,  diabetes  mellitus  anci, 
7o2 
due  to  liver  flukes,  543 
Gamniarus  pulex,  526 
Galton's  la^v,  35 

Ganglia,    sympathetic,    dialietes   melli- 
tus and,  753 
Gangrene  in  amtebic  dysentery,  505 
dial)etic,  7S1 

treatment  of,  798 
of  huig  in  scurvy,  899 
from  x-rays,  60 
Gastrodiscus  hominis,  549 
Gastro-intestinal    albuminuria   due   to 
auto-intoxications,  279 
anaemias,  279 
asthma  dyspepticum,  279 
auto-intoxication,  270 

tetany,  277 
catarrh  in  rickets,  885 
constipation,  278 
diseases    of    nervous    svstem, 

279 
nervous  dyspepsia,  278 
symptoms  in  amcebic  dysen- 
tery, 510 
tract  in  diabetes  mellitus,  769 
Gastrophilus,  637 

Gelatin,  influence  of,  on  proteid  metab- 
olism, 674 
Gemmation  of  protozoa,  356 
Generative  organs,  effects  of  rr-rays  on, 

60 
Genito-urinary  system^,  lead  poisoning 

in,  102 
Geophagia,  582 
Gigantorhynchus  gigas,  604 

moniliformis,  604 
Glaucoma  in  gout,  833 
Glossina  palpalis,  473 

distribution  of,  476 
Glucose,    overproduction    of,    diabetes 
mellitus  and.  766 
under-consumption     of,     diabetes 
mellitus  and,  766 
Glvcerin  in  urine  in  diabetes  mellitus, 

777 
Gh'ciphagus  domesticus,  631 

prunorum,  631 
GycocoU  and  gout,  823 
Glvcogen-formation,   metabolic   theorv 
of,  691 
metaljolism  of,  691 
in  urine  in  diabetes  mellitus,  780 
Glycolysis,  693 
Gh'colytic    ferment,    diabetes   mellitus 

and,  767 
Glycosuria,  317 

alimentary,  691,  762 
e  mnylo,  763 
e  saccharo,  763 


Glycosuria  in  gout,  833 

in  obesitj',  854 
Glycuronic  acid,  metabolism  of,  693 
in  urine  in  diabetes  mellitus, 
777 
Gnat  fever,  392.     See  Malarial  fevers. 
Gnathostomum,  582 

siamensc,  611 
Goitre,  exoplitlialmic,  excess  of  protein 

metal)olism  in.  302 
Gonliacea,  531,  582,  604 
Gordius  aquaticus,  623 
Gout,  80S 

acute.  828 

alimentarv  tract  in,  831 
arthritis  in,  826,  828,  829,  833 
as  aTi  auto-intoxication,  314 
biurate  deposition  in,  826,  834 
blood  in,  825,  829 

alkalinity  of,  820 
calculi  in,  831 
chalk-stones  in,  829 
chemistrv  of,  824 
chronic,  829 
complications  of,  832 
cardiovascular,  832 
diabetes,  833 
glvcosuria,  833 
renal,  832 
retrocedent,  833 
definition  of,  808 
diabetes  and,  751 
diagnosis  of,  833 
etiology  of,  809 

metabolic  causes,  811 

uric  acid,  812,  818 
predisposing  causes,  809 
age,  809 
alcohol,  810 
exercise,  810 
food,  810 
hereditary,  809 
lead,  811 
occupation,  811 
physique,  811 
race,  809 
sex,  809 

traumatism,  811 
glj^cosuria  in,  833 
heart  in,  832 
history  of,  808 
incidence  of,  808 
irregular,  830 
local  necrosis  in,  823 
lungs  in,  832 

metaboHsm  in,  313,  811,  818 
nephritis  in,  827 
nervous  manifestations  in,  831 

theory  of,  823 
obesity  and,  846 
ocular  changes  in,  831 
pathology  of,  825 
blood,  825 


INDEX 


921 


Gout,     pathology     of,     cardiovascular 
lesions,  828 
joint  changes,  82G 
kidneys,  827 
respiratory  system,  828 
prognosis  of,  835 
purin  bases,  relation  of,  to,  823 

metabohsm  in,  714 
relation  to  lead  poisoning,  102 
retrocedent,  833 
skin  in,  831 
symptoms  of,  828 
acute,  828 
chronic,  829 
irregular,  830 

alimentary    disorders    in, 

831 
cardiac  manifestations  in, 

832 
cutaneous    eruptions    in, 

831 
nervous  manifestations  in, 

831 
ocular  manifestations  in, 

831 
pulmonary     features    of, 

832 
urinary    disturbances   in, 
831 
urine  in,  832 
theories  of,  822 
tophi  in,  827,  829,  833 
treatment  of,  836 

alkalies  and  mineral  waters,839 
of  complications,  844 
dietetic,  837 
hygienic,  836 
local,  843 
medicinal,  840 
operative,  843 
prophylactic,  836 
uric  acid  oxidation,  843 
solvents,   842 
uraemia  in,  832 
uric  acid  elimination  in,  715 
relation  of,  to,  820 
urinary  disturbances  in,  831 
urine  in,  832 
Gouty  diathesis,  830 

kidney,  827 
Groin-glands,  varicose,  617 
Ground  itch,  588 
Guinea-worm  disease,  611 

infection,  611 
Gums,  changes  in,  in  infantile  scurvy, 

904 
Gynsecophorus  hsematobins,  550 


HiEMAGGLUTiNATiVE       principles        of 
venoms,  257 


IIff>mamnDbiasis,    392.     Hee    Malarial 

fever.s. 
Haimuto-chyluria,  618 
Haematuria,  bilharzian,  550 
Egyptian,  550 
endemic,  550 
in  gout,  831 
in  infantile  scurvy,  905 
HsDmenteria  officinalis,  026 
Hai'mochromatosis,  756 

diagnosis  of,  757 
Hsemoglobinuric     fever,     449.      See 

Black-water  fever. 
Hsemolytic  principles  of  venoms,  257 
Haemoptysis,  parasitic,  536,  537 
Hallucinosis,  acute,  190 
diagnosis,  192 
hallucinations  in,  190 
prognosis  of,  192 
symptoms  of,  190 
treatment  of,  192 
Halteridium,  400 
Halzoun,  547 
Hamularia,  623 
Harrison's  sulcus,  878 
Harvest  bug,  631 

mites,  631 
Head,  actinomycosis  of,  332 
nodding  in  rickets,  883 
sweating  in  rickets,  875 
Headache  in  gout,  831 
Heart  in  diabetes  mellitus,  770 
Heat,  efTect  of,  76 
exhaustion,  53 

treatment  of,  56 
production  in  body,  663 

influence   of  temperature   on, 
663 
Heberden's  nodes  in  gout,  830 
Helminthes,  526 
Helminthoma  elasticum,  617 
Hemiplegia  in  diabetes  mellitus,  783 
Hemorrhage,  cerebral,  diabetes  mellitus 
_  and,  752 
diabetes  insipidus  and,  801 
intestinal,    in   amoebic   dysentery, 

518 
into  skin  in  scurvy,  897 
Hemorrhagic  principles  of  venom,  257 
Hepatic  abscess,    diagnosis    of,     from 

malarial  fevers,  437 
Heredity  in  absinthism,  196 
in  alcoholism,  159 
in  morphinism,  214 
in  rickets,  867 
Herpes  zoster  in  diabetes  mellitus,  781 

in  gout,  831 
Heterophyes  heterophyes,  548,  549 
Hexathyridium  venarum,  546 
Hiccough  in  amoebic  dysentery,  512 
Higher  alcohols,  162 
Hill  fever,  392.     See  Malarial  fevers. 
Hirudinei,  531,  536 


922 


INDEX 


Histiogaster  spermaticus,  G31 
Holothyrus  coccinella,  B31 
Hook-worm  disciisc,  582 
Human    trypanosomiasis,    4GG.      See 

Trypanosomiasis,  human. 
Hunger  diabetes,  759 

faeces,  GOO 

metal)olism  during,  664 
Hyalonuna  a^gyptiiini,  G27 
Hybridism,  31 
Hydatid  disease,  576 
Hytlrocephalus,  diabetes  insipidus  and 
801 

diagnosis  of,  from  rickets,  SSG 

in  rickets,  8S3 
Hymenolepis,  564 

diminuta,  557,  566 

flaropvmctata,  566 

lanceolata,  557,  5G6 

murina,  564 

nana,  532,  557,  564 

fraterna,  557,  564,  565 
Hyperglyc;rmia  in  dial)etes,  764,  7GG 
Hypernutrition  ciu'cs,  diet  in,  744 
Hyperparasitism,  626 
Hvpoderma,  637 

bovis,  037 

diana,  637 

lineata,  637 


IcHTHYis:\ius,  223 
Ichthyotoxismus,  223 
Illuminating  gas  poisoning,  141 
diagnosis  of,  147 
etiology  of,  141 
mode     of    entrance     of, 

144 
pathogenesis  of,  144 
pathology  of,   144 
prognosis  of,  148 
symptoms  of,  145 
treatment  of,  148 
Immunity,  acquired,  44 
Impressions,  maternal,  19 

paternal,  19 
Indican,  metabohsm  of,  712,  721 
Individual  inheritance,  27 

different  forms  of,  29 
Inebriety,  periodic,  194 
Infantile  paralysis,   diagnosis  of,  from 
infantile  .scurvy,  906 
from  rickets,  885 
scurvy,    901.     See  Scurvy,    infan- 
"  tile. 

rickets  and,  885 
Infection  of  meat,  232 

placental,  of  offspring,  23 
through  spermatozoa,  24 
in  utero,  24 
Infections,  specific,  scurvy  due  to,  896 
susceptibility  to,   26 


Infectious  diseases,  diabetes  insipidus 
and,  803 
diabetes  mcUitvis  and,  752 
non-inheritance  of,  22 
Infusoria,  354 
Ingesta,  fate  of,  689 
Inheritance  of  acquired  characters,  28 
blended,  29,  34 
diatheses,  27,  49 
and  disease,  17 
dominant,  35 
exclusive,  35 

of  functional  modifications,  21 
of  gross  anomalies,  26 
indiviilual,  27 

different  forms  of,  29 
mosaic,  29,  35 
nervous  disturbances,  27 
particulate,  29,  35 
of  probal)le  anomalies  of  defect,  20 
theories  of,  35 

physico-chemical,  39 
of  variations,  26 
Inorganic  salts,  in  metabolism,  676 

lack  of,  677 
Insecta,  531,  632 
Insects,  parasitic,  632 
Insolation.     See  Sunstroke. 
Intake,  method  of  study  of,  643 

and  output,  comparison  of,  645 
Intermediary  metabolism,  689 

proteids  in,  70S 
Intermittent  fever,  392.     See  Malarial 

fevers. 
Intertrigo  in  obesity,  854 
Intestinal  and   muscular  roundworms, 
605 
putrefaction,  274 

table     of     aromatic     urinarj^ 
products  of,  275 
roundworms,  582 
tcTniasis,  557 
Intestine,  human,  amcoba  of,  491 

behaA'ior  of,  towartl  chem- 
ical substance, 
492 
physical     condi- 
tions, 492 
Intestines,  hemorrhage  of,  in  ama>bic 
dysentery,  518 
large,  in  amoebic  dysentery,  503 
perforation  of,  in  amoebic  dysen- 
tery, 517 
small,  in  amoebic  dysentery,  507 
Intoxication  by  absorption  of  digestive 
juices,  270 
action  of  acetone  complex  in,  325 
protein  metabolism,   302 
retention,  287 

carbon  dioxide,  288 
of   intestinal   origin,   282 
jaundice,  287 
perspiration,  291 


INDEX 


923 


Intoxication   retention,    .suppression  of 

urine,  292 
Intracellular  enzymes,  713 
Iritis  in  gout,  S33 
Iron,  excretion  of,  GTS 
Islands  of  Langerhans,  diabetes  melli- 

tus  and,  754 
Isodynamic  replacement   of  nutrients, 

661 
Itch,  Norwegian,  628,  629 

sarcoptic,  627 
Ixodes  hexagonus,  627 

ricinus,  627 
Ixodiasis,  626 
Ixodidai,  626 
Ixodoidse,  626 


Jaundice  in  black-water  fever,  456 

intoxication  due  to,  287 
Jigger  fleas,  infection  with,  633 
Joints,  changes  in,  in  gout,  826 

lead  poisoning  in,  102 
Jumping  fleas,  infection  with,  633 
Jungle  fever,  392.     See  Malarial  fevers. 


Katabolism,  639 
Kedani  mite,  631 
Kidney-worm,  canine,  624 
Kidneys  in  amoebic  dysentery,  507 
in  black-water  fever,  455 
in  diabetes  mellitus,  770 
in  gout,  827 
in  malarial  fevers,  412 
Korsakow's  psychosis,  196 
neuritis  in,  198 
paralysis  in,  198 
pathology  of,  196 
symptoms  in,  197 
Kreatinin,  intoxication  due  to,  298 
relation  of,  to  urcemia,  306 


Lamblia  duodenalis,  526 

Lancet  fluke  infection,  545 
parasite  of,  545 

Laryngismus  stridulus  in  rickets,  882 

Late  rickets,  890 

prognosis  of,  892 
symptoms  of,  891 
treatment  of,  892 

Lead  poisoning,   84 

accidental,  85,  91,  92 
action  of  lead  in,  96,  97 
albuminuria  in,  102 
arteriosclerosis  in,  101 
arthralgia  in,  102 


Lead   poisoning,  basic  granulation   in, 
98,  99,  109 
blindness  in,  107 
Ijlood  in,  98,  99,  100 
l>lue  line  in,  99,   109 
cachexia  in,  98 
in  children,  107 
colic  in,  108 
convulsions  in,  108 
paralysis  in,  108 
symptoms  of,  108 
chronic  nephritis  in,  102 
colic  in,  101 
coma  in,  106 
delirium  in,  106 
diagnosis  of,   108 

from    gastric    carcinoma, 

100 
from  uraemia,  109 
disturbances  of  sensation   in, 

103 
duration  of  exposure  to,  93 
encephalopathy  in,  106 
etiology  of,  86 
age  in,  87 
habits  in,  88 
heredity  in,  86 
occupation  in,  88 
period  of  year  in,  87 
previous    diseases    and 
previous    attacks    of 
saturnism  in,  88 
race  in,  86 
sex:  in,  87 
fever  in,  100,  107 
from  bullets,  93 
food,  92 
water,  91 
generalized  paralysis  in,  105 
gout,  relation  to,  102 
hallucinations  in,  106 
hemiplegia  in,  106 
hysteria  in,  106 
industrial,  85,  88 
inheritance  of,  44 
lead  in  urine  in,  109 
medicinal,  93 
metabolism  in,  97 
mode  of  entrance  of,  95 
muscular  spasm  in,  103 
neuralgic  pains  in,  102 
paralysis  in,   103 

of  cranial  nerves  in,  105 
pathogenesis  of,  95 
pathology  of,  94 
prognosis  of,  109 
prophj'laxis  of,  110 
cleanliness  in,  110 
regulations  for,  110 
symptoms  of,  97 
bones,  102 

cardiovascular       system, 
.101 


924 


INDEX 


Lead  poisoning,  symptoms  of,  cerel)ral, 
106 
digestive  tract,  100 
genito-urinarv  system,  102 
joints,  102 

nervous  system,  102 
,  ophthalmic,  107 
respiratory  tract,  101 
treatment  of,  110 

potassium  iodide  in,  112 
purgation  in.  111 
tremor  in,  103 
wrist -drop  in,  103 
Leeches,  626 
Leptodera,  5S2 
pellis,  624 
Leptus  americanus,  631 
autumnahs,  631 
irritans,  631 
Leukaemia,  acute  hinphatic,  diagnosis 

of,  from  scurvy,  899,  906 
Leukocytes  in  black-water  lever,  457 

in  malarial  fevers,  409 
Leukocytosis,  excess  of  protein  metab- 
olism in,  303 
Leukomains,  229 
Lice,  infection  with,  634 
Life-cycle  of  protozoa,  361 

malignant  forms,  365 
Light,  pathological  effects  of,  52 

physiological  effects  of,  51 
Linguatula  serrata,  632 
Linguatulidse,  531,  632 
Linnatis  nilotica,  626 
Lipsemia  in  diabetes  mellitus,  769 
Lipoids  in  metabolism,  699 
Lipomatosis      universalis,      845.       See 

Obesity. 
Lipuria  in  diabetes  mellitus,  780 
Lithsemia,  830 
Lithic-acid  diathesis,  830 
Liver,  abscess  of,  in  amoebic  dysentery, 
513 
in  black-water  fever,  455 
cancer  of,  diabetes  insipidus  and, 

802 
changes  in,  in  rickets,  871 
in  dialaetes  mellitus,  757,  770 
fluke  infection,  540 
Asiatic,  540 

diagnosis  of,  543 
frequency  of,  541 
infection  in,  541 
parasite  of,  541 
pathology  of,  542 
prevention  of,  543 
symptoms  in,  541 
treatment  of,  543 
Indian,  545 

parasite  of,  545 
Siberian,  543 

frequency  of,  544 
infection  in,  544 


Liver,  fluke   infection,  Siliorian,    para- 
site of,  544 
pathology  of,  544 
pre\ention  of,  545 
symptoms  of,  544 
in  malarial  fevers,  411,  431 
Loa,  620 

Lobsters,  poisoning  l)y,  231 
Lousiness,  634 
Lump  jaw,  327 

Lung,  aliscess  of,  in  amoebic  dysentery, 
516 
actinomj^cosis  of,  333 
conditions  of,  in  scurvy,  899 
fluke  infection,  536 
gangrene  of,  in  scurvy,  899 
Lymph  scrotum  in  filariasis,  617 

varices,  617 
Lymphangitis,  filarial,  616 
Lvmphatic   glands   in   amoebic   dysen- 
tery, 507 
trypanosoma   Gambiense     in, 
"471 
leuktemia,  acute,  difTerentiation  of, 
from  scurvy,  899 


M 


Macrogaiietes,  402 
Madura  foot.     See  Mj^cetoma. 
Malarial  fevers,  392 
age  and,  406 
albuminuria  in,  431 
altitude  and,  405 
ana?mia  in,  408,  431 
blood  examination  in,  433 
bone-marrow  in,  413 
brain  in,  410 
cachexia  in,  432 
classification  of,  415 
climate  and,  405 
combined  infections,  427 
complications  of,  428 
definition  of,  392 
diagnosis  of,  432 

from  appendicitis,  428 
from    cerebral    apoplexy, 

437 
from  dysentery,  437 
from      hepatic      abscess, 

437 
from  sunstroke,  437 
from  tuberculosis,  437 
from  typhoid  fever^   436 
from  ulcerative  endocar- 
ditis, 437 
from  yellow  fever,  436 
dysentery  and,  429 
etiology  of,  394 

contributing    factors    in, 
404 


INDEX 


925 


Malarial  fevers,  geographical  distribu- 
tion of,  393 
history  of,  392 
immunity  from,  407 
incubation  in,  414 
inoculation  of,  407 
irregular  and  remittent  forms, 

425 
kidneys  in,  412 
latent  and  masked  infections, 
427 
pathology  of,  413 
leukocytes  in,  409 
liver  in,  411,  431 
locality  and,  404 
melantemia  in,  408 
moisture  and,  405 
nephritis  in,  429,  431 
occupation  and,  406 
parasites  of,  394 
pathology  of,  407 
pernicious,  421 

algid  form,  424 
bilious  form,  425 
choleraic  form,  424 
comatose  form,  423 
dysenteric  form,  425 
irregular    and    remittent 
forms,  425 
Plasmodia  of,  cycle  of  develop- 
ment of,  402 
development     of,    within 

mosquito,  400 
staining  reactions  of,   404 
pneumonia  in,  429 
prognosis  of,  438 
prophylaxis  of,  439 
general,  439 

destruction    of   mos- 
quito, 389,  439 
isolation   of   patient, 

441 
use  of  quinine,  441 
personal,  441 
quartan,  fever  in,  418 
quotidian       sestivo-autumnal, 

fever  in,  421,  422 
race  and,  406 
remittent     type,      fever      in, 

426 
sequela  of,  430 
sex  and,  406 
soil  and,  405 
spleen  in,  412 

rupture  of,  431 
spontaneous  recovery  in,  427 
symptoms  of,  414 

sestivo-autumnal,  419 

quartan,  418 

quotidian    ajstivo-autum- 

nal,  421 
tertian,  416 

eestivo-autumnal,  419 


Malarial  fevers,  symptoms  of,  tertian, 
a!stivo-autum- 
nal,  cold  stage, 
419 
hot  stage,  420 
prodromal,  419 
cold  stage,  417 
hot  stage,  417 
sweating  stage,  417 
synonyms  of,  392 
tertian  anstivo-autumnal,  fever 
in,  420 
albuminuria  in,  418 
duration  of  paroxysm,  418 
fever  in,  416 
therapeutic  test  in,  435 
treatment  of,  442 

of    complications   and  se- 
quelae, 447 
hygienic,  443 
of  malarial  cachexia,  447 
medicinal,  443 
of   special   symptoms   of, 

447 
summary  of,  446 
typhoid  fever  and,  430 
urine  in,  410 
mosquitoes,  403 

parasites  in  black-water  fever,  452, 
457 
Malignant  diseases,  cachexia  of,  excess 

of  protein  metabolism  in,  302 
Malleolar  oedema  in  obesity,  853,  854 
Malnutrition,  582 

metabolism  in,  719 
Manganese  poisoning,  138,  140 
Marasmus,  suboxidation  in,  284 
Marsh  fever,  392.     See  Malarial  fevers. 
Mastigophora,  354 
Maternal  impressions,  19 
Meat  decomposed,  235 
diseased,  235 

organisms  in,  236 
and  paratyphoid  infections,  232,241 
poisonous,  232 
Medulla,    tumors  of,    diabetes   mellitus 

and,  752 
Melansemia  in  malarial  fevers,  408 
Mendel's  law,  29,  30,  47,  48 
Meningitis,  serous,  186 
Mercurial   cachexia,   differentiation  of, 

from  scurvy,  899 
Mercury,  mode  of  entrance  of,  127 
poisoning,  124 

accidental,  126 
convulsions  in,  128 
diagnosis  of,  130 
disturbance  of  speech  in,  128 
emotional  disturbances  in,  129 
etiology  of,  124 
hysteria  and,  129 
industrial,  124,  125 
medicinal,  126 


926 


INDEX 


Mercury  poisoning,  neuritis  in,  129 

pathology  of,  12G 

prognosis  of,  1.30 

prophylaxis  of,  130 

symptoms  of,  127 

treatment  of,  130 

tremor  in,  127 
Mermis,  023 

Merozoitos,  397,  398,  399,  403 
Metabolism,  G39 

adaptation  processes  in,  660 

in  alkai)tonuna,  713 

amino-aciils  in,  712 

anabolic,  ()39 

of  carbohytlratcs,  ()S9,  7(i(),  763 

acetone  complex  not  deranged 
in,  323 

anomalies  of,  694 

auto-intoxication     associated 
with,  315 

in  diabetes,  764 

intermediate  products  of,  694 

normal     qualitati\e,     acetone 
complex  with,  323 

variations  of,  762 
composition  changes  in,  642 
in  corpulence,  700,  719 
in  cystinuria,  713 
definition  of,  640 
disturbances  of,  diabetes  mellitus 

and,  760 
of  energ}',  650 
enzymes  in,  641 
of  fats,  695 

auto-intoxication      associated 
with,  321 

in  diabetes,  765 

intermediate  products  of,  700 
glycogen  in,   691 
in  gout,  714,  811 
influence  of  altitudes  on,  688 

of  appetite  on,  687 

of  climate  on,  688 

of  clothing  on,  688 

of  cold  bath  on,  688 

of  growth  on,  687 

of  hygiene  on,  688 

of  inorganic  salts  on,  676 

of  old  age  on,  687 

of  proteids  on,  672 

of  sexual  changes  on,  688 

of  work  on,  678 
intake,  643 

and    output,    comparison    of, 
645,  659 
intermediary,  689 

proteids  in,  708 
katabolic,  639 
in  lead  poisoning,  97 
of  lipoids,  699 
in  malnutrition,  719 
methods  of  study  of,  642 
modifications  of,  664 


Metabolism,    modifications    of,    during 
feeding,  671 
hunger,  664 
nature  of,  (540 
of  nitrogen,  645 

influence  of  work  on,  683 
output,  644 

channels  of,  644 
of  j)hosph()rus,  (il7 
])roteid,  700 

auto-intoxications    associated 

witli,  297 
in   cachexia,   301 
and  cellular  degeneration,  303 

exudates,  303 
in  diabetes,  765 
disturljances  of,  acetone  com- 
plex   associated    with, 
324 
dependent  on  input,  299 
independent  of  inj^ut,  300 
effects  of  non-nitrogenous  nu- 
trients on,  673 
excess  of,  301 
exophthalmic  goitre,  302 
in  i'e\er,  301 

influence  of  alcohol  on,  675. 
intoxications,  302 
leukocytosis  and,  303 
normal     qualitati\e,     acetone 

complex  with,  323 
theories  of,  704 
purin,  auto-intoxication  associated 
with,  308 
bodies  in,  710 
reactions  of,  641 
in  re-alimentation,  671 
in  staryation,  665 
sugars  in,  690 
of  sulphur,  647 
urea  in,  709 
uric  acid,  in  gout,  818 

under  normal  conditions, 
812 
waste  heat  in,  664 
Metallic  poisons  in  food,  228,  243 
Metastrongylus  apri,  610 
Methyl  alcohol  poisoning,  161 
treatment  of,  162 
toxicity  of,  161 
Metorchis  truncatus,  544,  545 
Microfilaria,  624 
Microgametes,  401,  403 
Microgametocyte,  401,  403 
Micronucleus,  356 
Migraine  in  gout,  831 
Milk,  poisonous,  241 
Miner's  disease,   143 
Mites,  chicken,  631 
harvest,  631 
kedani,  631 
Monocystis  ascidia>,  life-cycle  of,  359 
Monoetomulum  lentis,  556 


INDEX 


027 


Monostomuluni  lentis,  550 
Morphinism,  210 

cachexia  in,  211 
exaltation  in,  211 
hallucinations  in,  212 
incidence  of,  210 
intoxication  in,  211 
sj'mptoms  of,  211 

of  withdrawal,  215 
treatment  of,  216 
Mosaic  inlieritance,  29,  35 
Mosquitoes,  370 

breeding  of,  390 
classification  of,  371 
collection  of,  390 
of  genus  anopheles,  378 
culex,  373 
stegomyia,  386 
malarial,  403 

remedies  against,  389,  439 
Mountain  sickness,  71 

pathology  of,  72 
Multiceps,  559 
Multiple     sclerosis,     diabetes    mellitus 

and,  753 
Musca  domestica,  637 

vomitoria,  637 
Muscles,  changes  in,  in  rickets,  871 

swelling  of,  from  x-rays,  60 
Muscular  weakness  in  rickets,  876 
Mushroom    poisoning,  244 
Mussels,  poisoning  from,  230 
Mutations,  32 

Mutilations,  non-inheritance  of,  20 
Mutualism,  525 
Mycetoma,  344 

definition  of,  344 
diagnosis  of,  346 
etiology  of,  344 
pathology  of,  345 
prognosis  of,  346 
symptoms  of,  345 
treatment  of,  346 
Mycosis  mucorina,  352 
Myiasis,  637 

Myocarditis  in  gout,  832 
Myriapoda  infection,  632 
Mytilus  edulis,  230 
Myxoedema,  suboxidation  in,  283 


N 


Nagana,  462 

Nausea  in  amoebic  dysentery,  512 

Necator,  582 

americanus,  583 
Neck,  actinomycosis  of,  332 
Necrophagus  sanguinarius,  632 
Nemathelminthes,  582 

divisions  of,  582 
Nematoda,  531,  582 
Nematodes,  urogenital,  624 


Nephritis,  gout  and,  827,  K',2 

in  malarial  fevor,  ■^12!),    V.'A 
Nephrotoxication,  307 
Nerve,  vagus,  tumors  of,  diabetes  melli- 
tus and,  753 
Nervous  dyspepsia  and  auto-intoxica- 
tions, 278 
system    in   diabetes  meUitUH,    752 
770 
diseases  of,  due  to  auto-intoxi- 
cations, 279 
lead  poisoning  in,  102 
in  rickets,  882 
Neuralgias  in  gout,  831 
Neuritis,  optic,  in  dialjctes  mellitus,  784 
periplicral,  in  diabetes  mellitus,  782 
Neurotoxin  of  venom,  255 
Nitrogen  balance,  045 

metabolism  of,  645 
output  in  urine  in  diabetes  melli- 
tus, 779 
retention  of,  299 
starvation,  299 
Nocardia,  340 

divisions  of,  347 
synonyms  for,  340 
Nocardiosis,  340 

definition  of,  340 
diagnosis  of,  343 
etiology   of,   341 
granules  in,  344 
melanoid,  345 
metastasis  in,  343 
ochroid,  345 
pathology  of,  342 
prognosis  of,  344 
symptoms  of,  343 
treatment  of,  344 
Nomenclature,  zoological,  532 
Non-inheritance  of  mutilations,  20 
of  specific  infectious  diseases,  22 
Nutrients,  availability  of,  653 
co-efficients  of,  053 
energy  values  of,  654 
isodynamic  values  of,  661 
non-nitrogenous,    effect    of,    on 

proteid  metabolism,  673 
replacement  of,  660 
dynamic,  662 
isodynamic,  661 
Nutrition,  639 
artificial,  745 
composition  of  food  in  relation  to, 

735 
deficient,  670 
pathology  of,  715 
acidosis,  716 
autolysis,  715 
intracellular  enzymes,  715 
malnutrition,  719 
obesitv,  719 
in  rickets,  "868,  875 
Nutritive  equilibrium,  645 


928 


INDEX 


Obesity,  845 

albuminuria  in,  854 
ana>mic,  846,  853 
cardiac  astlima  in,  854 
circumscribed,  855 
complications  of,  854 
definition  of,  845 
in  diabetes,  750 
diagnosis  of,  855 
diets  in,  857 
etiologj'  of,  846 
excitino;,  848 
predisposing,  846 
age,  847 

enforced  rest,  848 
heredity,  846 
occupation,  848 
sex,  847 

temperament,  848 
exercise  in,  861 
gout  and,  846 
heart  in,  852 
histology  of,  851 
history  of,  845 
hydra^mic,  846 
metabolism  in,  719 
modes  of  death  from,  856 
myxccdema  and,  863 
pathogenesis  of,  850 
pathology  of,  849 
blood,  850 
heart,  849 
plethoric,  846,  851 
prognosis  of,  855 
sequela?  of,  854 
suboxidation  in,  282 
symptoms  of,  851 

anaemic  form,  853 

physical  signs  of,  854 
plethoric  form,  851 

physical  signs  of,  852 
synonyms  of,  845 
treatment  of,  856 
dietetic,  857 
local,  863 
mechanical,  861 
medicinal,  862 
prophylactic,  856 
thyroid  therapy  in,  862 
varieties  of,  846 
Ochromyia  anthropophaga,  637 
QEdema  of  feet  in  diabetes  mellitus,  781 

malleolar,   in   obesity,   853,   854 
Oertel  dietary  treatment  of  obesity,  858 
CEsophagostomum  brumpti,  parasite  of 

cecum,  Africa,  604 
Oidiomycosis,  346 
definition  of,  346 
diagnosis  of,  348 
etiology  of,  346 
pathology  of,  347 


Oidiomycosis,  prognosis  of,  349 

sym])toms  of,  348 

treatment  of,  349 
Oidium  albicans,  349 
Oocyst,  403 
Ookinete,  402 
Opisthorchiasis,  535,  540 

Asiatic,  540 

Indian,  545 

Siberian,  543 
Opisthorcliis,  540 

felineus,  540,  544 

noverca,  545 

pseudofelineus,  543 

sinensis,  541 
Opium,  history  of,  203 

by  moutli,  208 

symptoms  of,  209 

poisoning,  203 
acute,  204 

treatment  of,  204 
etiology  of,  204 

smoking,  205 

symptoms  of,  206 
Orchitis,  618 
Ornithodoros  megnini,  627 

savignyi,  627 
Ornithodows  talaje,  627 

tholozani,  627 

turicata,  627 
Osteomalacia,  diagnosis  of,  from  rick- 
ets, 885 
Otitis  inedia,  acute,  in  diabetes  mellitus, 

784 
Output  of  energy,  657 

method  of  study  of,  644 
Oxaluria  in  dial:)etes  mellitus,  779 

in  gout,  831 

purin  metaI)olism  and,  314 
Oxidation,    alanormalities   in   processes 
of,  280 

castration  and,  283 

exaggerations  of,  266 

muscular  exercise  and,  281 
Oxygen,  deficiency  of,  285 
Oxyuriasis,  599  , 

diagnosis  of,  601 

distriliution  of,  599 

frequency  of,  600 

infection  in,  600 

parasites  of,  600 

symptoms  of,  601 

treatment  of,  601 
Oxyurias,  600 
Oxyuris,  582 

yermicularis,  600,  620 
Oj'sters,  poisoning  b}',  231 


Paludal     feyer,     392. 
fever. 


See   Malarial 


INDEX 


929 


Paludisme,  392.     See  Malarial  fevers. 
Pancreas,  diseases  oF,  diabetes  mellitus 

and,  754 
Panophthalmitis,  suppurative,  in  gout, 

833 
Pansporoblasts,  356 
Paragordius  varius,  604 
Paragonimiasis,  535,  536,  537 
diagnosis  of,  539 
frequency  of,  536 
infection  in,  536 
pathology  of,  538 
prevention  of,  539 
symptoms  of,  537 
treatment  of,  539 
Paragonimus  westermanii,  536 
Paralj'^sis,  diver's,  72.     See  Caisson  dis- 
ease, 
infantile,  diagnosis  of,  from  infan- 
tile scurvy,  906 
from  rickets,  885 
in  lead  poisoning,  103,  104,  105 
treatment  of,  112 
Paramcecium   caudatum,   life-cycle  of, 

362 
Paraplegia,  diabetic,  783 
Parasites,  age  and  sex  of  patient,  527 
in  black-water  fever,  457 
chance,  526 
definition  of,  525 
distribution  of,  by  organs,  531 
fertility  of,  527 
frequency  of,  526 
heredity  of,  528 
influence  of,  528 
malarial,  394 

sestivo-autumnal,  human  cvcle 
of,  398,  399 
mosquito  cycle  of,  402 
quotidian,  from,  398 
classification  of,  396 
crescents,  402 
history  of  discovery  of,  394 

of  mosquito  cycle,  400 
quartan,  397 

human  cycle  of,  397 
mosquito  cycle  of,  401 
staining  of,  433 
tertian,  396,  399 

human  cycle  of,  396 
mosquito  cycle  of,  401 
origin  of,  528 
periodical,  526 
permanent,  526 
pseudo-,  526 
resistance  of,  527 
seasonal  periodicity  of,  527 
spurious,  526 
stationary,  526 
temporary,  526 
Parasitic  diseases,  diagnosis  of,  529 
prevention  of,  530 
treatment  of,  530 
59 


Parasitism,  simple,  526 
spurious,  637 
tru(!,  526 
Paratyphoid  fever  and  meat,  232,  241 
Paresis,  general,  diabetes  mellitus  and, 

753 
Paronychia  diabetica,  781 
Parotitis  in  gout,  831 
Particulate  inheritance,  29,  35 
Paternal  impressions,  19 
Pathological  drunkenness,  194 
effects  of  air,  69 
of  light,  .52 
of  x-rays,  59 
Pediculoides  ventricosus,  631    . 
Pediculosis,  634 

parasites  in,  634 
symptoms  of,  635 
treatment  of,  635 
Pediculus  capitis,  634 
cervicalis,  634 
corporis,  634 
humanus,  634 
inguinalis,  634 
pubis,  634 
tabescentium,  634 
vestimenti,  634 
Pelagra,  245 
Pelodera  setigera,  610 
Pelvis,  deformities  of,  in  rickets,  878 
Pericarditis  in  gout,  828,  832 
Periostitis,  diagnosis  of,  from  infantile 

scurvy,  906 
Peritonitis  in  amoebic  dysentery,   506 

517 
Pernicious  malarial  infections,  421 
Perspiration,  retention  of,  intoxication 

due  to,  291 
Pharyngitis  in  gout,  831 
Phlebitis  in  gout,  832 
Phloridzin  diabetes,  758 
Phora  rufipes,  637 
Phosphates  in  gout,  831 
Phosphatic  diabetes,  779 
Phosphorus  balance,  647 

metabolism  of,  647 
poisoning,  131 

accidental,  132 

diagnosis  of,  135 

etiology  of,  132 

fragility  of  bones  in,  133,  134 

industrial,  131,  132 

medicinal,  132 

metabolic  changes  in,  133,  693 

necrosis  in,  134 

pathology  of,  133 

acute,  133 
prognosis  of,  135 
prophylaxis  of,  135 
symptoms  of,  134 

acute,  134 
treatment  of,  135 
urine  in  acute,  134 


930 


INDEX 


Phthirius  inguinalis,  634  Po 

pubis,  634 
Physaloptera,  5S2 
caucasica,  602 
Physico-chemical  tlicorv  of  inheritance, 

39 
Physiological  effects  of  air,  69 
of  light,  51 
fish  poisons,  224 
properties  of  venom,  252 
Pigeon  chest,  cS78 
Pinworm  infection,  599 
Piophila  casei,  637 
Placental  infection  of  offspring,  23 
Plasmodium  falciparum,  398,  399 
malaria^  397 
vivax,  396 
Plerocercoides  prolifer,  581 
Plerocercus  prolifer,  581 
Plica  palonica,  635 
Plumb  ism,  84 

Pneumaturia  in  diabetes  mellitus,  780 
Pneumonia,  lobar,  in  diabetes  mellitus, 
770 
in  malarial  fever,  429 
in  scurvy,  899 
Poisoning,  alcohol,  157 
etiology  of,  157 
pathology  of,  160 
treatment  of,  200 
arsenic,  114  _ 

diagnosis  of,  121 
etiology  of,  114 
mode  of  entrance  of,  118 
pathogenesis  of,  118 
pathology  of,  117 
prognosis  of,  122 
prophylaxis  of,  122 
symptoms  of,  119 
treatment  of,  122 
brass,  138 
carbon  monoxide,  141 

diagnosis  of,  147 
etiology  of,  141 
mode  of  entrance  of,  144 
pathogenesis  of,  144 
pathology  of,  144 
prognosis  of,  148 
symptoms  of,  145 
treatment  of,  148 
cheese,  242 
cocaine,  217 

diagnosis  of,  221 
prognosis  of,  222 
treatment  of,  222 
combustion  products,  141 
diagnosis  of,  147 
etiology  of,  141 
mode  of  entrance  of,  144 
pathogenesis  of,  144 
pathology  of,  144 
prognosis  of,  148 
symptoms  of,  145 


isoning,  combustion  products,  treat- 
ment of,  148 
cojiper,  138 

diseased  meat,  symptoms  of,  236 
by  fish,  svmptoms  of,  227 
fugu,  224 
illuminating  gas,  141 

diagnosis  of,  147 
etiology  of,  141 
mode  of  entrance  of,  144 
pathogenesis  of,  144 
pathology  of,  144 
prognosis  of,  148 
symptoms  of,  145 
treatment  of,  148 
lead,  84 

in  children,  107 

symptoms  of,  108 
diagnosis  of,  108 
etiology  of,  86 
mode  of  entrance  of,  95 
pathogenesis  of,  95 
pathology  of,  94 
prognosis  of,  109 
prophylaxis  of,  110 
symptoms  of,  97 
treatment  of,  110 
loljsters,  231 
manganese,  138 
meat,  232 
mercury,  124 

diagnosis  of,  130 
etiology  of,  124 
mode  of  entrance  of,  127 
pathology  of,  126 
prognosis  of,  130 
prophylaxis  of,  130 
symptoms  of,  127 
treatment  of,  130 
metallic  from  food,  228,  243 
milk,  241 
morphine,  210 

treatment  of,  216 
mussel,  230 
oatmeal,  244 
opium,  203 
acute,  204 
etiology  of,  204 
oyster,  231 
phosphorus,  131 

diagnosis  of,  135 
etiology  of,  132 
pathology  of,  133 
prognosis  of,  135 
prophylaxis  of,  135 
symptoms  of,  134 
treatment  of,  135 
ptomain,  scurvy  due  to,  895 
silver,  136 

diagnosis  of,  137 
pathology  of,  136 
prognosis  of,  137 
prophylaxis  of,  138 


INDEX 


931 


Poisoning,  silver,  symptoms  of,  \'.M 
treatment  of,  13.S 
snake,  247 

mortality  from,  2()1 
symptoms  of,  2(jl 
treatment  of,  2()2 
specific,  203 
tin,  138 
vegetajile,  243 
zinc,  138 
Poisonous  fish,  223 

milk  and  its  products,  241 

shell-fish,  228 

snakes,  classification  of,  247 

geographical    distribution    of 
248  _ 
Poison.^,  bacterial,  224 
food,  223 
physiological,  224 
Poliencephalitis  hemorrhagica  superior, 

198 
Polonium,  63 

Polystomella  crispa,  life-cycle  of,  360 
Polyuria  experimental,  800 
Pons,  tumor  of,  diabetes  mellitus  and, 

752 
Pork  tapeworm,  561 
Porocephalus  moniliformis,  632 
Pot-belly,  rachitic,  884 
Potassium     in     blood,     deficiency     of, 

scurvy  due  to,  894 
Potential  energy  of  foodstuffs,  653 
Pregnancy,  diabetes  mellitus  and,  752, 

784 
Presbyopia  in  diabetes  mellitus,  784 
Products   of   femtientation   and   putre- 
faction, 272 
Proteid,  circulating,  704 
digestion  of,  702 
endogenous  metabolism  of,  707 
exogenous  metabolism  of,  707 
fat  cures,  diet  in,  744 
influence  of,  on  metabolism,  672 
metabolism  of,  700 

auto-intoxications    associated 

with,  297 
creatinin  in,  709 
disturbances  of,  acetone  com- 
plex   associated    with, 
324 
dependent  on  input,  299 
independent  of  input,  300 
effects  of  non-nitrogenous  nu- 
trients on,  673 
excess  of,  301 

influence  of  alcohol  on,  675 
intoxications,  302 
normal     qualitative,     acetone 

complex  Avith,  323 
theories  of,  704 
minimum  requirement  of,  724 
experiments  on,  726 
reduced  intake  of,  730 


I'rotnid  tissue,  704 

transfonna(,ioiis  of,  701 
veg(!table,  availability  of,  739 
Proteus  vulgaris,  232 
Protozoa,  353 

classification  of,  368 
divisions  of,  353 
infusoria,  354 
mastigophora,  354 
sarcodina,  354 
sporozoa,  354 
life-cycle  of,  361 
methods  of  reproduction  of,  355 
binary  fission,  355 
budding,  356 
gemmation,  356 
spore  formation,  356 
Protozoic  dermatitis,  346 
Pruritus  in  dial)etes  mellitus,  781 
treatment  of,  798 
in  obesity,  854 
Pseudotrichina,',  610 
Psoriasis  in  gout,  831 
Psorospermiasis,  346 
Psychosis,  Korsakow's,  196 
Ptomain  poisoning,  scurvy  due  to,  895 
Ptomains,  275 
Pulex  irritans,  633 
penetrans,  633 
Pulmonary   aspergillosis,   350 
definition  of,  350 
diagnosis  of,  352 
etiology  of,  350 
pathology  of,  351 
prognosis  of,  352 
symptoms  of,  352 
treatment  of,  352 
roundworms,  610 
Purin  bodies,  intermediary  metabolism 
of,  711 
metabolism  of,  710 

in  gout,  818 
perversion  of  metabolism  of, 
714 
metabolism,  308 

auto-intoxication     associated 

with,  308 
in  gout,  312 
Purpura  in  diabetes  mellitus,  781 

differentiation  of,  from  scurvy,  899 


Q 


Quartan     fever,     392.     See     Malarial 
fevers, 
parasite,  397 
Quinine,   action   of,   on   malarial   Plas- 
modia, 443 
administration  of,  in  malarial  fever, 

444,  445 
choice  of  preparation  of,  in  mala- 
rial fever,  444 


932 


INDEX 


Quinine,  contra-indications  to,  446 

use  of,  in    malarial  Plas- 
modia, 446 
dosage  of,  in  malarial  (ever,  446 
Quotidian    a'stivo-autunnial    parasites, 
39S 


Rachitic  pot-belly,  884 

Radium,  63 

Rat  try)ianosomc,  461 

Re-alimentation,  metabolism  in,  671 

Red  bus,  631 

Remittent    fever,    392.     See    Malarial 

fexers. 
Renal  diabetes,  758 
Respiratory    system,     clianj^ies    in,     in 
gout,  82S 
tract,  lead  poisoninji;  in,  lUl 
Retention  intoxications,  287 
carbon  dioxide,  288 
of  intestinal  origin,  292 
jaundice,  287 
perspiration,  291 
suppression  of  urine,  292 
of  lU'ine  and  metabolism,  294 
Retinitis,  diabetic,  783 

hemorrhagic,  in  gout,  833 
Reversion,  31 
Rhalxlitis,  582 

comwalli,  610 
genitalis,  624 
niellyi,  611 
terricola,  610 
Rhabdonemiasis,  595 
Rheumatism,  diagnosis  of,  from  infan- 
tile scurvy,  905 
Rhipicephalus  sanguineus,  627 
Ribs,  bending  of,  in  rickets,  876 
Rickets,  864 

bacteriology  of,  874 
l)lood  in,  884 
chemistry  of,  872 
complications  of,  884 
congenital,  889 

symptoms  of,  890 
treatment  of,  890 
course  of,  886 
diagnosis  of,  885 
diet  in,  886 
epiphyses  in,  876 
etiologj'  of,  866 
age,  866 

defective  hj'giene,  867 
dietetic,  868 
heredity,  867 
overcrowding,  867 
season,  866 
sex,  866 
syphilis,  868 
geographical    distribution   of,    864 
history  of,  864 


Rickets,  late,  890 

prognosis  of,  891 

symptoms  of,  891 

treatment  of,  892 
lime-salts  in,  872 
liver  in,  871,  884 
mori)iil  anatomy  of,  870 
nutrition  in,  868 
pathogeny  of,  872 
pathology  of,  870 

brain,  872 

muscles,  871 

spleen,  872 

viscera,  871 
prognosis  of,  886 

relation  of,  to  infantile  scurvy,  905 
symptoms  of,  874  * 

circulatory,  884 

cranium,  879 

gastro-intestinal,  883 

head  s^veating,  875 

muscular  \veakness,  876 

nervous,  881 

osseous,  876 

respiratory,  884 

teeth,  875 

temperature,  875 

tenderness,  883 
treatment  of,  886 

prophylactic,  886 

therapeutic,  887 
Rickety  rosary,  876 
Roundworms,  582 
intesthial,  582 

and  muscular,  605 
pulmonary,  610 
subcutaneous,  610 
urogenital,  624 


Saccharomycosis,  346 

Salts,  relation  of,  to  unemia,  306 

Sarcocystis,  mischeriana,  610 

Sarcodina,  354 

Sarcoma   of   skull,    diagnosis   of,   from 

infantile  scurvy,  906 
Sarcopsylla  penetrans,  633 
Sarcoptes  minor  cati,  628 
scabiei,  627 

anchcnitp,  628 

cameli,  628 

canis,  628 

capne,  628 

crustosa>,  628 

equi,  628 

leonis,  628 

oris    628 

suis,  628 

vulpis,  628 

worn  bat  i,  628 
Sausage  poison,  232 


INDEX 


933 


Scabies,  627 

crustosa,  629 
Schistosoma  catioi,  550 
ha-matobium,  550 
japonicum,  550 
Schizont,  357,  396,  397,  398 
Scleroderma  I'rom  ;c-rays,  60 
Sclerosis,    multiple,    diabetes    mellitus 

and,  753 
Scoleciasis,  637 
Scorbutus,  893.     See  Scurvy. 
Screwworm,  637 
Scurvy,  893 

diagnosis  of,  899 

from  acute  Ij^mphatic   leukae- 
mia, 899 
from  mercurial  cachexia,  899 
from   purpura    hemorrhagica, 
899 
diet  in,  900,  902 
etiology  of,  894  * 

history  of,  893 
infantile,  901 

diagnosis  of,  905 

from  acute  leukaemia,  906 
from  epiphysitis,  906 
from    infantile    paralysis, 

906 
from  periostitis,  906 
from    renal    hemorrhage, 

906 
frorn  rheumatism,  905 
from  sarcoma  of  skull,  906 
from     ulcerative    stoma- 
titis, 906 
etiology  of,  902 
history  of,  901 
morbid  anatomy  of,  903 
prognosis  of,  906 
rickets  and,  885 
symptoms  of,  904 

associated    with    rickets, 

905 
changes  in  blood,   905 
in  gums,  904 
treatment  of,  906 
morbid  anatomy  of,  896 
prognosis  of,  900 
symptoms  of,  897 

prodromal,  897 
treatment  of,  900 

prophylactic,  901 
Seat  worm,  600 
Serous  meningitis,  186 

treatment  of,  189 
Shell-fish,  poisonous,  228 
Shock,  electrical,  consequences  of,  65 
SiWer  poisoning,   136 

accidental,  136 
diagnosis  of,  137 
industrial,  136 
medicinal,  136 
pathology  of,  136 


Silver    poisoning,    pigmentation    in, 
137 
of  gums  in,  137 
prognosis  of,  137 
prophylaxis  of,  138 
symptoms  of,  137 
treatment  of,  138 
Siriasis,  56 

treatment  of,  56 
Skin  in  anxi^bic  dysentery,  512 
atrophy  of,  from  x-rays,  59 
hemorrhages     into,     in     scurvy, 
897 
Skull,   sarcoma  of,   diagnosis  of,   from 

infantile  scurvy,  906 
Sleeping  sickness.     See  Trypanosomia- 
sis, human. 
Snakes,  poisonous,  blood-clotting  com- 
ponent oF,  255 
classification  of,  247 
geographical    distribution    of, 

248 
mortality  from,  261 
neurotoxin  of,  255 
poison  organs  of,  251 
principles    of,    hajmagglutina- 
tive,  257 
hsemolytic,  257 
hemorrhagic,  257 
properties  of,  chemical,  252 

physiological,  252 
symptoms  of,  261 
toxicity  of,  259 
treatment  of,  262 
specific,  263 
Somatic  tteniasis,  574 
Sparganum  mansoni,  574,  581 

proliferum,  574,  581 
Spinal  caries,  diagnosis  of,  from  rickets, 
886 
cord,  conditions  of,  diabetes  insipi- 
dus and,  802 
Spiroptera  hominis,  526 
Spleen,   abscess  of,  in  amoebic  dysen- 
tery, 516 
in  black-water  fe^'er,  455 
changes  in,  in  rickets,  872 
in  malarial  fevers,  412 
rupture  of,  in  malarial  fever,  431 
Sporant,  357 

Spore  formation  in  protozoa,  356 
Sporoblast,  357,  403 
Sporont,  402 
Sporozoa,  354 
Sporozoites,  357,  403 
Sports,  30,  32 
Starvation,  323 

creatinin  in,  710 
faeces  in,  669 
heat  production  in,  669 
metabolism  in,  665,  669 
of  cells  in,  670 
proteid,  666,  724 


934 


INDEX 


Stan'ation,  nitrosjen  output  in,  007 
Steatorrlura  in  diabetes  niellitvis,  7S2 
Stegomyia  calopus,  373,  3S(i 
description  of,  3SS 
distril)ution  of,  38G 
Stomatitis,     ulcerative     diagnosis     of, 

from  infantile  scurvy,  906 
Striatula,  520 
Strongyloitles,  582 

stercoralis,  526,  595 
Strongyloidosis,  595 

diagnosis  of,  596 

distri!)ution  of,  595 

frequency  of,  590 

infection  in,  590 

parasite  of,  595 

symptoms  of,  596 

treatment  of,  596 
Strongvlus  instabilis,  602 

subtilis,  602 
Subcutaneous  roundworms,  611 
Suboxidation,  2S1 

in  ana'uiias,  284 

in  cachexia,  284 

strumipriva,  283 

of  fat,  322 

in  marasmus,  284 

in  mvxcedema,  283 

in  obesity,  282 

of  sugar,  317 
Sugar,    formation     of,     from     protein, 
318 
from  fats,  319 

metabolism  of,  690 

suboxidation  of,  317 

superoxidation  of,  317 
Sulphur  balance,  647 
Sunburn,  52 
Sunstroke,  53,  54 

diagnosis  of,  55 

from  malarial  fe^'e^s,  437 

pathogenesis  of,  54 

pathology  of,  54 

prognosis  of,  55 

prophylaxis  of,  57 

sequela'  of,  54 

symptoms  of,  54 

treatment  of,  56 
Sun-traumatism,  56 

treatment  of,  56 
Superoxidation,  285 

of  fat,  322 

acetonuria  and,  322 

of  sugar,  317 
Suppression  of  urine,  intoxication  due 

to,  292 
Surra,  461 
Swamp     fever,    392.       See     Malarial 

fevers. 
Syphilis,    cerebral,    diabetes    insipidus 
and,  802 

congenital,  23 

rickets  and,  868 


Tabes,  diabetic,  753,  782 
Ta:-nia,  532,  557,  559 
africana,  557,  560 
eanina,  557, 
cellulosa\  561 
ccenurus,  559 
confusa,  557,  563,  564 
cucumcrina,  567 
dimimita,  561 
echinococcus,  576 
clliptica,  567 
hinuliiiacca,  604 
honiinis,  557,  561 
hydatigena,  529,  561,  575 
inermis,  559 
lanccolata,  566 
lata,  537,  567 
medicocanellata,  559 

hominis,  559 
moniliformis,  527 
nuiriana,  532,  564 
nana,  564,  576 
pisiformis,  563 

saginata,  52(5,  527,  532,  557,  558, 
559,  560,  561,  562,  570,  573, 
575 
description  of,  559 
diagnosis  of,  560 
distribution  of,  558 
frequency  of,  560 
infection,  source  of,  559 
prevention  of,  560 
solium,    529,    557,   558,   559,   500, 
561,  562,  570,  571,  573,  574, 
575 
description  of,  561 
distriljution  of,  561 
frequency  of,  562 
infection  liy,  features  of,  562 
larval,  574 
source  of,  562 
pre^■ention  of,  563 
teniseformis,  563 
vulgaris,  567 
zittaviensis,  559 
Tasniarhynchus,  559,  560,  561 
Ta:niasis,  557 

intestinal,  557 

parasites  of,  557 
sj'mptoms  of,  569 
treatment  of,  571 

anthelmintic,  572 
in  children,  574 
expulsion  of  worm,  574 
preparatory,  572 
somatic,  557,  574 
forms  of,  574 
Trcniida?,  532 
Tapeworm  infection,  557 
Telianychus  molestissimus,  631 
Temperature,  effect  of,  76 


INDEX 


935 


Tendon  reflexes  in   clial)etes  rncUilus, 

783 
Terminology,  parasitic,  532 
Tertian  a-stivo-autumnal  parasite,  39!) 

fevers,   392.     (See  Malarial  fevers. 

•parasite,  39G 
Tetany  due  to  auto-intoxications,  277 

in  rickets,  882 
Tetramitus  chilomonas,  356 
Tetranychus  molestissimus,  G31 
Thorn-headed  worm  infection,  G04 
Thorax,  actinomycosis  of,  333 
Thrombosis,  venous,  in  gout,  832 
Thyroid  and  metabolism,  302 
Ticks,  infection  with,  626 
Tin  poisoning,  138,  139 
Tongue-worm  infection,  632 
Toxicity  of  venoms,  259 
Toxins  in  decomposed  fish,  226 
shell-fish,  229 

in  poisonous  fish,  225 
Toxocara  canis,  597 
Transformation  of  energy,   650 
Traumatism  of  brain,  diabetes  insipidus 

and,  801 
Trematode  infections,  531,  535 
Trichina,  532 

affinis,  610 

agilissima,  610 

anguillffi,  610 

contorta,  602 

cyprinorum,  610 

cystica,  600,  610,  619 

inflexa,  610 

lacerta;,  610 

microscopica,  610 

spiralis,  605 
Trichinella,  582 

spiralis,  605 
Trichiniasis,  605 
Trichinosis,  533,  605 

diagnosis  of,  608 

distribution  of,  605 

duration  of,  606 

infection  in,  606 

lethality  of,  608 

parasite  of,  605 

prevention  of,  609 

symptoms  of,  606 

treatment"  of,  609 
Trichinus  spiralis,  605 
Trichocephaliasis,  602 

diagnosis  of,  604 

distribution  of,  602 

frequency  of,  603 

infection  in,  603 

parasites  of,  603 

pathology  of,  603 

prevention  of,  604 

symptoms  of,  603 

treatment  of,  604 
Trichocephalus  dispar,  602 

hominis,  603 


Trichostrongylus,  582,  602 
instabilis,  fl02 
jtrohiiiurus,  602 
subiilis,  (i02 
vitrinuK,  602 
Triclniris,  582,  (i03 
tricliiura,  603 
Tricoma,  635 
Triodontopliorus  deminutus,  parasite  of 

intest.  as  Mayotto,  595 
Trombidium,  6.31 

tlalsahanto,  631 
Trypanosoma  brucei,  462 
evansi,  461 
fever,  478 

gambiense,  465,  468 
in  animals,  476 
in  cerebro-spinal  fluid,  471 
des«ription  of,  468 
effect  of  arsenic  on,  485 

on  man,  477 
life  history  of,  outside  of  body, 

472 
in  lymphatic  glands,  471 
in  man,  477 
method  of  leaving  the  Ijody, 

473 
mode  of  gaining  entrance  into 

human  organism,  473 
reproduction  of,  472 
staining  of,  468 
tissues  of  body  in  which  found, 
471 
lewisi,  461 
Trypanosome,  description  of,  460 

rat,  461 
Trypanosomiasis,  460 
human,  466,  477 
blood  in,  480 
diagnosis  of,  484 
etiology  of,  467 
fever  in,  481 

histological  changes  in,  482 
history  of,  466 
pathology  of,  481 
prognosis  of,  484 
prophylaxis  of,  486 
symptoms  of,  469 

in  alimentary  sj^stem,  479 
in  circulatory  system,  479 
in  cutaneous  system,  480 
in    hsemopoietic    system, 

480 
in  lymphatic  system,  480 
in  nervous  system,  479 
in  respiratory  system,  480 
in  urinary  system,  480 
temperature  curve  in,  481 
terminal  infection  in,  483 
treatment  of,  485 
Tsetse-fly  disease,  462 
Tuberculosis  in  diabetes  mellitus,  770, 
782 


936 


IXDEX 


Tuberculosis,  diagnosis  of,  from  malarial 

fevers,  437 
Tumors,    cerebral,    diabetes    insipitlus 

and,  801 
Tunnel  disease,  St.  Gothard,  5S2 
Tydeus  molestus,  G31 
Typhoid     fever,     diagnosis     of,     from 

malarial  fevers,  436 
Tyroglyphus  fariua>,"  G31 
Tyrotoxicon,  243 
longior,  G31 
siro,  631 
Tyrotoximus,  242 


U 


Ulcer  of  foot,  perforating,  in  diabetes 

mellitus,  7S1 
Ulcerative   endocarditis,  ^liagnosis   of, 
from  malarial  fevers,  437 
stomatitis,   diagnosis  of,    from    in- 
fantile  scurvy,   906 
IHcers  in  amcebic  dysentery,  504 
Uncinaria,  582 

americana,  583,  584 
criniformis,  583 
duodenalis,  584 
hominis,  583,  584 
vulpis,  583 
Uncinariasis,  582 
blood  in,  590 

bodily  development  in,  588 
diagnosis  of,  592 
distribution  of,  582 
frequenc}'  of,  586 
infection  in,  584 
lethality  of,  591 
parasite  in,  583 
pathology  of,  591 
prevention  of,  594 
symptoms  of,  587 
treatment  of,  593 
Uraemia,  explanation  of,  306 
nieta])olism  in,  305 
and  retention,  293 
Urea  formation,  297 

intoxications  due  to,  297 
metabolism  of,  709 
relation  of,  to  uraemia,  305 
Urethritis  in  gout,  831 
Uric  acid  in  the  blood,  311,  817 
in  gout,  819,  825 

origin   of,    excess  of, 
820 
diathesis,  830 
elimination   of,   in  gout,   312, 

715 
endogenous,  813,  817 
excretion  of,  daily,  818 

in  gout,  819 
exogenous,  813 

metabolism    of,    and    alcohol, 
810 


I'ric  acid,  metabolism  of,  in  gout,  SIS 
under  normal  conditions, 
812 
oxidation  of,  in  gout,  824 
precipitation    of,    as    biurate, 

822 
pin-in  bases,  relation  to,  813 
relation  of,  to  gout  820 
seat  of  formation  of,  814 
sources  of,  710 

endogenous,  711 
exogenous,  710 
in  urine  in  diabetes  mellitus, 
779 
Urinary  disturbances  in  gout,  831 
Urine,  ammonia  of,  intoxications  due 
to,  298 
in  amoebic  dysenterj^  513 
in  black-water  fe^•er,  456,  457 
in  diabetes  mellitus,  773 
acetone  in,  778 
alloxuric    liodies   in,    779 
ammonia  in,  779 

/?-oxvbutvric    acid    in, 
777,786" 
diacetic  acid  in,  778,  786 
glycerin  in,  777 
glycogen  in,  780 
glj'curonic  acid  in,  777 
lipuria  in,  780 
nitrogen  output  in,  779 
oxaluria  in,  779 
sugar  in,  774 

bismuth  test  for,  776 
Fehling's  test  for,  775 
fermentation  test  for, 

776 
phenylhydrazin    test 

for,  776 
polariscope   test   for, 

776 

Trommer's  test    for, 

775 

uric  acid  in,  779 

in  diabetes  mellitus,  yeast-cells  in, 

780 
in  gout,  832 
in  malarial  fevers,  410 
in  scurvy,  899 

suppression  of,  intoxication  due  to, 
292 
TTrogenital  nematodes,  624 


Vagus  nerve,  tumors  of,  diabetes  melli- 
tus and,  753 
Vegetables,  poisonous,  243 
Vegetarian,  diet  of,  743 
Vegetarianism,  740 
Venom,  action  of,  255 

chemicals  on,  254 


INDEX 


937 


Venom,  action  of  heat  on,  254 
light  on,  254 

amount  of,    252 

constituents  ol',  253 

principles  in,  255 

secretion  of,  251 

toxicity  of,  259 
Vermis  umbilicalis,  526 
Vetch  poisoning,  244 
Viscera,  changes  in,  in  rickets,  871 

in  malarial  fevers,  410 
Vomiting  in  amoebic  dysentery,  512 

in  gout,  833 


W 


Water  gas  poisoning,  142 
Wechselfieber,     392.     See     Malarial 

fevers. 
Weissmann's  theory,  36 
Whipvirorm  infection,  602 
Wet  brain,  186 
Wood  alcohol,  161 

Work,    factors    influencing    energy    re- 
quired, 680 
influence  of,  on  metabolism,  678 
nitrogen  metabolism,  influence  on, 
683 
Wrist-drop  in  lead  poisoning,  103 
Wuchereria  filaria,  615 


X-RAYS,  58 

alopecia  from,  60 
atrophy  (jf  skin  from,  59 
cancer  froiri,  60 
dermatitis  from,  59 
effect  of,  on  internal  organs,  espe- 
cially  generative  organs,  60 
eye  lesions  from,  60 
gangrene  from,  60 
general  symptoms  from,  60 
lesions,  pathogenesis  of,  62 

treatment  of,  63 
pathological   efft^ct  of,  59 
scleroderma-like  changes  from,  60 
swelling  of  muscles  from,  60 

Xanthoma  diabeticorum,  781 


Yeast-cells  in  urine  in  diabetes  melli- 

tus,  780 
Yellow  fever,  diagnosis  of,  from  malarial 

fevers,  436 


Zinc  poisoning,  138 
Zoo-parasitic  diseases,  525 


COLUMBIA  UNIVERSITY 


0032456107 


DATE  DUE 

Demco,  Inc.  38-293 


